Mechanism of fibroblast growth factor 1 regulating fatty liver disorder in mule ducks.

Mule ducks tend to accumulate abundant fat in their livers via feeding, which leads to the formation of a fatty liver that is several times larger than a normal liver. However, the mechanism underlying fatty liver formation has not yet been elucidated. Fibroblast growth factor 1 (FGF1), a member of the FGF superfamily, is involved in cellular lipid metabolism and mitosis. This study aims to investigate the regulatory effect of FGF1 on lipid metabolism disorders induced by complex fatty acids in primary mule duck liver cells and elucidate the underlying molecular mechanism. Hepatocytes were induced by adding 1,500:750 µmol/L oleic and palmitic acid concentrations for 36 h, which were stimulated with FGF1 concentrations of 0, 10, 100, and 1000 ng/mL for 12 h. The results showed that FGF1 significantly reduced the hepatic lipid droplet deposition and triglyceride content induced by complex fatty acids; it also reduced oxidative stress; decreased reactive oxygen species fluorescence intensity and malondialdehyde content; upregulated the expression of antioxidant factors nuclear factor erythroid 2 related factor 2 (Nrf2), HO-1, and NQO-1; significantly enhanced liver cell activity; promoted cell cycle progression; inhibited cell apoptosis; upregulated cyclin-dependent kinase 1 (CDK1) and BCL-2 mRNA expression; and downregulated Bax and Caspase-3 expression. In addition, FGF1 promoted AMPK phosphorylation, activated the AMPK pathway, upregulated AMPK gene expression, and downregulated the expression of SREBP1 and ACC1 genes, thereby alleviating excessive fat accumulation in liver cells induced by complex fatty acids. In summary, FGF1 may alleviate lipid metabolism disorders induced by complex fatty acids in primary mule duck liver cells by activating the AMPK signaling pathway.

Association of Rare NOTCH3 Variants With Prevalent and Incident Stroke and Dementia in the General Population.

BACKGROUND: It is uncertain whether rare NOTCH3 variants are associated with stroke and dementia in the general population and whether they lead to alterations in cognitive function. This study aims to determine the associations of rare NOTCH3 variants with prevalent and incident stroke and dementia, as well as cognitive function changes. METHODS AND RESULTS: In the prospective community-based Shunyi Study, a total of 1007 participants were included in the baseline analysis. For the follow-up analysis, 1007 participants were included in the stroke analysis, and 870 participants in the dementia analysis. All participants underwent baseline brain magnetic resonance imaging, carotid ultrasound, and whole exome sequencing. Rare NOTCH3 variants were defined as variants with minor allele frequency <1%. A total of 137 rare NOTCH3 carriers were enrolled in the baseline study. At baseline, rare NOTCH3 variant carriers had higher rates of stroke (8.8% versus 5.6%) and dementia (2.9% versus 0.8%) compared with noncarriers. After adjustment for associated risk factors, the epidermal growth factor-like repeats (EGFr)-involving rare NOTCH3 variants were associated with a higher risk of prevalent stroke (odds ratio [OR], 2.697 [95% CI, 1.266-5.745]; P=0.040) and dementia (OR, 8.498 [95% CI, 1.727-41.812]; P=0.032). After 5 years of follow-up, we did not find that the rare NOTCH3 variants increased the risk of incident stroke and dementia. There was no statistical difference in the change in longitudinal cognitive scale scores. CONCLUSIONS: Rare NOTCH3 EGFr-involving variants are genetic risk factors for stroke and dementia in the general Chinese population.

Neuroprognostication value of serum neurofilament light chain for out-of-hospital cardiac arrest: A systematic review and meta-analysis.

BACKGROUND: Neurofilament light chain (NfL) is a novel biomarker for the assessment of neurological function after cardiac arrest (CA). Although meta-analysis has confirmed its predictive value, it has not conducted a more detailed analysis of its research. We conducted a meta-analysis to evaluate the relationship between serum NfL level and neurological prognosis in patients with spontaneous circulation recovery after CA, and subgroup analysis was conducted according to sample collection time, time to assess neurological function, study design, whether TTM was received, the method of specimen determination, and the presence of neurological disease in patients. To analyze the influence of these factors on the predictive value of serum NfL. METHODS: Published Cochrane reviews and an updated, extended search of MEDLINE, Cochrane Library, Embase, Scopus, ClinicalKey, CINAHL, and Web of Science for relevant studies until March 2022 were assessed through inclusion and exclusion criteria. The standard mean difference and 95% confidence interval were calculated using the random-effects model or fixed-effects model to assess the association between one variable factor NfL level and the outcome of CA patients. Subgroup analysis according to sample collection time was performed. The prognosis analysis and publication bias were also assessed using Egger's and Begg's tests. RESULTS: Among 1209 related articles for screening, 6 studies (1360 patients) met the inclusion criteria and were selected for meta-analysis. The level of serum NfL in the good prognosis group (CPC1-2, CPC: cerebral performance category score) was significantly lower than that in the poor prognosis group (CPC3-5)SMD(standardized mean difference) = 0.553, 95%CI(confidence interval) = 0.418-0.687, I2 = 65.5% P<0.05). And this relationship also exists at each sampling time point (NfL specimens were collected on admission: SMD:0.48,95%CI:0.24-0.73; Samples were collected 24 hours after CA: SMD:0.60,95%CI:0.32-0.88;Specimens were obtained 48 hours after CA: SMD:0.51, 95%CI:0.18-0.85;Specimens were obtained 72 hours after CA: SMD:0.59, 95%CI:0.38-0.81). CONCLUSION: NfL may play a potential neuroprognostication role in postcardiac arrest patients with spontaneous circulation, regardless of when the sample was collected after CA.

P38-DAPK1 axis regulated LC3-associated phagocytosis (LAP) of microglia in an in vitro subarachnoid hemorrhage model.

BACKGROUND: The phagocytosis and homeostasis of microglia play an important role in promoting blood clearance and improving prognosis after subarachnoid hemorrhage (SAH). LC3-assocaited phagocytosis (LAP) contributes to the microglial phagocytosis and homeostasis via autophagy-related components. With RNA-seq sequencing, we found potential signal pathways and genes which were important for the LAP of microglia. METHODS: We used an in vitro model of oxyhemoglobin exposure as SAH model in the study. RNA-seq sequencing was performed to seek critical signal pathways and genes in regulating LAP. Bioparticles were used to access the phagocytic ability of microglia. Western blot (WB), immunoprecipitation, quantitative polymerase chain reaction (qPCR) and immunofluorescence were performed to detect the expression change of LAP-related components and investigate the potential mechanisms. RESULTS: In vitro SAH model, there were increased inflammation and decreased phagocytosis in microglia. At the same time, we found that the LAP of microglia was inhibited in all stages. RNA-seq sequencing revealed the importance of P38 MAPK signal pathway and DAPK1 in regulating microglial LAP. P38 was found to regulate the expression of DAPK1, and P38-DAPK1 axis was identified to regulate the LAP and homeostasis of microglia after SAH. Finally, we found that P38-DAPK1 axis regulated expression of BECN1, which indicated the potential mechanism of P38-DAPK1 axis regulating microglial LAP. CONCLUSION: P38-DAPK1 axis regulated the LAP of microglia via BECN1, affecting the phagocytosis and homeostasis of microglia in vitro SAH model. Video Abstract.

Risk factors and prognosis of early neurological deterioration in patients with posterior circulation cerebral infarction.

BACKGROUND: The incidence, risk factors, and pathogenesis of early neurological deterioration (END) in posterior circulation stroke are still unclear. In this study, we aimed to determine the risk factors and prognosis of END in patients with acute posterior circulation cerebral infarction. METHODS: Acute posterior circulation ischemic stroke patients who had completed neuroimaging within 72 h of onset were selected from a prospective registry study Demographic characteristics, physiological data, medical history, laboratory data, in-hospital evaluation, neurological severity and TOAST classification, treatment, and the modified Rankin Scale (mRS) score of patients were assessed. Early neurological deterioration was defined as an increase of 2 points in the National Institutes of Health Stroke Scale score between the baseline and 72 h evaluation. Favorable and poor outcomes were defined as mRSs of 02 and≥ 3, respectively, at 3 months. The incidence and risk factors were evaluated by univariate and multivariate regression analysis (step-back method). RESULTS: The analysis included 455 subjects with an acute posterior circulation non-cardiac ischemic stroke, 330 (72.53 %) of them male, with an average age of 63.12 ( ± 10.14) years and with 47 (10.33 %) having END. The results of univariate and multivariate logistic regression analysis showed that BATMAN scores ≥ 5 (OR: 0.1, 95 % CI: 0.02-0.53, P < 0.01), large artery atherosclerosis (OR: 11.55, 95 % CI: 4.18-31.93, P < 0.01), vascular stenosis > 50 % (OR: 2.44, 95 % CI: 1.1-5.42, P = 0.029), reperfusion therapy (OR: 4.21, 95 % CI: 1.66-10.64, P < 0.01), and the distribution of pontine lesions (OR: 5.66, 95 % CI: 2.39-13.44, P < 0.01) were significantly associated with END. Patients with END had a lower rate of favorable outcomes at discharge and long-term follow-up (P < 0.001), regardless of whether they received reperfusion therapy. CONCLUSION: The lesion distribution of the pons, the progression of temporo-occipital lobe lesions, and large arterial atherosclerosis are independent risk factors of END that might predict a poor short- and long-term prognosis.

Aquaporin-4 Antibody Dynamics and Relapse Risk in Seropositive Neuromyelitis Optica Spectrum Disorder Treated with Immunosuppressants.

OBJECTIVE: To investigate aquaporin-4 antibody (AQP4-IgG) dynamics and relapse risk in patients with seropositive neuromyelitis optica spectrum disorder treated with immunosuppressants. METHODS: This observational cohort study with prospectively collected data included 400 neuromyelitis optica spectrum disorder patients seropositive for AQP4-IgG and treated with immunosuppressants. Serum AQP4-IgG was detected by fixed cell-based assay every 6 months. RESULTS: After treatment with immunosuppressants, 128 patients became AQP4-IgG seronegative. The median time to become seronegative for 400 patients was 76.4 months (61.4 months, NA). Among those patients with negative change of AQP4-IgG, the mean annualized relapse rate significantly decreased after patients became seronegative (0.20 vs 0.77, p < 0.001), and a positive correlation was observed between time to become seronegative and relapse (OR 1.018, 95% CI 1.001-1.035, p < 0.05). Independent risk factors for AQP4-IgG becoming seronegative were older age at onset, initiation of immunosuppressants at onset, and shorter disease duration before maintenance therapy. Independent risk factors for relapse included younger age (≤46.4 years) at onset, poly-system involvement in the first attack, and unchanged or increased AQP4-IgG titer. The relapse risk was not associated with sex, combination with connective tissue disease, seropositivity for systemic autoimmune antibodies, or incomplete recovery from the first attack. INTERPRETATION: Patients with younger age at onset, poly-system involvement in the first attack, and unchanged or increased titer of AQP4-IgG are most likely to experience relapse under treatment with immunosuppressants. Time to AQP4-IgG becoming seronegative and change of AQP4-IgG titer may become the surrogate efficacy biomarkers in clinical trials. ANN NEUROL 2023;93:1069-1081.

Predictive Value of Leucine-Rich Alpha-2 Glycoprotein 1 in Cerebrospinal Fluid for the Prognosis of Aneurysmal Subarachnoid Hemorrhage: A Prospective Study.

OBJECTIVE: To determine whether leucine-rich alpha-2 glycoprotein 1 (LRG1) is a potential prognostic and severity biomarker in patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: This observational and prospective study included 44 patients with aSAH from Nanjing Drum Tower Hospital from June to December 2020. Concentrations of LRG1 in the cerebrospinal fluid (CSF) were determined by enzyme-linked immunosorbent assay within 24 hours after aSAH. We further determined the relationship of CSF LRG1 levels with disease severity and prognosis 3 months after aSAH. RESULTS: Higher CSF LRG1 levels were associated with a higher Hunt-Hess grade (P < 0.05). Using univariate analysis, poor outcomes at 3 months were associated with higher World Federation of Neurological Surgeons scale grade, higher Hunt-Hess grade, higher CSF LRG1 levels, and higher Fisher grade. Logistic regression analysis revealed a significant impact of LRG1 on poor outcomes as well as after adjustment for confounding factors. CONCLUSIONS: These findings suggest an increase in CSF LRG1 levels in patients with aSAH, which may serve as a potential biomarker of unfavorable prognosis and disease severity.

Four pair of enantiomeric benzofuran lignans from the fruits of Crataegus pinnatifida bunge.

Phytochemical investigation of the fruits of Crataegus pinnatifida Bunge led to the isolation of four pairs enantiomeric benzofuran lignans (1a/1b-4a/4b) including four undescribed compounds (1a, 2b, 3b and 4b). Their structures were determined by extensive spectroscopic methods and the absolute configurations were further determined by the comparison of experimental and calculated ECD spectra. All the enantiomeric lignans were evaluated for their inhibitory activities to tyrosinase. Among them, compound 4a showed moderate inhibition activity (IC50 = 0.54 mM).

[Application of ultrasound in treating postpartum pubis symphysis diastasis by bone setting manipulation].

OBJECTIVE: To explore application value of ultrasound in treating postpartum pubis symphysis diastasis by bone setting manipulation. METHODS: Retrospective analysis was performed on 30 patients (case group) with postpartum pubis symphysis diastasis diagnosed in Wangjing Hospital, China Academy of Chinese Medical Sciences from June 2017 to January 2021, aged from 21 to 43 years old, with an average of (33.0±3.5) years old. The main clinical manifestations were mobility disorders such as turning over and walking, and all patients were treated by bone setting manipulation. Before and after treatment, pain and degree of pubic symphysis separation were evaluated by visual analogue scale(VAS) and ultrasonography. In normal group, 30 menopausal women aged from 49 to 59 years old with an average of(54.0±2.9) years old who wanted to remove intra uterine device(IUD) and were underwent conventional pelvic plain radiographswere selected, and the width of pubic symphysis space was measured by ultrasound and plain radiographs. RESULTS: In normal group, the width of pubic symphysis was about (5.2±1.7) mm by ultrasonography, X-ray measurement was (5.0±2.1) mm, and showed no difference(P>0.05).In case group, the width of pubic symphysis measured by ultrasound before manipulation was about (9.5±1.8) mm, VAS was 6.05(5.27, 6.80) scores;while the width of pubic symphysis measured by ultrasound before manipulation was about (5.8±1.3) mm, VAS was 0(0, 0) scores, and there were statistical difference before and after manipulation (P<0.05). CONCLUSION: Ultrasound is examation method with safe, non radioactive, easy to repeat for many times, could clearly show cartilage, ligament and bone structure around pubic symphysis, and is more suitable for the imaging diagnosis of postpartum pubis symphysis diastasis, which provide quantitative imaging basis for clinical evaluation of the curative effect of bone setting manipulation in treating postpartum pubis symphysis diastasis.

Development and external validation of models to predict acute respiratory distress syndrome related to severe acute pancreatitis.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a major cause of death in patients with severe acute pancreatitis (SAP). Although a series of prediction models have been developed for early identification of such patients, the majority are complicated or lack validation. A simpler and more credible model is required for clinical practice. AIM: To develop and validate a predictive model for SAP related ARDS. METHODS: Patients diagnosed with AP from four hospitals located at different regions of China were retrospectively grouped into derivation and validation cohorts. Statistically significant variables were identified using the least absolute shrinkage and selection operator regression method. Predictive models with nomograms were further built using multiple logistic regression analysis with these picked predictors. The discriminatory power of new models was compared with some common models. The performance of calibration ability and clinical utility of the predictive models were evaluated. RESULTS: Out of 597 patients with AP, 139 were diagnosed with SAP (80 in derivation cohort and 59 in validation cohort) and 99 with ARDS (62 in derivation cohort and 37 in validation cohort). Four identical variables were identified as independent risk factors for both SAP and ARDS: heart rate [odds ratio (OR) = 1.05; 95%CI: 1.04-1.07; P < 0.001; OR = 1.05, 95%CI: 1.03-1.07, P < 0.001], respiratory rate (OR = 1.08, 95%CI: 1.0-1.17, P = 0.047; OR = 1.10, 95%CI: 1.02-1.19, P = 0.014), serum calcium concentration (OR = 0.26, 95%CI: 0.09-0.73, P = 0.011; OR = 0.17, 95%CI: 0.06-0.48, P = 0.001) and blood urea nitrogen (OR = 1.15, 95%CI: 1.09-1.23, P < 0.001; OR = 1.12, 95%CI: 1.05-1.19, P < 0.001). The area under receiver operating characteristic curve was 0.879 (95%CI: 0.830-0.928) and 0.898 (95%CI: 0.848-0.949) for SAP prediction in derivation and validation cohorts, respectively. This value was 0.892 (95%CI: 0.843-0.941) and 0.833 (95%CI: 0.754-0.912) for ARDS prediction, respectively. The discriminatory power of our models was improved compared with that of other widely used models and the calibration ability and clinical utility of the prediction models performed adequately. CONCLUSION: The present study constructed and validated a simple and accurate predictive model for SAP-related ARDS in patients with AP.

Stellerasespenes A‒E: Sesquiterpenoids from Stellera chamaejasme and their anti-neuroinflammatory effects.

Five undescribed sesquiterpenoids stellerasespenes A‒E and four reported congeners were isolated from the roots of Stellera chamaejasme. The structures were elucidated by comprehensive spectroscopic analyses together with X-ray single crystal diffraction and theoretical calculations. The structure of holosericin B was revised. All the isolated compounds were evaluated for NO production in murine microglial BV2 cells induced by LPS. Stellerasespene A showed better inhibitory activity than the positive control minocycline, inhibiting NO production and overexpression of pro-inflammatory cytokine IL-1ß in LPS-activated BV2 cells.

Investigating the Genetic Characteristics of Hippocampal Volume and Plasma ß-Amyloid in a Chinese Community-Dwelling Population.

BACKGROUND AND OBJECTIVES: The genetic characteristics and correlations of hippocampal volume and plasm Aß, probable endophenotypes for dementia, remain to be explored in Chinese community cohort. Using whole-exome sequencing and SNP-array genotyping, we sought to identify rare and common variants and genes influencing these two endophenotypes, and calculate their heritability and genetic correlation. METHODS: Association analyses with both whole-exome sequencing and SNP-array genotyping data were performed for hippocampal volumes and plasm Aß with mixed-effect linear regression model adjusted for sex, age, and total intracranial volume or APOE ε4 while considering familial relatedness. We also performed gene-level analysis for common and gene-burden analysis for rare variants. Heritability and genetic correlation were further examined. RESULTS: Totally 1,261 participants from a Chinese community cohort were included and we identified one gene, PTPRT, for hippocampal volume, with the top significant SNPs by whole genome-wide association study. rs6030076 (P=5.48×10-8, ß=-0.092, SE=0.017) from whole-exome sequencing and rs6030088 (P=8.24×10-9, ß=-105.22 SE=18.09) from SNP-array data, both located in this gene. Gene-burden analysis based on rare mutations detected 6 genes to be significantly associated with Aß. The SNP-based heritability was 0.43±0.13 for hippocampal volume and 0.2-0.3 for plasma Aß. The SNP-based genetic correlation between hippocampal volume and plasma Aß were negative. DISCUSSION: In this study, we identified several SNPs and one gene, PTPRT, which were not reported in previous GWASs, associated with hippocampal volume. Besides, the heritability and the genetic correlation gave an overview of hippocampal volume and plasma Aß. Our findings provide insights into the mechanisms behind the individual variances in these endophenotypes.

Prognostic value of left atrial mechanics in cardiac light-chain amyloidosis with preserved ejection fraction: a cohort study.

BACKGROUND: Light-chain amyloidosis is a plasma cell disorder associated with poor outcomes, especially when the heart is involved. The characteristics of left atrial (LA) function and its prognostic implications in cardiac amyloidosis (CA) have not been fully investigated. METHODS: Between April 2014 and June 2019, 93 patients with a diagnosis of CA, normal left ventricular ejection fraction (LVEF) and sinus rhythm were included. Their clinical, baseline echocardiographic and follow-up data were investigated. LA function, including LA strain and strain rate, was assessed using 2D speckle tracking echocardiography in different LA functional phases. RESULTS: Among all patients, 38 (40.9%) died. Multivariate Cox regression analyses showed that LA mechanics regarding LA reservoir and booster pump functions were independent predictors for overall survival. Traditional echocardiographic parameters for LA structure like LA volume index and LA width were not associated with mortality. Moreover, LA strain and strain rate in reservoir and contractile phases improved the discrimination and goodness of fit of the conventional prognostic model, the Mayo criteria 2004 and 2012, in our study population. Decreased LA mechanics were associated with impaired left ventricular (LV) systolic and diastolic function, and LA reservoir and contractile functions were associated with LA structure. CONCLUSIONS: Assessment of LA reservoir and contractile functions via 2D speckle tracking echocardiographic LA mechanical indices provide clinical and prognostic insights into cardiac light-chain amyloidosis patients, especially those with preserved EF and sinus rhythm. Emphasizing the monitoring of LA function may be beneficial for the prognosis prediction of CA.

Different Types of Circulatory Inflammatory Biomarkers Associated with Cerebral Arterial Atherosclerosis and Dolichoectasia.

BACKGROUND: Although inflammation is found to be related to arteriopathy pathogenesis, it is yet to be determined the distinct correlations of specific inflammatory biomarker types contributing to different cerebral large vessel diseases. We aimed to investigate the association between multiple inflammatory biomarkers and cerebral atherosclerosis and dolichoectasia in a community-based sample. METHODS: A total of 960 participants of the Shunyi study were included. A panel of 14 circulatory inflammatory biomarkers was assessed and then grouped in three sets as systemic, endothelial-related, and media-related inflammation, based on underlying different inflammatory cascades. Intracranial atherosclerotic stenosis (ICAS), dolichoectasia estimated by magnetic resonance angiography, and carotid plaques estimated by ultrasound were also performed. RESULTS: Endothelial-related inflammatory group was related to the presence of ICAS (R2 = 0.215, p = 0.024) and carotid plaques (R2 = 0.342, p = 0.013). Backward stepwise elimination showed that E-selectin was prominent (ß = 0.67, 95% CI: 0.54-0.85, p = 0.001; ß = 0.79, 95% CI: 0.68-0.93, p = 0.005). Systemic inflammatory group was associated with an increased basilar artery diameter (R2 = 0.051, p < 0.001), and backward stepwise elimination showed that IL-6 was prominent (ß = 0.07, 95% CI: 0.03-0.11, p < 0.001). CONCLUSION: Different types of inflammatory biomarkers were associated with atherosclerosis and dolichoectasia, respectively, implying dissimilar inflammatory processes. Further confirming of their distinct anti-inflammatory roles as potential therapeutic targets is warrant.

Inflammatory biomarkers and cerebral small vessel disease: a community-based cohort study.

BACKGROUND AND PURPOSE: Although inflammation has been proposed to be a candidate risk factor for cerebral small vessel disease (CSVD), previous findings remain largely inconclusive and vary according to disease status and study designs. The present study aimed to investigate possible associations between inflammatory biomarkers and MRI markers of CSVD. METHODS: A group of 15 serum inflammatory biomarkers representing a variety of those putatively involved in the inflammatory cascade was grouped and assessed in a cross-sectional study involving 960 stroke-free subjects. The biomarker panel was grouped as follows: systemic inflammation (high-sensitivity C reactive protein (hsCRP), interleukin 6 and tumour necrosis factor α), endothelial-related inflammation (E-selectin, P-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), CD40 ligand, lipoprotein-associated phospholipase A2, chitinase-3-like-1 protein and total homocysteine (tHCY)) and media-related inflammation (matrix metalloproteinases 2, 3 and 9, and osteopontin). The association(s) between different inflammatory groups and white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs), enlarged perivascular space (PVS) and the number of deep medullary veins (DMVs) were investigated. RESULTS: High levels of serum endothelial-related inflammatory biomarkers were associated with both increased WMH volume (R2=0.435, p=0.015) and the presence of lacunes (R2=0.254, p=0.027). Backward stepwise elimination of individual inflammatory biomarkers for endothelial-related biomarkers revealed that VCAM-1 was significant for WMH (ß=0.063, p=0.005) and tHCY was significant for lacunes (ß=0.069, p<0.001). There was no association between any group of inflammatory biomarkers and CMBs or PVS. Systemic inflammatory biomarkers were associated with fewer DMVs (R2=0.032, p=0.006), and backward stepwise elimination of individual systemic-related inflammatory biomarkers revealed that hsCRP (ß=-0.162, p=0.007) was significant. CONCLUSION: WMH and lacunes were associated with endothelial-related inflammatory biomarkers, and fewer DMVs were associated with systemic inflammation, thus suggesting different underlying inflammatory processes and mechanisms.

Anatomical variations in the Circle of Willis and the formation and rupture of intracranial aneurysms: A systematic review and meta-analysis.

Background: The anterior (AcomA) and posterior communicating arteries (PcomA) are two of the most frequent sites for intracranial aneurysms. Anatomical variations in the Circle of Willis (COW) are frequently observed in patients with AcomA and PcomA aneurysms. Strong evidence is needed to determine the pooled estimate of the effect of COW variations on the formation and rupture of these aneurysms. Aim: This systematic review and meta-analysis aimed to establish the effect of COW variations on the formation and rupture of AcomA and PcomA aneurysms using available studies. Summary of review: PubMed, Embase, and Web of Science databases were systematically searched for studies published in English before September 21, 2022. Studies investigating AcomA aneurysms and the hypoplastic/aplastic A1 segment of the anterior cerebral artery and PcomA aneurysms and hypoplastic/aplastic PcomA or fetal-type posterior cerebral artery (FTP) were included. The heterogeneity of the studies was assessed using Cochran Q-test and I2 statistic. Pooled estimate was assessed using either a random- or fixed-effects model based on the heterogeneity of the studies. Among the 4,932 studies, 21 were eligible and included in the analysis. The presence of hypoplastic/aplastic A1 was significantly correlated with the formation [OR (95% confidence interval [CI]) = 7.97 (5.58, 11.39), P < 0.001] and rupture [OR (95%CI) = 1.87 (1.29, 2.72), P < 0.001] of AcomA aneurysms. Significant associations between FTP and both the formation [OR (95%CI) = 2.15 (1.41, 3.30), P < 0.001] and rupture [OR (95%CI) = 1.72 (1.26, 2.36), P < 0.001] of PcomA aneurysms were observed. Conclusions: Significant associations were observed between COW variations and both the formation and rupture of AcomA and PcomA aneurysms. This can help in determining interventions for patients with aneurysms. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=225149, identifier: CRD42021225149.

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Oridonin (OD), which is the major active ingredient of the traditional Chinese medicine Rabdosia rubescens, reportedly exerts anti-inflammatory and antioxidative effects. Here, we first find that OD protects against APAP-induced hepatotoxicity. The results of hepatic tissue-associated RNA-seq and metabolomics showed that the protective effects of OD were dependent upon urea cycle regulation. And such regulation of OD is gut microbiota partly dependent, as demonstrated by fecal microbiota transplantation (FMT). Furthermore, using 16S rRNA sequencing, we determined that OD significantly enriched intestinal Bacteroides vulgatus, which activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to regulate redox homeostasis against APAP by urea cycle. In conclusion, our study suggests that the Bacteroides vulgatus-urea cycle-Nrf2 axis may be a potential target for reducing APAP-induced liver injury, which is altered by OD.

Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Researches on rare variants of NOTCH3 in the general Chinese population are lacking. This study aims to describe the spectrum of rare NOTCH3 variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare NOTCH3 variants and age-related cerebral small vessel disease. METHODS: The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging. NOTCH3 variants with minor allele frequency<1% in all 4 public population databases (1000 Genomes, ESP6500siv2_ALL, GnomAD_ALL, and GnomAD_EAS) were defined as rare variants. Multivariable linear and logistic regressions were used to investigate the associations between rare NOTCH3 variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare NOTCH3 variant carriers were summarized. RESULTS: Sixty-five rare NOTCH3 variants were identified in 147 of 1065 (13.8%) participants, including 57 missense single nucleotide polymorphisms (SNPs), 5 SNPs in splice branching sites, and 3 frameshift deletions. A significantly higher volume of white matter hyperintensities and heavier burden of cerebral small vessel disease was found in carriers of rare NOTCH3 EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving NOTCH3 variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, P=0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing NOTCH3 variant carriers but not in 2 cysteine-altering NOTCH3 variant carriers. CONCLUSIONS: Carriers of rare NOTCH3 variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.

Right ventricular systolic function is associated with health-related quality of life: a cross-sectional study in community-dwelling populations.

BACKGROUND: Considerable evidence has been presented that heart and health-related quality of life are directly linked in patients with various diseases. This exploratory study investigated whether cardiac structure and function were associated with health-related quality of life in the general population. METHODS: This cross-sectional study was performed in five villages of Shunyi, a suburban district of Beijing, from June 2013 to April 2016. All inhabitants aged 35 years or older living in five villages of Shunyi were invited to participate. Exclusion criteria were individuals who declined participation, who had incomplete Health-related quality of life (HRQoL) data, and who had suboptimal echocardiograms. HRQoL was evaluated by the Mandarin version of SF-36. The association between the echocardiography-derived cardiac structure and function and each domain of SF-36 was analyzed by the multivariate linear regression analysis after adjusted for conventional risk factors affecting HRQoL. RESULTS: The baseline data of 990 individuals were analyzed. The median age of the participants was 57 (50-63) years, and 367 (37.1%) were male, the average physical and mental component summary scores were 89.3 (79.8-94.3) and 90 (83.5-95) respectively. Tricuspid annular plane systolic excursion, an echocardiography-derived right ventricular parameter, was associated with all the subscales and summarized scores of SF-36 (all P<0.05). The independent association between tricuspid annular plane systolic excursion and physical/mental component summary scores remained after adjusting for age, gender, body mass index, education level, annual personal income, smoking and drinking status, and comorbidities (ß=0.65, 95% confidence interval 0.30-1.01, P<0.01 and ß=0.49, 95% confidence interval 0.23-0.76, P<0.01 for physical and mental component summary scores respectively). Compared with the participants with tricuspid annular plane systolic excursion ≥21 mm, the participants with tricuspid annular plane systolic excursion <21 mm had lower adjusted scores of physical and mental component summary scores (81.8 vs. 84.5, P=0.015, and 85.5 vs. 88.1, P<0.01 for physical and mental component summary scores respectively). CONCLUSIONS: In this population-based study, right ventricular systolic function assessed by tricuspid annular plane systolic excursion was independently associated with health-related quality of life assessed by SF-36.

Metabolic syndrome, intracranial arterial stenosis and cerebral small vessel disease in community-dwelling populations.

BACKGROUND AND PURPOSE: This study aimed to investigate the association of metabolic syndrome (MetS) with both intracranial atherosclerotic stenosis (ICAS) and imaging markers of cerebral small vessel disease (CSVD) in a community-based sample. METHODS: This study included 943 participants (aged 55.6±9.2 years, 36.1% male) from the community-based Shunyi cohort study. MetS was defined according to the joint interim criteria and quantified by the MetS severity Z-score. ICAS was evaluated by brain magnetic resonance angiography. The MRI markers of CSVD, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces (EPVS), were assessed. Multiple regression models were used to investigate the association of MetS severity Z-score with ICAS and these CSVD markers. RESULTS: We found that risk of ICAS (OR=1.75, 95% CI 1.39 to 2.21, p<0.001) increased consistently with MetS severity. MetS severity was significantly associated with higher risks of WMH volume (ß=0.11, 95% CI 0.01 to 0.20, p=0.02) and lacunes (OR=1.28, 95% CI 1.03 to 1.59, p=0.03) but not the presence of CMBs (OR=0.93, 95% CI 0.74 to 1.16, p=0.51) and PVS severity (EPVS in basal ganglia: OR=0.96, 95% CI 0.84 to 1.09, p=0.51 and EPVS in white matter: OR=1.09, 95% CI 0.96 to 1.23, p=0.21). CONCLUSIONS: Our findings suggest that WMH and lacunes share risk factors with atherosclerosis of the cerebral artery, whereas the impact of glucose and lipid metabolic disorder to CMB or EPVS might be weak.