Predicting fluid responsiveness in spontaneously breathing parturients undergoing caesarean section via carotid artery blood flow and velocity time integral measured by carotid ultrasound: a prospective cohort study.

BACKGROUND: Present evidence suggests that the Doppler ultrasonographic indices, such as carotid artery blood flow (CABF) and velocity time integral (VTI), had the ability to predict fluid responsiveness in non-obstetric patients. The purpose of this study was to assess their capacity to predict fluid responsiveness in spontaneous breathing parturients undergoing caesarean section and to determine the effect of detecting and management of hypovolemia (fluid responsiveness) on the incidence of hypotension after anaesthesia. METHODS: A total of 72 full term singleton parturients undergoing elective caesarean section were enrolled in this study. CABF, VTI, and hemodynamic parameters were recorded before and after fluid challenge and assessed by carotid artery ultrasonography. Fluid responsiveness was defined as an increase in stroke volume index (SVI) of 15% or more after the fluid challenge. RESULTS: Thirty-one (43%) patients were fluid responders. The area under the ROC curve to predict fluid responsiveness for CABF and VTI were 0.803 (95% CI, 0.701-0.905) and 0.821 (95% CI, 0.720-0.922). The optimal cut-off values of CABF and VTI for fluid responsiveness was 175.9 ml/min (sensitivity of 74.0%; specificity of 78.0%) and 8.7 cm/s (sensitivity of 67.0%; specificity of 90.0%). The grey zone for CABF and VTI were 114.2-175.9 ml/min and 6.8-8.7 cm/s. The incidence of hypotension after the combined spinal-epidural anaesthesia (CSEA) was significantly higher in the Responders group 25.8% (8/31) than in the Non-Responders group 17.1(7/41) (P < 0.001). The total incidence of hypotension after CSEA of the two groups was 20.8% (15/72). CONCLUSIONS: Ultrasound evaluation of CABF and VTI seem to be the feasible parameters to predict fluid responsiveness in parturients undergoing elective caesarean section and detecting and management of hypovolemia (fluid responsiveness) could significantly decrease incidence of hypotension after anaesthesia. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR) ( www.chictr.org ), registration number was ChiCTR1900022327 (The website link: https://www.chictr.org.cn/showproj.html?proj=37271 ) and the date of trial registration was in April 5, 2019. This study was performed in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of Women's Hospital, Zhejiang University School of Medicine (20,180,120).

Matrix metalloproteinase-9 inhibition prevents aquaporin-4 depolarization-mediated glymphatic dysfunction in Parkinson's disease.

INTRODUCTION: The glymphatic system offers a perivascular pathway for the clearance of pathological proteins and metabolites to optimize neurological functions. Glymphatic dysfunction plays a pathogenic role in Parkinson's disease (PD); however, the molecular mechanism of glymphatic dysfunction in PD remains elusive. OBJECTIVE: To explore whether matrix metalloproteinase-9 (MMP-9)-mediated ß-dystroglycan (ß-DG) cleavage is involved in the regulation of aquaporin-4 (AQP4) polarity-mediated glymphatic system in PD. METHODS: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and A53T mice were used in this study. The glymphatic function was evaluated using ex vivo imaging. TGN-020, an AQP4 antagonist, was administered to investigate the role of AQP4 in glymphatic dysfunction in PD. GM6001, an MMP-9 antagonist, was administered to investigate the role of the MMP-9/ß-DG pathway in regulating AQP4. The expression and distribution of AQP4, MMP-9, and ß-DG were assessed using western blotting, immunofluorescence, and co-immunoprecipitation. The ultrastructure of basement membrane (BM)-astrocyte endfeet was detected using transmission electron microscopy. Rotarod and open-field tests were performed to evaluate motor behavior. RESULTS: Perivascular influx and efflux of cerebral spinal fluid tracers were reduced in MPTP-induced PD mice with impaired AQP4 polarization. AQP4 inhibition aggravated reactive astrogliosis, glymphatic drainage restriction, and dopaminergic neuronal loss in MPTP-induced PD mice. MMP-9 and cleaved ß-DG were upregulated in both MPTP-induced PD and A53T mice, with reduced polarized localization of ß-DG and AQP4 to astrocyte endfeet. MMP-9 inhibition restored BM-astrocyte endfeet-AQP4 integrity and attenuated MPTP-induced metabolic perturbations and dopaminergic neuronal loss. CONCLUSION: AQP4 depolarization contributes to glymphatic dysfunction and aggravates PD pathologies, and MMP-9-mediated ß-DG cleavage regulates glymphatic function through AQP4 polarization in PD, which may provide novel insights into the pathogenesis of PD.

Comparison of Dural Puncture Epidural, Epidural and Combined Spinal-Epidural Anesthesia for Cesarean Delivery: A Randomized Controlled Trial.

Purpose: Catheter-based techniques such as combined spinal-epidural (CSE) anesthesia which are sometimes indicated for obstetric anesthesia have a complex mechanism of action. The application of the dural puncture epidural (DPE) anesthesia for cesarean section (CS) has not been well investigated. The present study compared the relatively novel DPE technique with epidural (EA) and CSE anesthesia. Patients and Methods: We randomly assigned 150 parturients who underwent elective CS to receive DPE, EA or CSE anesthesia. The primary outcome was the onset of sensory anesthesia to the T5 dermatome assessed using the Cox proportional hazards model. Secondary outcomes included median time to sensory block, quality of block, patient and surgeon satisfaction, APGAR scores and other side effects. Results: For DPE anesthesia versus EA anesthesia, the onset of anesthesia was faster (hazard ratio 2.47 [95% CI 1.56 to 3.90], adjusted P < 0.001) and the median time to surgical level was shorter (16 [IQR 14-18] min versus 19 [15.5-21] min, adjusted P < 0.001); the incidence of intraoperative pain was lower (7/48 versus 17/47, adjusted P = 0.046) and the median patient satisfaction score was higher (9 [IQR 9-10] versus 8 [8-9.5], adjusted P = 0.004). In the CSE group, the onset of anesthesia was faster than in the other two but the incidence of hypotension was higher (P < 0.001) and the phenylephrine requirement was greater (P < 0.001). Conclusion: DPE anesthesia had a faster onset and better quality of block than EA anesthesia and provided less influence to maternal hemodynamic parameters than CSE anesthesia for CS. These results suggest that the dural puncture plays a significant role in enhancing the effectiveness of epidural top-ups during CSE anesthesia and indicates enlightenment that contributes to the satisfaction of anesthetic effect in DPE technique labor analgesia transferred to CS.

The effects of AQP4 rs162009 on resting-state brain activity in Parkinson's disease.

BACKGROUND: We previously identified a significant association between Aquaporin-4 (AQP4) and Parkinson's disease (PD). OBJECTIVES: To identify whether AQP4 single-nucleotide polymorphism (SNP) rs162009 affects regional brain activity and clinical phenotypes of PD. METHODS: Low-frequency fluctuation amplitude (ALFF) was used to evaluate spontaneous brain activity, regional homogeneity (ReHo) was used to evaluate the pace of activity of adjacent voxel regions, and degree centrality (DC) was used to describe the functional connection strength between a voxel and the whole brain. Disease severity and PD stage were assessed with the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale and Hoehn and Yahr scales, and the Montreal Cognitive Assessment (MoCA) was used to assess the participants' cognitive function. RESULTS: In patients with PD, AQP4 SNP rs162009 was associated with a significant higher ALFF in the right caudate head and the left occipital gyrus, a significant lower ReHo in the right inferior frontal gyrus, a different DC in the right frontal gyrus, the left calcarine, and the right inferior temporal gyrus. A significant positive correlation between ALFF in the right caudate head and MoCA in rs162009_A carriers was found. A significant negative correlation between the DC at the left calcarine and MDS-UPDRS and MDS-UPDRS III in rs162009_A noncarriers was found. CONCLUSIONS: Our study further revealed the effect of AQP4 SNP rs162009 on brain activity in PD, indicating that AQP4 may play an important role in PD neuropathophysiology.

Efficacy and Safety of Esketamine for Supplemental Analgesia During Elective Cesarean Delivery: A Randomized Clinical Trial.

Importance: Epidural anesthesia is a primary choice for cesarean delivery, but supplemental analgesics are often required to relieve pain during uterine traction. Objective: To investigate the sedative and analgesic effects of intravenous esketamine administered before childbirth via cesarean delivery with the patient under epidural anesthesia. Design, Setting, and Participants: This multicenter, double-blind randomized clinical trial assessed 903 women 18 years or older who had full-term single pregnancy and were scheduled for elective cesarean delivery with epidural anesthesia in 5 medical centers in China from September 18, 2021, to September 20, 2022. Intervention: Patients were randomized to receive intravenous injection of 0.25 mg/kg of esketamine or placebo before incision. Main Outcomes and Measures: The coprimary outcomes included scores on the numeric rating scale of pain (an 11-point scale, with 0 indicating no pain and 10 indicating the worst pain; a difference of ≥1.65 points was clinically meaningful) and Ramsay Sedation Scale (a 6-point scale, with 1 indicating restlessness and 6 indicating deep sleep without response; a difference of ≥2 points was clinically meaningful) immediately after fetal delivery. Secondary outcomes included neonatal Apgar score assessed at 1 and 5 minutes after birth. Results: A total of 600 women (mean [SD] age, 30.7 [4.3] years) were enrolled and randomized; all were included in the intention-to-treat analysis. Immediately after fetal delivery, the score on the numeric rating scale of pain was lower with esketamine (median [IQR], 0 [0-1]) than with placebo (median [IQR], 0 [0-2]; median difference, 0; 95% CI, 0-0; P = .001), but the difference was not clinically important. The Ramsay Sedation Scale scores were higher (sedation deeper) with esketamine (median [IQR], 4 [3-4]) than with placebo (median [IQR], 2 [2-2]; median difference, 2; 95% CI, 2-2; P < .001). The neonatal Apgar scores did not differ between the 2 groups at 1 minute (median difference, 0; 95% CI, 0-0; P = .98) and at 5 minutes (median difference, 0; 95% CI, 0-0; P = .27). Transient neurologic or mental symptoms were more common in patients given esketamine (97.7% [293 of 300]) than in those given placebo (4.7% [14 of 300]; P < .001). Conclusions and Relevance: For women undergoing cesarean delivery under epidural anesthesia, a subanesthetic dose of esketamine administered before incision produced transient analgesia and sedation but did not induce significant neonatal depression. Mental symptoms and nystagmus were common but transient. Indications and the optimal dose of esketamine in this patient population need further clarification, but study should be limited to those who require supplemental analgesia. Trial Registration: ClinicalTrials.gov Identifier: NCT04548973.

ASC specks exacerbate α­synuclein pathology via amplifying NLRP3 inflammasome activities.

BACKGROUND: Inflammasome activation has a pathogenic role in Parkinson's disease (PD). Up-regulated expressions of inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and assembly of ASC specks have been observed in postmortems of human PD brains and experimental PD models. Extracellular ASC specks behave like danger signals and sustain prolonged inflammasome activation. However, the contribution of ASC specks in propagation of inflammasome activation and pathological progression in PD has not been fully established. METHODS: Herein, we used human A53T mutant α-synuclein preformed fibrils (PFFs)-stimulated microglia in vitro and unilateral striatal stereotaxic injection of PFFs-induced mice model of PD in vivo, to investigate the significance of ASC specks in PD pathological progression. Rotarod and open-field tests were performed to measure motor behaviors of indicated mice. Changes in the molecular expression were evaluated by immunofluorescence and immunoblotting (IB). Intracellular knockdown of the ASC in BV2 cells was performed using si-RNA. Microglial and neuronal cells were co-cultured in a trans-well system to determine the effects of ASC knockdown on cytoprotection. RESULTS: We observed a direct relationship between levels of ASC protein and misfolded α­synuclein aggregates in PD mice brains. ASC specks amplified NLRP3 inflammasome activation driven by α-synuclein PFFs stimulation, which aggravated reactive microgliosis and accelerated α­synuclein pathology, dopaminergic neurodegeneration and motor deficits. Endogenous ASC knockdown suppressed microglial inflammasome activation and neuronal α­synuclein aggregation. CONCLUSIONS: In conclusion, our study elucidated that ASC specks contribute to the propagation of inflammasome activation-associated α­synuclein pathology in PD, which forms the basis for targeting ASC as a potential therapy for PD.

Noninvasive neuroimaging provides evidence for deterioration of the glymphatic system in Parkinson's disease relative to essential tremor.

INTRODUCTION: Growing evidence has demonstrated dysfunction of the glymphatic system in α-synucleinopathy and related diseases. In this study, we aimed to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) and MRI-visible enlarged perivascular spaces (EPVS) to evaluate glymphatic system function quantitatively and qualitatively and its relationship to clinical scores of disease severity in Parkinson's disease (PD) and essential tremor (ET). METHODS: Overall, 124 patients with PD, 74 with ET, and 106 healthy controls (HC) were enrolled. Two trained neurologists performed quantitative calculations of ALPS on DTI and visual ratings of EPVS on T2-weighted images in the centrum semiovale (CSO), basal ganglia (BG), midbrain, and cerebellum. RESULTS: The ALPS index was lower in patients with PD than in patients with ET (p < 0.001) and HC (p < 0.001). Similarly, patients with PD showed a more severe EPVS burden in the CSO, BG, and midbrain compared to ET and HC. Moreover, the ALPS index was negatively correlated with disease severity in the PD subgroups; however, it did not differ within the ET subgroup. No differences in ALPS or EPVS were observed between the ET and HC groups. CONCLUSION: In conclusion, DTI-ALPS and EPVS both provide neuroimaging evidence of glymphatic system dysfunction in PD, which further supports that PD is an α-synucleinopathy disease, while ET is a cerebellar dysfunction-related disease.

Can ultrasonographic measurement of respiratory variability in the diameter of the internal jugular vein and the subclavian vein predict fluid responsiveness in parturients during cesarean delivery? A prospective cohort study.

Background: Ultrasonic measurements of the respiratory variability in the diameter of internal jugular vein (IJV-CI) and subclavian vein (SCV-CI) have recently been reported to be useful in predicting fluid responses in non-obstetric patients with spontaneous respiration. This study evaluated whether IJV-CI and SCV-CI could reliably predict fluid responsiveness in parturients undergoing elective cesarean delivery. Objective: This study was conducted to determine whether two indicators measured by ultrasound are good predictors of fluid responsiveness of parturients with spontaneous respiration in elective cesarean delivery. Design: A prospective cohort study. Setting: A single-center tertiary specialty hospital in China. Patients: A total of 86 patients scheduled for elective cesarean section were included and 6 were excluded for various reasons. Interventions: Based on the results of the fluid challenge, the included parturients were divided into two groups, with those who responded to fluid challenge defined as the positive group and those who did not respond defined as the negative group. Main outcome measures: The primary endpoint was to determine the predictive value of IJV-CI and SCV-CI for fluid responsiveness (≥15% increases in SVI after fluid challenge) in spontaneous respiration patients. Results: Forty-three (53.8%) parturients were fluid responders. IJV-CI and SCV-CI proved to be the independent predictors for fluid responsiveness by multivariate logistic regression. The area under the ROC curve for IJV-CI and SCV-CI were 0.881 (95% CI, 0.808-0.953, p < 0.0005) and 0.757 (95% CI, 0.648-0.865, p < 0.0008), respectively. Their optimal cut-off values for IJV-CI and SCV-CI were 20.7% (sensitivity of 60%; specificity of 79%) and 32.0% (sensitivity of 34%; specificity of 96%), respectively. The grey zone for IJV-CI and SCV-CI for fluid responsiveness were 20.4-32.4% and 30.4-44.6% and included 25% and 23% of the patients, respectively. Conclusion: Ultrasonic-derived IJV-CI is better than SCV-CI in predicting fluid responsiveness in spontaneously breathing parturients. Both IJV-CI and SCV-CI are the accurate and readily accessible indices of fluid responsiveness in parturients undergoing elective cesarean delivery. Trial registration: chictr.org.cn (ChiCTR1900028450).

Corrected flow time and respirophasic variation in blood flow peak velocity of radial artery predict fluid responsiveness in gynecological surgical patients with mechanical ventilation.

BACKGROUND: Recent evidence suggests that ultrasound measurements of carotid and brachial artery corrected flow time (FTc) and respirophasic variation in blood flow peak velocity (ΔVpeak) are valuable for predicting fluid responsiveness in mechanical ventilated patients. We performed the study to reveal the performance of ultrasonic measurements of radial artery FTc and ΔVpeak for predicting fluid responsiveness in mechanical ventilated patients undergoing gynecological surgery. METHODS: A total of eighty mechanical ventilated patients were enrolled. Radial artery FTc and ΔVpeak, and non-invasive pulse pressure variation (PPV) were measured before and after fluid challenge. Fluid responsiveness was defined as an increase in stroke volume index (SVI) of 15% or more after the fluid challenge. Multivariate logistic regression analyses and receiver operating characteristic (ROC) curve were used to screen multivariate predictors of fluid responsiveness and identify the predictive abilitie of non-invasive PPV, ΔVpeak and FTc on fluid responsiveness. RESULTS: Forty-four (55%) patients were fluid responders. Multivariate logistic regression analysis showed that radial artery FTc, ΔVpeak, and non-invasive PPV were the independent predictors of fluid responsiveness, with odds ratios of 1.152 [95% confidence interval (CI) 1.045 to 1.270], 0.581 (95% CI 0.403 to 0.839), and 0.361 (95% CI, 0.193 to 0.676), respectively. The area under the ROC curve of fluid responsiveness predicted by FTC was 0.802 (95% CI, 0.706-0.898), and ΔVpeak was 0.812 (95% CI, 0.091-0.286), which were comparable with non-invasive PPV (0.846, 95%CI, 0.070-0.238). The optimal cut-off values of FTc for fluid responsiveness was 336.6 ms (sensitivity of 75.3%; specificity of 75.9%), ΔVpeak was 14.2% (sensitivity of 88.2%; specificity of 67.9%). The grey zone for FTc was 313.5-336.6 ms and included 40 (50%) of the patients, ΔVpeak was 12.2-16.5% and included 37(46%) of the patients. CONCLUSIONS: Ultrasound measurement of radial artery FTc and ΔVpeak are the feasible and reliable methods for predicting fluid responsiveness in mechanically ventilated patients. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR)(www.chictr.org), registration number ChiCTR2000040941.

Specific immune status in Parkinson's disease at different ages of onset.

Recent evidence suggests that innate and adaptive immunity play a crucial role in Parkinson's disease (PD). However, studies regarding specific immune cell classification in the peripheral blood in PD remain lacking. Therefore, we aimed to explore the different immune status in patients with PD at different ages of onset. We included 22 patients; among them were 10 who had early-onset PD (EOPD) and 12 had late-onset PD (LOPD) and 10 young healthy controls (YHCs) and 8 elder HCs (EHCs). Mass cytometry staining technology was used to perform accurate immunotyping of cell populations in the peripheral blood. Motor symptoms and cognitive function were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) III score and Mini-mental State Examination (MMSE) score, respectively. T test and ANOVA statistical analysis were performed on the frequency of annotated cell population. Linear regression model was used to analyze the correlation between clusters and clinical symptoms. We characterized 60 cell clusters and discovered that the immune signature of PD consists of cluster changes, including decreased effector CD8+ T cells, lower cytotoxicity natural killer (NK) cells and increased activated monocytes in PD patients. In summary, we found that CD8+ T cells, NK cells, and monocytes were associated with PD. Furthermore, there may be some differences in the immune status of patients with EOPD and LOPD, suggesting differences in the pathogenesis between these groups.

Associations of Body Mass Index-Metabolic Phenotypes with Cognitive Decline in Parkinson's Disease.

BACKGROUND: Growing evidence suggests important effects of body mass index (BMI) and metabolic status on neurodegenerative diseases. However, the roles of BMI and metabolic status on cognitive outcomes in Parkinson's disease (PD) may vary and are yet to be determined. METHODS: In total, 139 PD patients from the whole PD cohort in Parkinson's Progression Markers Initiative database underwent complete laboratory measurements, demographic and anthropometric parameters at baseline, and were enrolled in this study. Further, they were categorized into 4 different BMI-metabolic status phenotypes using Adult Treatment Panel-III criteria. Motor and cognition scales at baseline and longitudinal changes after a 48-month follow-up were compared among the 4 groups. Repeated-measure linear mixed models were performed to compare PD-related biomarkers among BMI-metabolic status phenotypes across time. RESULTS: We found that PD patients in the metabolically unhealthy normal weight group showed more cognitive decline in global cognition and visuospatial perception after a 48-month follow-up than those in the other 3 groups (p < 0.05). No difference was found in motor scales among different BMI-metabolic status phenotypes. Finally, compared to the metabolically healthy normal weight group, the metabolically healthy obesity group had lower CSF Aß42 and serum neurofilament levels in repeated-measure linear mixed models adjusting for age, gender, APOE e4 carrier status, and years of education (p = 0.031 and 0.046, respectively). CONCLUSION: The MUNW phenotype was associated with a rapid cognitive decline in PD.

The effect of the PARK16 rs11240572 variant on brain structure in Parkinson's disease.

Increasing evidence suggests that genetic factors play a key role in the development of Parkinson's disease (PD). The variant rs11240572 in the PARK16 gene locus is strongly associated with PD. However, its effect on the pathogenesis of PD is yet to be clarified. The objective of the study was to explore the effect of the PARK16 rs11240572 variant on brain structure in PD patients. A total of 51 PD patients were enrolled in the study and genotyped for the rs11240572 variant. Clinical assessments and MRI scans were conducted across all participants. Voxel-based morphometry (VBM) was used to investigate gray matter volume (GMV) of the whole brain between these two groups. Correlation analysis was performed to identify the relationships between GMV and clinical features. There were 17 rs11240572-A variant carriers and 34 non-carriers, with no significant demographic differences between these two groups. Compared with non-carriers, rs11240572-A carriers showed increased GMV in the left caudate nucleus and putamen, but decreased GMV in the left superior temporal gyrus and supramarginal gyrus. In non-carriers, left basal ganglia GMV was positively correlated with UPDRS III (r = 0.365, p = 0.034) and bradykinesia (r = 0.352, p = 0.042), but negatively correlated with MMSE (r = - 0.344, p = 0.047), while in carriers negative correlation between basal ganglia GMV and MMSE was also observed (r = - 0.666, p = 0.004). Moreover, the GMV of left temporoparietal cortex was positively associated with cognitive function in both groups (carriers, r = 0.692, p = 0.002; non-carriers, r = 0.879, p < 0.001). When reducing the sample size of non-carriers to the level of the carrier sample, similar correlations were observed in both groups. Our study showed that the PARK16 rs11240572 variant affects the brain structure of patients with PD, especially in the basal ganglia and temporoparietal cortex. This indicated that this variant might play an important role in the pathogenesis of PD.

lncRNA Xist regulates sevoflurane-induced social and emotional impairment by modulating miR-98-5p/EDEM1 signaling axis in neonatal mice.

Long non-coding RNA (lncRNA) X-inactive specific transcript (Xist) is involved in apoptosis and inflammatory injury. This study aimed to assess the role of lncRNA Xist in sevoflurane-induced social and emotional impairment and neuronal apoptosis in neonatal mice and hippocampal neuronal cells. The performance in social and emotional tests and the expression levels of lncRNA Xist and microRNA (miR)-98-5p after sevoflurane exposure were measured. Moreover, the effects of suppression of lncRNA Xist on neuronal apoptosis and endoplasmic reticulum (ER) stress were determined. Subsequently, the association among lncRNA Xist, miR-98-5p, and ER degradation-enhancing α-mannosidase-like 1 protein (EDEM1) was explored. Our results showed that lncRNA Xist increased, miR-98-5p decreased, and social and emotional impairment appeared after sevoflurane exposure. Furthermore, suppression of lncRNA Xist improved sevoflurane-induced social and emotional impairment and reduced sevoflurane-induced neuronal apoptosis and ER stress in vivo and in vitro. Moreover, lncRNA Xist negatively regulated miR-98-5p expression, and it contributed to sevoflurane-induced neuronal apoptosis and ER stress by sponging miR-98-5p. Additionally, EDEM1 was identified as a target of miR-98-5p. Our findings revealed that the knockdown of lncRNA Xist ameliorates sevoflurane-induced social and emotional impairment through inhibiting neuronal apoptosis and ER stress by targeting the miR-98-5p/EDEM1 axis.

Aquaporin-4 Polymorphisms Are Associated With Cognitive Performance in Parkinson's Disease.

Objective: Aquaporin-4 (AQP4) facilitates a sleep-enhanced interstitial brain waste clearance system. This study was conducted to determine the clinical implication of AQP4 polymorphisms in Parkinson's disease (PD). Methods: Three-hundred and eighty-two patients with PD and 180 healthy controls with a mean follow-up time of 66.1 months from the Parkinson's Progression Marker Initiative study were analyzed. We examined whether AQP4 SNPs were associated with an altered rate of motor or cognitive decline using linear mixed model and Cox regression. We then investigated whether AQP4 SNPs were associated with Aß burden as measured by 18F Florbetapir standard uptake values. Furthermore, we examined if AQP4 SNPs moderated the association between REM sleep behavior disorder (RBD) and CSF biomarkers. Results: In patients with PD, AQP4 rs162009 (AA/AG vs. GG) was associated with slower dementia conversion, better performance in letter-number sequencing and symbol digit modalities, lower Aß deposition in the putamen, anterior cingulum, and frontotemporal areas. In the subgroup of high RBD screening questionnaire score, rs162009 AA/AG had a higher CSF Aß42 level. rs162009 AA/AG also had better performance in semantic fluency in healthy controls. Besides, rs68006382 (GG/GA vs. AA) was associated with faster progression to mild cognitive impairment, worse performance in letter-number sequencing, semantic fluency, and symbol digit modalities in patients with PD. Interpretation: Genetic variations of AQP4 and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD. AQP4 rs162009 is likely a novel genetic prognostic marker of glymphatic function and cognitive decline in PD.

MRI-visible perivascular spaces are associated with cerebrospinal fluid biomarkers in Parkinson's disease.

Perivascular spaces in the brain have been known to communicate with cerebrospinal fluid and contribute to waste clearance in animal models. In this study, we sought to determine the association between MRI-visible enlarged perivascular spaces (EPVS) and disease markers in Parkinson's disease (PD). We obtained longitudinal data from 245 patients with PD and 98 healthy controls from the Parkinson's Progression Marker Initiative. Two trained neurologists performed visual ratings on T2-weighted images to characterize EPVS in the centrum semiovale (CSO), the basal ganglia (BG) and the midbrain. We found that a greater proportion of patients with PD had low grade BG-EPVS relative to healthy controls. In patients with PD, lower grade of BG-EPVS and CSO-EPVS predicted lower CSF α-synuclein and t-tau. Lower grade of BG-EPVS were also associated with accelerated Hoehn &Yahr stage progression in patients with baseline stage 1. BG-EPVS might be a valuable predictor of disease progression.

Tetramethylpyrazine Attenuated Sevoflurane-Induced Neurotoxicity by Enhancing Autophagy through GPR50/CREB Pathway in SH-SY5Y Cells.

Tetramethylpyrazine has shown neuroprotective and axonal outgrowth-promoting effects and can improve cognitive deficit in a rat model of chronic hypoperfusion. However, the role of tetramethylpyrazine in sevoflurane-induced neurotoxicity is still vague. Therefore, this study was designed to investigate the effects and mechanisms of tetramethylpyrazine on sevoflurane-induced autophagy, apoptosis, and the expression of BACE1 and A[Formula: see text] in SH-SY5Y cells. We measured the expression levels of the apoptosis protein markers Bax and Bcl-2, autophagy protein markers Atg5 and LC3-II, BACE1, and A[Formula: see text] in SH-SY5Y cells after sevoflurane treatment and determined the effects of tetramethylpyrazine on sevoflurane-induced expression of these proteins after silencing GPR50 or Atg5 with siRNA in vitro. We found that exposure to 3.4% sevoflurane for 6 h decreased the expression of autophagy protein markers and increased the expression of the apoptosis protein markers, BACE1, and A[Formula: see text] in SH-SY5Y cells. The number of red puncta (autolysosomes) and yellow puncta (autophagosomes) in each SH-SY5Y cell decreased after transient transfection with the mRFP-GFP-LC3 expression plasmid. Silencing of GPR50 decreased the expression of pCREB, Atg5, and LC3-II, while silencing of Atg5 increased the expression of BACE1 and A[Formula: see text] in SH-SY5Y cells. Our results demonstrate that tetramethylpyrazine attenuated sevoflurane-induced neurotoxicity by enhancing autophagy through the GPR50/CREB pathway in SH-SY5Y cells.

The predictive ability of carotid artery corrected flow time and respirophasic variation in blood flow peak velocity measured by ultrasonography for fluid responsiveness in parturients for cesarean delivery.

BACKGROUND: Ultrasonic measurements of carotid artery corrected flow time (FTc) and respirophasic variation in blood flow peak velocity (ΔVpeak) were recently introduced to predict fluid responsiveness in non-obstetric patients. We designed the present study to evaluate the performance of these two ultrasonic indices in predicting fluid responsiveness in healthy parturients. METHODS: Seventy-five parturients undergoing elective cesarean delivery were enrolled. Carotid doppler parameters including FTc, ΔVpeak, the inferior vena cava diameter at the end of expiration (IVCexp) and inspiration (IVCins), Inferior Vena Cava Collapsibility Index (IVCCI), and Stroke Volume Index (SVI) were measured before and after fluid challenge. Fluid responsiveness was defined as a 15% or more increase in SVI as assessed by transthoracic echocardiography after the fluid challenge. RESULTS: FTc and ΔVpeak but not IVCins, IVCexp and IVCCI were proved to be two independent predictors for fluid responsiveness by multivariate logistic regression, with the odds ratios of 1.191 (95% confidence interval (CI), 1.070 to 1.326) and 0.521 (95% CI, 0.351 to 0.773). The area under the ROC curve to predict fluid responsiveness for FTc was 0.846 (95% CI, 0.751-0.940) and for ΔVpeak was 0.810 (95% CI, 0.709-0.910), which were significantly higher than those for IVCins (0.436, 95% CI, 0.300-0.572), IVCexp (0.595, 95% CI, 0.460-0.730) and IVCCI (0.548, 95% CI, 0.408-0.688). CONCLUSIONS: Compared with IVCins, IVCexp and IVCCI, FTc and ΔVpeak measured by ultrasonography seem to be the highly feasible and reliable methods to predict fluid responsiveness in parturients with spontaneous breathing undergoing elective cesarean delivery.

Evaluation of 2 ultrasonic indicators as predictors of difficult laryngoscopy in pregnant women: A prospective, double blinded study.

BACKGROUND: Ultrasonic measurements of tongue thickness and condylar translation were recently introduced to predict difficult laryngoscopy in non-obstetric patients. We designed the present study to evaluate the performance of these two ultrasonic indicators in predicting difficult laryngoscopy in healthy parturients. METHODS: The 119 parturients undergoing elective cesarean delivery were enrolled. Tongue thickness and condylar translation measured by ultrasonography, and Modified Mallampati test (MMT) score, inter-incisor distance (IID) and modified Cormack-Lehane grading system (MCLS) were measured and recorded before anesthesia. The primary outcome was difficult laryngoscopy defined as MCLS 3 or 4. The association between these variables and difficult laryngoscopy were analyzed by using multivariable logistic regression and receiver operating characteristic (ROC) curve. RESULTS: Compared to the Easy Laryngoscopy Group, the tongue thickness was significantly higher and the condylar translation and IID were significantly lower in the Difficult Laryngoscopy Group. Tongue thickness and condylar translation but not MMT score and IID were proved to be two independent predictors for difficult laryngoscopy by multivariate logistic regression, with the odds ratios of 2.554 (95% confidence interval (CI), 1.715 to 3.802) and 0.457 (95% CI, 0.304 to 0.686). The area under the ROC curve to predict difficult laryngoscopy for tongue thickness was 0.93 (95% CI, 0.88-0.98) and for condylar translation was 0.77 (95% CI, 0.67-0.86), which were significantly higher than those for MMT score (0.67, 95% CI, 0.56-0.77) and IID (0.65, 95% CI, 0.55-0.76). CONCLUSIONS: Compared with MMT and IID, tongue thickness and condylar translation measured by ultrasonography appear to be better indicators for predicting difficult laryngoscopy in parturients.The trial was registered at the Chinese Clinical Trial Registry (ChiCTR)(www.chictr.org), registration number ChiCTR-ICR-1800019991.

Nystagmus-related FRMD7 gene influences the maturation and complexities of neuronal processes in human neurons.

AIMS: Idiopathic congenital nystagmus (ICN) is an oculomotor disorder caused by the defects in the ocular motor control regions of the brain. Mutations in FRMD7, a member of the FERM family of proteins, associated with cytoskeletal dynamics, are the most frequent causes of X-linked ICN. Previous studies illustrated that FRMD7 is involved in the elongation of neurites during neuronal development; however, almost all the studies were performed on mice cell models. The complexity in the human neuronal network might suggest a unique vulnerability of human neurons to FRMD7 mutations. METHODS: Herein, we successfully established human neuronal cell models with FRMD7 mutations, from fibroblasts-reprogrammed neurons (iNs). In these neurons, the complexity of the neuronal processes was measured by the induced ratio, total neurite length, the number of terminals, and the number of maturation neurons. RESULTS: The complexity of the neuronal processes was greatly reduced during various reprogramming stages in the presence of FRMD7 mutations. Consistently, the expression of the three main Rho GTPases was significantly increased by FRMD7 mutations. Interestingly, a slightly diverse phenotype is observed in different derived neurons. CONCLUSION: We established ideal human neuron models and confirmed that the mutation in FRMD7 influences the maturation and complexities of neuronal processes, which might be involved with the Rho GTPase signaling.