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Hepatocellular carcinoma (HCC) progresses fast and has a poor prognosis, but the growth rate in different TNM stages is not clear. The present study was to estimate the growth rate of HCC with different TNM stages at diagnosis.Baseline demographics and tumor characteristics were analyzed for 10145 patients in Surveillance, Epidemiology, and End Results (SEER) Program-registered HCC. Multiple linear regression models were used for age adjustment with patient race, sex, marital status, and HCC grade.The age at diagnosis was younger in Caucasians and males. The adjusted average age of patients with stage I HCC was 65.26 years. The adjusted age of patients with stage II, IIIA, IIIB, and IIIC was -0.17, -0.25, -0.29, and -0.55 adjusted-year younger compared with patients with stage I HCC (all P 0.001). The adjusted average age of patients with T1 was 65.26 years. The age adjustment was -0.17, -0.26, and -0.55 respectively (all P 0.001) for T2, T3 or T4 tumors without distant metastases.These findings demonstrated that the more advanced the HCC stage at diagnosis, the younger the age at diagnosis and the faster the HCC growth from tumor occurrence.

To explore clinical efficacy of staged surgery in treating complex closed Pilon fracture.From June 2019 to January 2021, 29 patients with complex closed Pilon fracture were treated by staging surgery, including 18 males and 11 females, aged ranged from 31 to 68 years old with an average of (43.50±6.62) years old;7 cases were typeⅡand 22 cases were type Ⅲ according to Ruedi-Allgower classification. All patients had fresh closed fractures without talus and calcaneal fractures. The time from injury to closed reduction and external fixation, the interval between two stages of surgery, fracture healing time and complications were recorded. American Orthopedic Foot and Ankle Society(AOFAS) was used to assess clinical effects. Burwell-Charnley system was used to evaluate radiological reduction.All 29 patients were followed up from 13 to 30 months with an aver age of (15.43±5.31) months. All fractures healed well from 2 to 6 months with an average of (3.77±1.22) months. No internal fixation fracture, screw loosening, infection, internal fixation irritation, ankle stiffness occurred. The time from injury to closed reduction and cross-ankle fixation ranged from 1.22 to 7.34 h with an average of(2.31±3.52) h, the interval between two stages ranged from 5 to 9 days with an average of (5.98±2.11) days. AOFAS score was improved from 34.11±6.89 before operation to 90.10±10.11 after oepration at 12 months(Staged surgery for complex closed Pilon fracture has advantages of less complications, statisfied reduction, stable fixation, which could obtain good recovery of ankle joint.

Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM_022454.4: c.379C>T; p. (Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode β-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.

Mutations in serotonin pathway genes, especially the serotonergic receptor subunit gene HTR3A, are associated with autism. However, the association of HTR3A deficiency with autism and the underlying mechanisms remain unknown. Methods: The Htr3a knockout (KO) mice were generated using transcription activator-like effector nuclease technology. Various behavior tests, including social interaction, social approach task, olfactory habituation/dishabituation, self-grooming, novel object recognition, contextual fear conditioning, elevated plus maze, open field and seizure susceptibility, were performed to assess the phenotypes. Transcriptome sequencing was carried out to search for molecular network and pathways underlying the phenotypes. Electrophysiological recordings, immunoblotting, immunofluorescence staining, immunoprecipitation, and quantitative real-time PCR were performed to verify the potential mechanisms. The N-methyl-D-aspartate receptor (NMDAR) antagonist memantine was used to treat the KO mice for rescuing the phenotypes. Results: The Htr3a KO mouse model showed three phenotypic domains: autistic-like behaviors (including impaired social behavior, cognitive deficits, and increased repetitive self-grooming), impaired memory, and attenuated susceptibility to pentylenetetrazol-induced seizures. We observed enhanced action potential-driven γ-aminobutyric acid-ergic (GABAergic) transmission in pyramidal neurons and decreased excitatory/inhibitory (E/I) ratio using the patch-clamp recording. Transcriptome sequencing on the hippocampus revealed the converged pathways of the dysregulated molecular networks underlying three phenotypic domains with upregulation of NMDAR. We speculated that Htr3a KO promotes an increase in GABA release through NMDAR upregulation. The electrophysiological recordings on hippocampal parvalbumin-positive (PV+) interneuron revealed increased NMDAR current and NMDAR-dependent excitability. The NMDAR antagonist memantine could rescue GABAergic transmission in the hippocampus and ameliorate autistic-like behaviors of the KO mice. Conclusion: Our data indicated that upregulation of the NMDAR in PV+ interneurons may play a critical role in regulating GABAergic input to pyramidal neurons and maybe involve in the pathogenesis of autism associated with HTR3A deficiency. Therefore, we suggest that the NMDAR system could be considered potential therapeutic target for autism.

Autism spectrum disorder (ASD) is a neuronal developmental disorder with impaired social interaction and communication, often with abnormal intelligence and comorbidity with epilepsy. Disturbances in synaptic transmission, including the GABAergic, glutamatergic, and serotonergic systems, are known to be involved in the pathogenesis of this disorder, yet we do not know if there is a common molecular mechanism. As mutations in the GABAergic receptor subunit gene GABRA4 are reported in patients with ASD, we eliminated the Gabra4 gene in mice and found that the Gabra4 knockout mice showed autistic-like behavior, enhanced spatial memory, and attenuated susceptibility to pentylenetetrazol-induced seizures, a constellation of symptoms resembling human high-functioning autism. To search for potential molecular pathways involved in these phenotypes, we performed a hippocampal transcriptome profiling, constructed a hippocampal interactome network, and revealed an upregulation of the NMDAR system at the center of the converged pathways underlying high-functioning autism-like and anti-epilepsy phenotypes.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations are noted in ASD patients and animal models. However, whether astrocyte dysfunction is causal or consequential to ASD-like phenotypes in mice is unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca2+ release from intracellular Ca2+ stores results in the activation of astrocytes. Mutations of the IP3R2 gene are associated with ASD. Here, we show that both IP3R2-null mutant mice and astrocyte-specific IP3R2 conditional knockout mice display ASD-like behaviors, such as atypical social interaction and repetitive behavior. Furthermore, we show that astrocyte-derived ATP modulates ASD-like behavior through the P2X2 receptors in the prefrontal cortex and possibly through GABAergic synaptic transmission. These findings identify astrocyte-derived ATP as a potential molecular player in the pathophysiology of ASD., Astrocytes contribute to autism spectrum disorder (ASD) pathophysiology. Here, the authors show that IP3R2 conditional KO mice show ASD-like behaviours and identify astrocyte-derived ATP as a modulator of these behaviours in mice.

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.

Background To evaluate whether a shorter time of lying supine without a pillow and fasting for solids and liquids (LSFSL) after a lumbar puncture (LP) is associated with a higher risk of post-lumbar puncture headache (PLPH) and post-lumbar puncture lower back pain (PLPBP) in a randomized, assessor-blinded, controlled trial. Methods Paediatric patients who underwent their first LP after hospital admission were randomly allocated to either the group with half an hour of LSFSL (0.5 h LSFSL) or 4 h of LSFSL (4 h LSFSL) immediately after LP. The primary outcome is PLPH after LP. The incidence of PLPH, PLPBP, and vomiting; vital signs (respiratory rate, heart rate, blood pressure); and other post-procedure conditions after LP were measured as the outcomes. The Non-inferiority test and Wilcoxon rank-sum test were used to analyse the outcome data. Results In total, 400 patients (201 in the 0.5-h LSFSL group and 199 in the 4-h LSFSL group) were included in this trial. Twelve (5.97%) of 201 patients experienced PLPH in the 0.5 h LSFSL group versus 13 (6.53%) of 199 patients in the 4 h LSFSL group (difference 0.56, 95% CI -4.18 to 5.31; p = 0·0108 for the non-inferiority test). Fourteen (6.97%) of 201 patients experienced PLPBP in the 0.5 h LSFSL group versus 17 (8.54%) of 199 patients in the 4 h LSFSL group (difference 1.57, 95% CI -3.66 to 6.82; p = 0.007 for the non-inferiority test). The changes in heart rate (HR), respiratory rate (RP) and systolic blood pressure (SBP) before and after the LP were not different between the 0.5-h LSFSL group and the 4-h LSFSL group. No other adverse events were reported. Conclusions Compared with 4 h of LSFSL after LP, 0.5 h of LSFSL was not associated with a higher risk of PLPH, PLPBP or other adverse events. In conclusion, 0.5 h of LSFSL is sufficient for children undergoing LP. Trial registration Clinical trial NCT02590718. The date of registration was 08/25/2015.

Internalized stigma, an adverse psychological process, severely impedes the lives of people diagnosed with schizophrenia and restricts them from social integration and recovery. The aim of this study was to empirically evaluate an integrative model of relationship between internalized stigma and patients’ recovery-related outcomes among people diagnosed with schizophrenia in a rural Chinese community. A total of 232 people diagnosed with schizophrenia in Xinjin, Chengdu, participated in this study and completed measures of internalized stigma, social interaction, perceived social support, social functioning, and symptoms. The internalized stigma of mental illness scale (ISMI) was used to measure the internalized stigma. Path analysis was used to test the association between internalized stigma and recovery-related outcomes. There were no significant differences in mean scores of ISMI by gender, age (18–64 years and ≥ 65 years), education, marital status, or economic capacity. Internalized stigma was negatively associated with perceived social support and social interaction. Furthermore, higher level of internalized stigma was associated with impaired social functioning, and a lower level of social functioning was significantly associated with more severe symptoms. Internalized stigma is associated with poor social interaction and weakened perceived social support in people diagnosed with schizophrenia, and is linked negatively to outcomes in their recovery. It is essential to tailor interventions related to reducing internalized stigma within a Chinese context and evaluate the effectiveness of anti-stigma intervention on recovery for people diagnosed with schizophrenia.

Background Health-related quality of life (HRQoL) is a key metric to understand the impact of stroke from patients’ perspective. Yet HRQoL is not readily measured in clinical practice. This study aims to investigate the extent to which clinical outcomes during admission predict HRQoL at 3 months and 1 year post-stroke. Methods Stroke patients admitted to five tertiary hospitals in Singapore were assessed with Shah-modified Barthel Index (Shah-mBI), National Institute of Health Stroke Scale (NIHSS), Modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), and Frontal Assessment Battery (FAB) before discharge, and the EQ-5D questionnaire at 3 months and 12 months post-stroke. Association of clinical measures with the EQ index at both time points was examined using multiple linear regression models. Forward stepwise selection was applied and consistently significant clinical measures were analyzed for their association with individual dimensions of EQ-5D in multiple logistic regressions. Results All five clinical measures at baseline were significant predictors of the EQ index at 3 months and 12 months, except that MMSE was not significantly associated with the EQ index at 12 months. NIHSS (3-month standardized β = − 0.111; 12-month standardized β = − 0.109) and mRS (3-month standardized β = − 0.122; 12-month standardized β = − 0.080) were shown to have a larger effect size than other measures. The contribution of NIHSS and mRS as significant predictors of HRQoL was mostly explained by their association with the mobility, self-care, and usual activities dimensions of EQ-5D. Conclusions HRQoL at 3 months and 12 months post-stroke can be predicted by clinical outcomes in the acute phase. NIHSS and mRS are better predictors than BI, MMSE, and FAB.

Background There are limit studies about pediatric brain abscess in China. The aim of this study was to analyze clinical characteristics and outcomes of pediatric brain abscess in recent years in China. Methods The clinical information of children with brain abscess hospitalized in Beijing Children's Hospital between January 1, 2007 and December 31, 2016 were retrospectively reviewed. Results Ninety-four children were enrolled in this study. A Streptococcus milleri group (13.8%) was identified as the most common causative organisms, followed by Staphylococcus aureus (6.4%). The overall mortality was 21.6%, with 50.0% of deaths happening in the first week after diagnosis. Long-term outcomes of 74 patients were assessed with Glasgow Outcome Scale-Extended Pediatric Reversion: 50 patients with a score of 1-2 (favorable outcome) and 24 patients with a score of 3-8 (unfavorable outcome). Patients with multiple abscesses (P = 0.029) and intraventricular rupture of brain abscess/hydrocephalus (P = 0.024) had higher risk of unfavorable outcomes. Conclusions Brain abscess is a serious disease with high mortality in children; more aggressive treatments should be considered in the first week of diagnosis because of high risk of death, and for patients with multiple brain abscesses and intraventricular rupture of brain abscess/hydrocephalus because of their higher risk of unfavorable.

Context: It is necessary to explore a minimally invasive, effective, and efficient treatment for those lung cancer patients who are poor candidates for surgery. Aim: This study aimed to investigate the application of microwave ablation (MWA) in the treatment of lung cancer. Settings and Design: A total of 43 patients with 44 pulmonary lesions were examined following identical procedures before being randomly divided into two groups. The experimental group consists of 17 patients with a total of 18 pulmonary lesions, while the control group consists of 26 patients with a total of 26 pulmonary lesions. Materials and Methods: The experimental group was treated using magnetic resonance imaging (MRI)-guided MWA while the control group was treated using computer tomography (CT)-guided MWA. A transverse relaxation time-turbo spin echo (T2-TSE) sequence was used for signal collection in the experimental group to determine puncture location and microwave needle position while T2-TSE, T1-turbo field echo, and diffusion-weighted MRI (DWI) sequences were used for timely efficacy evaluation. Whereas in the control group, CT axial scanning was performed to serve similar purposes. Statistical Analysis Used: A nonparametric Wilcoxon test, median (M [25%, 75%]). Results: All of the 44 lesions were successfully located on the first attempt. The mean time for scanning and locating lung lesions under MRI and CT guidance were 64.53 and 42.96 min, the mean times of positioning were 12 and 18 min, and the mean durations of MWA were 12.48 and 15.06 min, respectively. Conclusions: As a minimally invasive method for treating lung tumors, MRI-guided MWA requires fewer localization scans, a shorter MWA duration, no radiation, real-time observation of the curative effect, and it prevents overtreatment.

Reports of cerebral venous thrombosis (CVT) after messenger RNA (mRNA)-based SARS-CoV-2 vaccination has caused safety concerns, but CVT is also known to occur after SARS-CoV-2 infection. Comparing the relative incidence of CVT after infection vs vaccination may provide a better perspective of this complication.To compare the incidence rates and clinical characteristics of CVT following either SARS-CoV-2 infection or mRNA-based SARS-CoV-2 vaccines.Between January 23, 2020, and August 3, 2021, this observational cohort study was conducted at all public acute hospitals in Singapore, where patients hospitalized with CVT within 6 weeks of SARS-CoV-2 infection or after mRNA-based SARS-CoV-2 vaccination (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) were identified. Diagnosis of SARS-CoV-2 infection was based on quantitative reverse transcription-polymerase chain reaction or positive serology. National SARS-CoV-2 infection data were obtained from the National Centre for Infectious Disease, Singapore, and vaccination data were obtained from the National Immunisation Registry, Singapore.SARS-CoV-2 infection or mRNA-based SARS-CoV-2 vaccines.Clinical characteristics, crude incidence rate (IR), and incidence rate ratio (IRR) of CVT after SARS-CoV-2 infection and after mRNA SARS-CoV-2 vaccination.Among 62 447 individuals diagnosed with SARS-CoV-2 infections included in this study, 58 989 (94.5%) were male; the median (range) age was 34 (0-102) years; 6 CVT cases were identified (all were male; median [range] age was 33.5 [27-40] years). Among 3 006 662 individuals who received at least 1 dose of mRNA-based SARS-CoV-2 vaccine, 1 626 623 (54.1%) were male; the median (range) age was 50 (12-121) years; 9 CVT cases were identified (7 male individuals [77.8%]; median [range] age: 60 [46-76] years). The crude IR of CVT after SARS-CoV-2 infections was 83.3 per 100 000 person-years (95% CI, 30.6-181.2 per 100 000 person-years) and 2.59 per 100 000 person-years (95% CI, 1.19-4.92 per 100 000 person-years) after mRNA-based SARS-CoV-2 vaccination. Six (66.7%) received BNT162b2 (Pfizer-BioNTech) vaccine and 3 (33.3%) received mRNA-1273 (Moderna) vaccine. The crude IRR of CVT hospitalizations with SARS-CoV-2 infection compared with those who received mRNA SARS-CoV-2 vaccination was 32.1 (95% CI, 9.40-101; P .001).The incidence rate of CVT after SARS-CoV-2 infection was significantly higher compared with after mRNA-based SARS-CoV-2 vaccination. CVT remained rare after mRNA-based SARS-CoV-2 vaccines, reinforcing its safety.

Acute ischemic stroke (AIS) is a life-threatening complication of coronavirus disease 2019 (COVID-19) infection. Increasing reports suggest an association between COVID-19 and AIS, although the underlying mechanism remains uncertain. We performed a systematic review to characterize the clinical characteristics, neuroimaging findings, and outcomes of AIS in COVID-19 patients. A literature search was performed in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 29th May 2020. All studies reporting AIS occurrence in COVID-19 patients were included. A total of 39 studies comprising 135 patients were studied. The pooled incidence of AIS in COVID-19 patients from observational studies was 1.2% (54/4466) with a mean age of 63.4 ± 13.1 years. The mean duration of AIS from COVID-19 symptoms onset was 10 ± 8 days, and the mean NIHSS score was 19 ± 8. Laboratory investigations revealed an elevated mean d-dimer (9.2 ± 14.8 mg/L) and fibrinogen (5.8 ± 2.0 g/L). Antiphospholipid antibodies were detected in a significant number of cases. The majority of AIS neuroimaging patterns observed was large vessel thrombosis, embolism or stenosis (62.1%, 64/103), followed by multiple vascular territory (26.2%, 27/103). A high mortality rate was reported (38.0%, 49/129). We report the pooled incidence of AIS in COVID-19 patients to be 1.2%, with a high mortality rate. Elevated d-dimer, fibrinogen and the presence of antiphospholipid antibodies appear to be prominent in COVID-19 patients with concomitant AIS, but further mechanistic studies are required to elucidate their role in pathogenesis. Electronic supplementary material The online version of this article (10.1007/s11239-020-02228-y) contains supplementary material, which is available to authorized users.

The clinical guidance of the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system is established only in biological factors and does not include nonbiological factors (NBFs). We assessed the clinical value of incorporating NBFs into the TNM staging system in point of the clinical management and prognostic prediction accuracy of rectal cancer.We used the Surveillance, Epidemiology and End Results (SEER) database and identified 12,515 patients with rectal cancer who were diagnosed between 1 January 2011 and 31 December 2015. Multivariate Cox proportional hazards regression analysis and Kaplan-Meier curves were used to determine the probabilities of cancer-specific survival (CSS) according to different TNM-NBF stages.Multivariate Cox regression analysis showed that county percentage with a bachelor's degree, insurance status, unemployment status, and marital status were all significant prognostic NBFs (p 0.05). The concordance index of TNM-NBF stages was 0.815 (95% confidence interval (CI) 0.8072-0.8228). Multivariate Cox analyses showed that, compared with NBF0-stage, NBF1-stage was contacted with a 54.5% increased risk of cancer-specific mortality in rectal cancer, which increased to 68.3% in non-metastatic rectal cancer (all p 0.001). NBF0-stage showed a CSS benefit as compared with NBF1-stage (p 0.001).We found that NBF-stage was an independent prognostic factor for survival in rectal cancer. The influence of NBFs on survival in rectal cancer warrants greater clinical attention. Furthermore, the consolidation of NBF-stage into the TNM staging system is crucial to better prognostic prediction accuracy and individualized risk-adaptive therapies.

P2X2 and P2X3 receptors are widely expressed in both the peripheral nervous system and the central nervous system and have been proven to participate in different peripheral sensory functions, but there are few studies on the involvement of P2X2 and P2X3 receptors in animal behaviors. Here we used P2X2 and P2X3 knockout mice to address this issue. P2X2 knockout mice showed normal motor function, exploratory behavior, anxiety-like behaviors, learning and memory behaviors and passive coping response to behavioral challenge. Nevertheless, the effect of ATP infusion in the medial prefrontal cortex (mPFC) on the passive coping response was blocked by P2X2 but not P2X3 receptor deletion. Additionally, no deficits in a wide variety of behavioral tests were observed in P2X3 knockout mice. These findings demonstrate a role of P2X2 receptor in the mPFC in adenosine-5'-triphosphate modulation of the passive coping response to behavioral challenge and show that the P2X2/P2X3 receptor is dispensable for behaviors.

Background Acute ischemic stroke is a time-sensitive emergency where accurate diagnosis is required promptly. Due to time pressures, stroke mimics, whom present with similar signs and symptoms as acute ischemic stroke, pose a diagnostic challenge to the emergency physician. With limited access to investigative tools, clinical prediction tools, based only on clinical features, may be useful to identify stroke mimics. We aim to externally validate the performance of 4 stroke mimic prediction scales and aim to derive a novel decision tree, to improve identification of stroke mimics. Methods We performed a retrospective cross-sectional study at a primary stroke centre, served by a telestroke hub. We included consecutive patients whom were administered intravenous thrombolysis for suspected acute ischemic stroke from January 2015 to October 2017. Four stroke mimic prediction tools (FABS, simplified FABS, Telestroke Mimic Score and Khan Score) were rated simultaneously, using only clinical information prior to administration of thrombolysis. The final diagnosis was ascertained by an independent stroke neurologist. Area under receiver operating curve (AUROC) analysis was performed. A classification tree analysis was also conducted using variables which were found to be significant in the univariate analysis. Results Telestroke Mimic Score had the highest discrimination for stroke mimics among the 4 scores tested (AUROC = 0.75, 95% CI = 0.63–0.87), although it was not statistically significantly better. Telestroke Mimic Score had the highest sensitivity (91.3%), while Khan score had the highest specificity (88.2%). All 4 scores had high positive predictive value (88.1–97.5%) and low negative predictive values (4.7–32.3%). A novel decision tree, using only age, presence of migraine and psychiatric history, had a higher prediction performance (AUROC = 0.80). Conclusion Four tested stroke mimic prediction scales performed similarly well to identify stroke mimics in the emergency setting. A novel decision tree may improve the identification of stroke mimics.

Every organism inevitably experiences stress. In the face of acute, intense stress, for example, periods of passivity occur when an organism’s actions fail to overcome the challenge. The occurrence of inactive behavior may indicate that struggling would most likely be fruitless. Repeated serious stress has been associated with mood disorders such as depression. The modulation of passive coping response patterns has been explored with a focus on the circuit level. However, the cellular and molecular mechanisms are largely uncharacterized. Here, we report that lactate is a key factor in the astrocytic modulation of the passive coping response to behavioral challenge in adult mice. We found increased extracellular lactate in the medial prefrontal cortex (mPFC) when mice experienced the forced swimming test (FST). Furthermore, we discovered that disturbing astrocytic glycogenolysis, which is a key step for lactate production in the mPFC, decreased the duration of immobility in the FST. Knocking down monocarboxylate transporter 4 (MCT4), which is expressed exclusively in astrocytes and transports lactate from astrocytes to the extracellular space, caused similar results in the FST. The behavioral effect of both the pharmacological disturbance of astrocytic glycogenolysis and viral disruption of MCT4 expression was rescued via the administration of L-lactate. Moreover, we found that both pharmacological and viral modulation of astrocyte-derived lactate in mPFC slices increased the excitability of layer V pyramidal neurons, and this enhancement was reversed by exogenous L-lactate administration. These results highlight astrocyte-derived lactate as a biological mechanism underlying the passive coping response to behavioral challenge and may provide new strategies to prevent mood disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-020-00553-z) contains supplementary material, which is available to authorized users.

Background A validated histopathological tool to precisely evaluate bowel fibrosis in patients with Crohn’s disease is lacking. We attempted to establish a new index to quantify the severity of bowel fibrosis in patients with Crohn’s disease-associated fibrostenosis. Methods We analyzed the histopathological data of 31 patients with Crohn’s disease strictures undergoing surgical resection. The most representative sections of resected strictured segments were stained with Masson trichrome to manifest bowel fibrosis. The collagen area fraction and histological fibrosis score were simultaneously calculated for the same section to evaluate the severity of bowel fibrosis. Results Collagen area fraction strongly correlated with histological fibrosis scores (r = 0.733, P (r = 0.561, P ) with the degree of bowel strictures than the histological fibrosis score did (r = 0.468, P P P P Conclusions Collagen area fraction is a simple and reliable index to quantify the severity of bowel fibrosis in patients with Crohn’s disease-associated fibrostenosis.

Objective This study examined the differences in 14-year outcomes of persons with schizophrenia with and without family history of psychosis in a rural community in China. Methods All participants with schizophrenia (n = 510) aged 15 years and older were identified in a 1994 epidemiological investigation of 123,572 people and followed up in 2004 and 2008 in Xinjin County, Chengdu, China. Results Individuals with positive family history of schizophrenia had significantly younger age of first onset than those with negative family history of schizophrenia in 1994 and 2004. Compared with individuals with negative family history of schizophrenia, those with positive family history of schizophrenia had significantly higher rate of homelessness and lower rate of death due to other reasons in 10-year (2004) and 14-year follow-up (2008). There were no significantly differences of mean scores on PANSS, SDSS and GAF in 2008 between positive and negative family history groups. Conclusions The positive family history of schizophrenia is strongly related to younger age of onset, and may predict a poorer long-term outcome (e.g., higher rate of homelessness) in persons with schizophrenia in the rural community. The findings have implications for further studies on specific family-related mechanisms on clinical treatment and rehabilitation, as well as for planning and delivering of community-based mental health services.

Purpose We describe the spectrum of acute neurological disorders among hospitalized patients who recently had COVID-19 mRNA vaccination. Method We performed a prospective study at 7 acute hospitals in Singapore. Hospitalized patients who were referred for neurological complaints and had COVID-19 mRNA vaccines, BNT162b2 and mRNA-1273, in the last 6 weeks were classified into central nervous system (CNS) syndromes, cerebrovascular disorders, peripheral nervous system (PNS) disorders, autonomic nervous system (ANS) disorders and immunization stress-related responses (ISRR). Results From 30 December 2020 to 20 April 2021, 1,398,074 persons (median age 59 years, 54.5% males) received COVID-19 mRNA vaccine (86.7% BNT162b2, 13.3% mRNA-1273); 915,344(65.5%) completed 2 doses. Four hundred and fifty-seven(0.03%) patients were referred for neurological complaints [median age 67(20–97) years, 281(61.5%) males; 95.8% received BNT162b2 and 4.2% mRNA-1273], classified into 73(16.0%) CNS syndromes, 286(62.6%) cerebrovascular disorders, 59(12.9%) PNS disorders, 0 ANS disorders and 39(8.5%) ISRRs. Eleven of 27 patients with cranial mononeuropathy had Bell's palsy. Of 33 patients with seizures, only 4 were unprovoked and occurred within 2 weeks of vaccination. All strokes occurred among individuals with pre-existing cardiovascular risk factors. We recorded 2 cases of cerebral venous thrombosis; none were vaccine-induced thrombotic thrombocytopenia. Five had mild flares of immune-mediated diseases. Conclusion Our observational study does not establish causality of the described disorders to vaccines. Though limited by the lack of baseline incidence data of several conditions, we observed no obvious signal of serious neurological morbidity associated with mRNA vaccination. The benefits of COVID-19 vaccination outweigh concerns over neurological adverse events.

It is unknown whether there are differences in self-stigma among persons with different types of severe mental illness (SMI) in rural communities.This study was to examine the differences of self-stigma and its correlates in persons with schizophrenia, major depressive disorder or bipolar disorder in a rural community in China.A total of 453 persons with schizophrenia, major depressive disorder or bipolar disorder in a rural community participated in the study. The Internalized Stigma of Mental Illness (ISMI) was used to measure self-stigma. The t-test and analyses of variance (ANOVA) were used to examine the differences in mean scores of ISMI and subscales among the three diagnoses. Logistic regression was used to explore the contributing factors to the level of self-stigma among the three groups.Self-stigma was moderate and severe with 94.7% of the total sample. Persons with schizophrenia had significantly higher mean scores of total ISMI, alienation and discrimination experience than those with bipolar disorders. Lower family income was significantly associated with higher levels of self-stigma in persons with schizophrenia and major depressive disorder. Factors predicting the level of self-stigma among the three groups were various.Self-stigma is common and severe in persons with schizophrenia, major depressive disorder and bipolar disorder, especially those with lower income status in rural community in China. Persons with schizophrenia may have higher levels of self-stigma than those with bipolar disorder. Individual-level interventions should be developed to reduce self-stigma among persons with SMI in Chinese rural communities.

Significance Implantable electrical probes have led to fundamental neuroscience advances and treatment of neurological diseases, yet are unable to stably track the long-term evolution of large numbers of individual neurons critical to brain functions. Here, we demonstrate a scalable scheme for highly multiplexed mesh electronics probes that overcomes this long-standing challenge. We illustrate this scheme through fabrication of 32 to 128 channel probes with macroporous neural network-like structure and flexibility comparable to the brain. Following implantation into rodent brains, we demonstrate chronic 128-channel recordings with single-neuron-level stability from multiple brain regions over 4 mo. These scalable mesh electronics probes represent an ideal platform for mapping, tracking, and modulating the single-neuron-level circuit changes associated with learning, aging, and neurodegenerative diseases., Implantable electrical probes have led to advances in neuroscience, brain−machine interfaces, and treatment of neurological diseases, yet they remain limited in several key aspects. Ideally, an electrical probe should be capable of recording from large numbers of neurons across multiple local circuits and, importantly, allow stable tracking of the evolution of these neurons over the entire course of study. Silicon probes based on microfabrication can yield large-scale, high-density recording but face challenges of chronic gliosis and instability due to mechanical and structural mismatch with the brain. Ultraflexible mesh electronics, on the other hand, have demonstrated negligible chronic immune response and stable long-term brain monitoring at single-neuron level, although, to date, it has been limited to 16 channels. Here, we present a scalable scheme for highly multiplexed mesh electronics probes to bridge the gap between scalability and flexibility, where 32 to 128 channels per probe were implemented while the crucial brain-like structure and mechanics were maintained. Combining this mesh design with multisite injection, we demonstrate stable 128-channel local field potential and single-unit recordings from multiple brain regions in awake restrained mice over 4 mo. In addition, the newly integrated mesh is used to validate stable chronic recordings in freely behaving mice. This scalable scheme for mesh electronics together with demonstrated long-term stability represent important progress toward the realization of ideal implantable electrical probes allowing for mapping and tracking single-neuron level circuit changes associated with learning, aging, and neurodegenerative diseases.

This paper discusses variations of laparoscopic transgastric cystogastrostomy in management of retrogastric pancreatic pseudocysts for 8 patients with symptom or pseudocysts (larger than 6 cm) companied with clinical manifestations. Using a Harmonic scalpel, two 3-5-cm incisions were made in the anterior and posterior gastric wall respectively. In the last step, the anterior gastrotomy was closed with an Endo-GIA stapler. All cases were successfully treated without large blood loss and without conversion to open surgery. The mean operative time was 114.29±19.24 min, blood loss was 157.14±78.70 mL, and mean hospital stay was 8.29±2.98 days. Gastric fistula occurred in one case on the postoperative day 7, and closed 1 month later. No bleeding was seen in all patients during the perioperative follow-up period. CT scans, given one month after the surgeries, displayed that the pancreatic pseudocysts disappeared or decreased in size, and ultrasounds showed no fluid or food residue in stomas at the third and fifth month following surgery. No patient experienced a recurrence during the follow-up period. Transgastric laparoscopic cystogastrostomy is a minimally invasive surgical procedure with a high rate of success and a low rate of recurrence, accompanied by rapid recovery. It is easy to master, safe to perform and may be the preferred option to treat retrogastric pancreatic pseudocysts.

To describe the spectrum of COVID-19 neurology in Singapore.We prospectively studied all microbiologically-confirmed COVID-19 patients in Singapore, who were referred for any neurological complaint within three months of COVID-19 onset. Neurological diagnoses and relationship to COVID-19 was made by consensus guided by contemporaneous literature, refined using recent case definitions.47,572 patients (median age 34 years, 98% males) were diagnosed with COVID-19 in Singapore between 19 March to 19 July 2020. We identified 90 patients (median age 38, 98.9% males) with neurological disorders; 39 with varying certainty of relationship to COVID-19 categorised as: i) Central nervous system syndromes-4 acute disseminated encephalomyelitis (ADEM) and encephalitis, ii) Cerebrovascular disorders-19 acute ischaemic stroke and transient ischaemic attack (AIS/TIA), 4 cerebral venous thrombosis (CVT), 2 intracerebral haemorrhage, iii) Peripheral nervous system-7 mono/polyneuropathies, and a novel group, iv) Autonomic nervous system-4 limited dysautonomic syndromes. Fifty-one other patients had pre/co-existent neurological conditions unrelated to COVID-19. Encephalitis/ADEM is delayed, occurring in critical COVID-19, while CVT and dysautonomia occurred relatively early, and largely in mild infections. AIS/TIA was variable in onset, occurring in patients with differing COVID-19 severity; remarkably 63.2% were asymptomatic. CVT was more frequent than expected and occurred in mild/asymptomatic patients. There were no neurological complications in all 81 paediatric COVID-19 cases.COVID-19 neurology has a wide spectrum of dysimmune-thrombotic disorders. We encountered relatively few neurological complications, probably because our outbreak involved largely young men with mild/asymptomatic COVID-19. It is also widely perceived that the pandemic did not unduly affect the Singapore healthcare system.

Background Maintaining gamma-aminobutyric acidergic (GABAergic) inhibition in the amygdala within a physiological range is critical for the appropriate expression of emotions such as fear and anxiety. The synaptic GABA type A receptor (GABA A R) is generally known to mediate the primary component of amygdala inhibition and prevent inappropriate expression of fear. However, little is known about the contribution of the extrasynaptic GABA A R to amygdala inhibition and fear. Methods By using mice expressing green fluorescent protein in interneurons (INs) and lacking the δ subunit-containing GABA A R (GABA A (δ)R), which is exclusively situated in the extrasynaptic membrane, we systematically investigated the role of GABA A (δ)R in regulating inhibition in the lateral amygdala (LA) and fear learning using the combined approaches of immunohistochemistry, electrophysiology, and behavior. Results In sharp contrast to the established role of synaptic GABA A R in mediating LA inhibition, we found that either pharmacological or physiological recruitment of GABA A (δ)R resulted in the weakening of GABAergic transmission onto projection neurons in LA while leaving the glutamatergic transmission unaltered, suggesting disinhibition by GABA A (δ)R. The disinhibition arose from IN-specific expression of GABA A (δ)R with its activation decreasing the input resistance of local INs and suppressing their activation. Genetic deletion of GABA A (δ)R attenuated its role in suppressing LA INs and disinhibiting LA. Importantly, the GABA A (δ)R facilitated long-term potentiation in sensory afferents to LA and permitted the expression of learned fear. Conclusions Our findings suggest that GABA A (δ)R serves as a brake rather than a mediator of GABAergic inhibition in LA. The disinhibition by GABA A (δ)R may help to prevent excessive suppression of amygdala activity and thus ensure the expression of emotion.

Background & Aims Aberrant estrogen receptor-α (ERα) expression and signaling are implicated in the development of hepatocellular carcinoma (HCC), but its regulation in HCC remains enigmatic. Herein, we aimed to identify a new mechanism by which ERα signaling is regulated in HCC, which may lead to a potential new strategy for HCC therapy. Methods Expression levels of Erbin and ERα in human HCC samples were evaluated by immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of Erbin and ERα signaling on HCC cell growth. Crosstalk between Erbin and ERα signaling was analyzed by molecular methods. Animal models of diethylnitrosamine (DEN) or DEN/CCl 4 -induced HCC in wild-type Erbin +/+ and mutant Erbin ΔC/ΔC mice were observed. The regulatory effects of Erbin on tamoxifen treatment of HCC were evaluated in vitro and in vivo . Results Erbin inactivated ERα signaling to drive tumorigenesis of HCC, acting to enhance binding of Chip to ERα via its interaction with ERα and thereby promoting ubiquitination and degradation of ERα. Deletion of the PDZ domain of Erbin in Erbin ΔC/ΔC mice, disrupted the interaction of Chip and ERα, increased the stability of ERα protein, and thus inhibited tumorigenesis of HCC. Silencing of Erbin effectively sensitized the response of HCC after tamoxifen treatment in vitro and in vivo . Conclusions Our data uncovered an important role of Erbin in regulating HCC tumorigenesis through inactivating ERα-mediated tumor-suppressive signaling, suggesting a new strategy for tamoxifen therapy in HCC by targeting Erbin/ERα signaling axis. Lay summary Erbin expression is significantly elevated in human hepatocellular carcinoma (HCC) tissue. This elevated expression of Erbin contributes to tumorigenesis of HCC by negatively regulating ERα signaling. However, restoring ERα signaling by inhibiting Erbin expression enhances the sensitivity of HCC cells to tamoxifen treatment, providing a new approach for tamoxifen treatment in HCC.

ERBB4, one member of the epidermal growth factor receptor (EGFR) family, plays a key role in physiological and pathological processes. Recently, we identified that ERBB4 played a protective role from chronic hepatitis B virus infection. However, the role of ERBB4 in hepatocellular carcinoma (HCC) is still unclear. Here, we explore the role of ERBB4 in the development of HCC using in vitro models, in vivo animal models and clinical samples of HCC. Liver-specific ERBB4 knockout alleles and full ERBB4 except heart knockout mice were used in this study. Liver inflammation and tumor models of mice were produced by carbon tetrachloride (CCl4) and diethylnitrosamine (DEN) administration, respectively. Commercial tissue arrays of 90 HCC patients with paired counterparts were used to evaluate the expression and the prognostic value of ERBB4. Genes altered in the setting of ERBB4 loss was studied by microarray analysis and further validated by real-time PCR. We have found that depletion of ERBB4 in mice leads to more severe injury and liver tumor formation and loss of ERBB4 contributes to the development of hepatocellular tumor. In clinic samples of HCC, ERBB4 is down-regulated and exhibit prognostic value of HCC patients. Mechanistically, loss of ERBB4 suppressed p53 expression by inhibiting the expression of the tumor suppressor tp53inp1. Our study uncovers ERBB4 as a suppressor in the development of HCC and implies an ERBB4-TP53INP1-P53 axis in HCC.

This study was performed to compare the treatment status between older (≥65 years) and younger adults (18-64 years) with severe mental illness (SMI) and explore factors associated with treatment status in rural China. Persons with SMI were identified in one mental health survey in 2015 in 6 townships of Xinjin County, Chengdu, China. Logistic regressions were conducted to explore factors associated with treatment status. Older adults with SMI, especially major depressive disorder, reported significantly lower rates of treatment than younger group. Older age, longer duration of illness, and poor mental status were risk factors for never-treated status in these patients. Never-treated status (46.3%) and poor treatment status in these older patients are serious issues. Different treatment statuses in these patients had various influencing factors. It is crucial to develop culture-specific, community-based mental health services to improve early identification, diagnosis, treatment, and recovery of older adults with SMI in rural China.

Rationale: Vertebral augmentation has become the main treatment for osteoporotic vertebral fractures (VFs). In this article, we report a very rare case of vertebral collapse and polymethylmethacrylate (PMMA) breakage after vertebroplasty. We describe the clinical characteristics and revision surgery performed to remove the broken PMMA cement, maintain stability, and corrects the kyphotic deformity, and we analyze the possible causes. Patient concerns: A 72-year-old man who suffered back pain underwent first lumbar vertebra (L1) percutaneous vertebroplasty (PVP) due to osteoporosis and a vertebral fracture in May 2013. Postoperatively, the patient's back pain was markedly alleviated. Unfortunately, his lumbar back pain recurred in November 2015. Diagnoses: Plain radiographs showed collapse of the L1 vertebral body, breakage of the PMMA cement, and severe kyphosis at the thoracolumbar junction. Interventions: The posterior pedicle was internally fixed and an anterior artificial vertebral body implant was placed to maintain stability and correct the kyphotic deformity in a 2-step surgical procedure. Outcomes: The back pain was alleviated and the patient returned to daily life for more than two years. Lessons: This case demonstrates that PVP is not a simple minimally invasive surgery, and significant postsurgical care is necessary. The true cause of this rare phenomenon remains unclear, but the long-term use of steroids, new injuries, and poorly corrected kyphosis after PVP may play a role. Surgeons must be aware of the kinds of complications that may occur, including rare complications such as vertebral lysis.

Background:Improving patients’ perception of social support is significant not only for their re-adaptation to life but also for alleviating caregivers’ burden.Aim:This study aims to examine an integrated model regarding social support, psychotic symptoms and caregiver burden.Methods:Persons with schizophrenia ( N1 = 300) and their family caregivers ( N2 = 300) in Xinjin County, Chengdu, China, completed the survey to report their demographics, patients’ perception of social support (Duke Social Support Index), psychotic symptoms (Positive and Negative Syndrome Scale) and caregiver burden (Burden Scale for Family Caregivers, Short Version). Structural equation modelling was utilised to test the proposed model.Results:The degree of caregiver burden differed significantly within subgroups of patients’ gender and education, as well as caregivers’ gender, education and employment. Caregiver burden was negatively related to patients’ age and household income. Social interaction partially mediated the relationship between instrumental and subjective social support (total effect = 0.451, p Conclusion:This study shows the associations of patients’ social support with psychotic symptoms and caregiver burden. Culture-specific psychosocial interventions should be provided for both patients and caregivers to enrich external support and reduce psychotic symptoms and caregivers’ burden within the health care environment.

Reperfusion therapy is currently the gold standard treatment for acute ischemic stroke. However, reperfusion injuries such as oedema and haemorrhagic transformation largely limit the use of this potent treatment to a narrow time window. Recently, transient receptor potential melastatin 4 (TRPM4) channel has emerged as a potential target for vascular protection in stroke management. Non-specificity and side effects are major concerns for current TRPM4 blockers. The present study was undertaken to develop a novel TRPM4 blocker for stroke management. We report the generation of a TRPM4-specific antibody M4P which binds to a region close to the channel pore. M4P could inhibit TRPM4 current and downregulate TRPM4 surface expression, therefore prevent hypoxia-induced cell swelling. In the rat model of 3-h stroke reperfusion, application of M4P at 2 h after occlusion ameliorated reperfusion injury by improving blood–brain barrier integrity, and enhanced functional recovery. Our results demonstrate that TRPM4 blockade could attenuate reperfusion injury in stroke recanalization. When applied together with reperfusion treatments, TRPM4 blocking antibody has the potential to extend the therapeutic time window for acute ischemic stroke. Electronic supplementary material The online version of this article (10.1007/s00424-019-02326-8) contains supplementary material, which is available to authorized users.

Background There is currently no research on the diagnostic value of metagenomic next-generation sequencing (mNGS) for a single pathogens in CSF. The aim of this study was to analyse the value of mNGS for identifying Streptococcus pneumoniae (S. pneumoniae) in paediatric bacterial meningitis. Methods Bacterial meningitis (BM) cases from October 23, 2014, to December 31, 2016, and December 1, 2017, to July 31, 2018 at Beijing Children’s Hospital were reviewed. Clinical features and pathogens were analysed. Results We diagnosed 135 patients with BM in this study. A total of 43 S. pneumoniae were identified by combination methods. 26/135 (19.3%) patients had positive results in S. pneumoniae by blood and/or cerebrospinal fluid (CSF) culture. Alere BinaxNow®Streptococcus pneumoniae Antigen test was positive in 35/135(25.9%) cases. 32/135 (23.7%) S. pneumoniae were identified by mNGS. Six CSF samples were identified as S. pneumoniae only by mNGS technology. Taking culture as the gold standard, the sensitivity and specificity of mNGS for diagnosing S. pneumoniae meningitis were 73.1 and 88.1%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) of diagnosing S. pneumoniae meningitis by mNGS were 59.4 and 93.2%, respectively. When comparison between mNGS and combined tests (culture and Alere BinaxNow®Streptococcus pneumoniae Antigen test), the sensitivity and specificity of mNGS for S. pneumoniae identification were 70.3 and 93.9%, the PPV and NPV in the identification of S. pneumoniae by mNGS were 81.4 and 89.3%, respectively. The difference in number of unique reads of S. pneumoniaein from CSF sample ( 14 days from onset) was statistically significant (170.5 VS. 13, P = 0.019). The difference in the collected time of CSF for culture and mNGS was statistically significant (4 days VS. 14 days, P

Background Health services research aimed at understanding service use and improving resource allocation often relies on collecting subjectively reported or proxy-reported healthcare service utilization (HSU) data. It is important to know the discrepancies in such self or proxy reports, as they have significant financial and policy implications. In high-dependency populations, such as stroke survivors, with varying levels of cognitive impairment and dysphasia, caregivers are often potential sources of stroke survivors’ HSU information. Most of the work conducted on agreement analysis to date has focused on validating different sources of self-reported data, with few studies exploring the validity of caregiver-reported data. Addressing this gap, our study aimed to quantify the agreement across the caregiver-reported and national claims-based HSU of stroke patients. Methods A prospective study comprising multi-ethnic stroke patient and caregiver dyads (N = 485) in Singapore was the basis of the current analysis, which used linked national claims records. Caregiver-reported health services data were collected via face-to-face and telephone interviews, and similar health services data were extracted from the national claims records. The main outcome variable was the modified intraclass correlation coefficient (ICC), which provided the level of agreement across both data sources. We further identified the amount of over- or under-reporting by caregivers across different service types. Results We observed variations in agreement for different health services, with agreement across caregiver reports and national claims records being the highest for outpatient visits (specialist and primary care), followed by hospitalizations and emergency department visits. Interestingly, caregivers over-reported hospitalizations by approximately 49% and under-reported specialist and primary care visits by approximately 20 to 30%. Conclusions The accuracy of the caregiver-reported HSU of stroke patients varies across different service types. Relatively more objective data sources, such as national claims records, should be considered as a first choice for quantifying health care usage before considering caregiver-reported usage. Caregiver-reported outpatient service use was relatively more accurate than inpatient service use over shorter recall periods. Therefore, in situations where objective data sources are limited, caregiver-reported outpatient information can be considered for low volumes of healthcare consumption, using an appropriate correction to account for potential under-reporting. Electronic supplementary material The online version of this article (10.1186/s12913-018-3634-4) contains supplementary material, which is available to authorized users.

The intestinal ischemia/reperfusion (I/R) injury is a common clinical event related with high mortality in patients undergoing surgery or trauma. Estrogen exerts salutary effect on intestinal I/R injury, but the receptor type is not totally understood. We aimed to identify whether the G protein–coupled estrogen receptor (GPER) could protect the intestine against I/R injury and explored the mechanism. Adult male C57BL/6 mice were subjected to intestinal I/R injury by clamping (45 min) of the superior mesenteric artery followed by 4 h of intestinal reperfusion. Our results revealed that the selective GPER blocker abolished the protective effect of estrogen on intestinal I/R injury. Selective GPER agonist G-1 significantly alleviated I/R-induced intestinal mucosal damage, neutrophil infiltration, up-regulation of TNF-α and cyclooxygenase-2 (Cox-2) expression, and restored impaired intestinal barrier function. G-1 could ameliorate the impaired crypt cell proliferation ability induced by I/R and restore the decrease in villus height and crypt depth. The up-regulation of inducible nitric oxide synthase (iNOS) expression after I/R treatment was attenuated by G-1 administration. Moreover, selective iNOS inhibitor had a similar effect with G-1 on promoting the proliferation of crypt cells in the intestinal I/R model. Both GPER and iNOS were expressed in leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) positive stem cells in crypt. Together, these findings demonstrate that GPER activation can prompt epithelial cell repair following intestinal injury, which occurred at least in part by inhibiting the iNOS expression in intestinal stem cells (ISCs). GPER may be a novel therapeutic target for intestinal I/R injury.

Background There has been increasing reports associating the coronavirus disease 2019 (COVID-19) with thromboembolic phenomenon including ischemic strokes and venous thromboembolism. Cerebral venous thrombosis (CVT) is a rare neurovascular emergency that has been observed in some COVID-19 patients, yet much remains to be learnt of its underlying pathophysiology. Objective We present a case series of local patients with concomitant COVID-19 infection and CVT; and aim to perform a systematic review of known cases in the current literature. Methods We describe two patients with concomitant COVID-19 infection and CVT from a nationwide registry in Singapore. We then conducted a literature search in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 11th June 2020. All studies reporting CVT in COVID-19 patients were included. Results Nine studies and 14 COVID-19 patients with CVT were studied. The median age was 43 years (IQR=36-58) and majority had no significant past medical conditions (60.0%). The time taken from onset of COVID-19 symptoms to CVT diagnosis was a median of 7 days (IQR=6-14). CVT was commonly seen in the transverse (75.0%) and sigmoid sinus (50.0%); 33.3% had involvement of the deep venous sinus system. A significant proportion of patients had raised D-dimer (75.0%) and CRP levels (50.0%). Two patients reported presence of antiphospholipid antibodies. Most patients received anticoagulation (91.7%) while overall mortality rate was 45.5%. Conclusions The high mortality rate of CVT in COVID-19 infection warrants a high index of suspicion from physicians, and early treatment with anticoagulation should be initiated.

// Yao Liu 1, 2, * , Qun Zhou 1, * , Xiao-Shun He 1 , Li-Ming Song 3 , Lin Chen 3 , Wei-Juan Jiao 1 , Tong Shen 1 , Su Yao 3 , Hua Wu 1 , Zhi-Bin Hu 2 , Tian-Ming Gao 4 , Jian-Ming Li 1, 3 1 Department of Pathology, Medical College of Soochow University, Suzhou 215123, People’s Republic of China 2 Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 211166, People’s Republic of China 3 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China 4 Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Jian-Ming Li, e-mail: jianmingli@suda.edu.cn Tian-Ming Gao, e-mail: tgao@fimmu.com Zhi-Bin Hu, e-mail: zhibin_hu@njmu.edu.cn Keywords: ERBB4, hepatitis B virus, polymorphism, inflammation Received: August 13, 2015 Accepted: December 05, 2015 Published: December 18, 2015 ABSTRACT Background: The role of ERBB4 in liver disease has seldom been reported. This study aims to find genetic markers at ERBB4 for chronic hepatitis B virus (HBV) infection and determine the role of ERBB4 in liver injury. Methods: We selected and genotyped three single nucleotide polymorphisms and one insertion/deletion (Ins/Del) at the 5' and 3’ untranslated region (UTR) of ERBB4 in a case-control study including 1344 pairs of HBV carriers and HBV natural clearance subjects. The luciferase reporter system was applied to study the regulative role of Ins/Del on ERBB4. Further, ERBB4 knockout mice were used to study the role of ERBB4 in liver injury. Proteomic quantification was performed by HPLC-MS/MS analysis to identify liver protein profile change between liver-specific ERBB4 knockout and control mice. Results: rs6147150 Ins/Del and rs1836724 T>C at the 3’ UTR of ERBB4 were associated with reduced risk of chronic HBV infection ( P = 0.002 and 0.004, respectively). Besides, the 12bp deletion at the 3’ UTR increased ERBB4 expression due to lacking let-7c binding site. In addition, loss of ERBB4 led to more severe acute or chronic inflammation in mouse liver injury models. Further, quantitative proteomic analysis and data from the cancer genome atlas revealed that ACLY, an enzyme key for de novo lipogenesis, was negatively correlated with ERBB4. Conclusions: ERBB4 plays protective role from liver injury and its 3'UTR genetic variants could be genetic markers for chronic HBV infection.

IntroductionPreliminary evidence from clinical observations suggests that Tai Chi exercise may offer potential benefits for patients with chronic coronary syndrom (CCS). However, the advantages for CCS patients to practice Tai Chi exercise as rehabilitation have not been rigorously tested and there is a lack of consensus on its benefits. This study aims to develop an innovative Tai Chi Cardiac Rehabilitation Program (TCCRP) for CCS patients and to assess the efficacy, safety and acceptability of the programme.Methods and analysisWe propose to conduct a multicentre randomised controlled clinical trial comprising of 150 participants with CCS. The patients will be randomly assigned in a 1:1 ratio into two groups. The intervention group will participate in a supervised TCCRP held three times a week for 3 months. The control group will receive supervised conventional exercise rehabilitation held three times a week for 3 months. The primary and secondary outcomes will be assessed at baseline, 1 month, 3 months after intervention and after an additional 3-month follow-up period. Primary outcome measures will include a score of 36-Item Short Form Survey and Chinese Perceived Stress Scale. The secondary outcome measures will include body composition, cardiopulmonary exercise test, respiratory muscle function, locomotor skills, echocardiogram, New York Heart Association classification, heart rate recovery time and laboratory examination. Other measures also include Seattle Angina Scale, Pittsburgh Sleep Quality Index, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 and Berg Balance Scale. All adverse events will be recorded and analysed.Ethics and disseminationThis study conforms to the principles of the Declaration of Helsinki and relevant ethical guidelines. Ethical approval has been obtained from the Ethics Committee of Chinese People’s Libration Army General Hospital (approval number: S2019-060-02). Findings from this study will be published and presented at conferences for widespread dissemination of the results.Trial registration numberNCT03936504.

ObjectiveTo study the association of caregiver factors and stroke survivor factors with supervised community rehabilitation (SCR) participation over the first 3 months and subsequent 3 to 12 months post-stroke in an Asian setting.DesignProspective cohort study.SettingCommunity setting.ParticipantsWe recruited stroke survivors and their caregivers into our yearlong cohort. Caregiver and stroke survivor variables were collected over 3-monthly intervals. We performed logistic regression with the outcome variable being SCR participation post-stroke.Outcome measuresSCR participation over the first 3 months and subsequent 3 to 12 months post-strokeResults251 stroke survivor-caregiver dyads were available for the current analysis. The mean age of caregivers was 50.1 years, with the majority being female, married and co-residing with the stroke survivor. There were 61%, 28%, 4% and 7% of spousal, adult-child, sibling and other caregivers. The odds of SCR participation decreased by about 15% for every unit increase in caregiver-reported stroke survivor’s disruptive behaviour score (OR: 0.845; 95% CI: 0.769 to 0.929). For every 1-unit increase in the caregiver’s positive management strategy score, the odds of using SCR service increased by about 4% (OR: 1.039; 95% CI: 1.011 to 1.068).ConclusionWe established that SCR participation is jointly determined by both caregiver and stroke survivor factors, with factors varying over the early and late post-stroke period. Our results support the adoption of a dyadic or more inclusive approach for studying the utilisation of community rehabilitation services, giving due consideration to both the stroke survivors and their caregivers. Adopting a stroke survivor-caregiver dyadic approach in practice settings should include promotion of positive care management strategies, comprehensive caregiving training including both physical and behavioural dimensions, active engagement of caregivers in rehabilitation journey and conducting regular caregiver needs assessments in the community.

erbb4 is a known susceptibility gene for schizophrenia. Chandelier cells (ChCs, also known as axo-axonic cells) are a distinct GABAergic interneuron subtype that exclusively target the axonal initial segment, which is the site of pyramidal neuron action potential initiation. ChCs are a source of ErbB4 expression and alterations in ChC-pyramidal neuron connectivity occur in the medial prefrontal cortex (mPFC) of schizophrenic patients and animal models of schizophrenia. However, the contribution of ErbB4 in mPFC ChCs to the pathogenesis of schizophrenia remains unknown. By conditional deletion or knockdown of ErbB4 from mPFC ChCs, we demonstrated that ErbB4 deficits led to impaired ChC-pyramidal neuron connections and cognitive dysfunctions. Furthermore, the cognitive dysfunctions were normalized by L-838417, an agonist of GABAAα2 receptors enriched in the axonal initial segment. Given that cognitive dysfunctions are a core symptom of schizophrenia, our results may provide a new perspective for understanding the etiology of schizophrenia and suggest that GABAAα2 receptors may be potential pharmacological targets for its treatment.

As an important application of functional biomaterials, neural probes have contributed substantially to studying the brain. Bioinspired and biomimetic strategies have begun to be applied to the development of neural probes, although these and previous generations of probes have had structural and mechanical dissimilarities from their neuron targets that lead to neuronal loss, neuroinflammatory responses and measurement instabilities. Here, we present a bioinspired design for neural probes—neuron-like electronics (NeuE)—where the key building blocks mimic the subcellular structural features and mechanical properties of neurons. Full three-dimensional mapping of implanted NeuE–brain interfaces highlights the structural indistinguishability and intimate interpenetration of NeuE and neurons. Time-dependent histology and electrophysiology studies further reveal a structurally and functionally stable interface with the neuronal and glial networks shortly following implantation, thus opening opportunities for next-generation brain–machine interfaces. Finally, the NeuE subcellular structural features are shown to facilitate migration of endogenous neural progenitor cells, thus holding promise as an electrically active platform for transplantation-free regenerative medicine. Neural probes mimicking the size and mechanical properties of neurons interpenetrate the brain tissue, allowing stable single-unit recordings from implantation up to at least three months, and acting as scaffolds for the migration of new-born neurons.

The aim of this study was to evaluate the safety and efficacy of percutaneous vertebroplasty (PVP) in Kambin triangle approach for the treatment of osteoporotic vertebral compression fractures (OVCFs). Between November 2017 and September 2018, 109 patients (144 vertebral bodies) with OVCFs, with a mean age of 76.7 ± 9.9 years (55–96 years), underwent PVP in Kambin triangle approach. The time of operation, the volume of bone cement, the incidence of complication, the Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) score, the position of puncture needles, and the spread of polymethylmethacrylate (PMMA) in vertebral body (VB) were recorded. All patients had been completed the operation successfully and were followed up 9.1 ± 2.9 months. The average operation time of each VB was 24.0 ± 3.5 minutes. The average volume of cement was 4.8 ± 0.6 ml. The mean VAS scores were 8.4 ± 0.7 preoperatively, 1.6 ± 0.6 at the first day postoperatively, and 1.2 ± 0.6 at the last follow-up. The mean ODI scores were 70.97 ± 7.73 preoperatively, 27.99 ± 4.12 at the first day postoperatively, and 19.65 ± 3.49 at the last follow-up. The position of puncture needles in the VB was: 119 vertebral puncture needles reached the midline, 15 were close to the midline, and 10 exceeded the midline. The spread of PMMA in the VB was: type 1 in 81 levels (56.3%), type 2 in 37 (25.7%), type 3 in 18 (12.5%), type 5 in 8 (5.5%), and no case in type 4. One case developed pneumothorax after operation. No other complications (hematoma, cement embolism, spinal cord, and nerve injury) occurred. Kambin triangle approach in PVP, which can deliver the puncture needle to the midline of VB easily and with excellent cement distribution, is a safe and effective method.

To evaluate the safety, efficacy and tolerability of China-made sildenafil citrate (Jinge) in the treatment of ED.We conducted a multi-center, randomized, double-blind and placebo-controlled clinical trial among 222 ED patients in five urological or andrological clinics of China. The patients were randomly assigned to receive sildenafil citrate (SC, n = 111) or placebo (n = 111) for 8 weeks. We obtained and analyzed the demographic and clinical characteristics of the patients, the scores of International Index of Erectile Function (IIEF), the success rate of sexual intercourse, and the incidence of adverse events.No statistically significant differences were found between the patients of the SC and those of the placebo group in the mean age (［47.2±11.32］ yr vs ［46.67±13.08］ yr, P0.05), psychological etiology (27.93% vs 23.42%, P0.05), organic etiology (21.62% vs 29.73%, P0.05) or mixed etiology (50.45% vs 46.85%, P0.05), nor in height, weight, nationality, or history of smoking, drinking or allergy. Compared with the placebo controls, the SC-treated patients showed significant increases in the excellence rate of effectiveness (29.91% vs 78.90%, P0.01), success rate of sexual intercourse (29.16% vs 63.87%, P0.01), and total effectiveness rate (34.58% vs 77.98%, P0.01). The effectiveness rates on organic, psychogenic and mixed types ED were remarkably higher in the SC group (64.52%, 83.33%, and 82.14%) than in the placebo control (46.15%, 21.21%, and 25.00%) (P0.01). Mild or temporary adverse events were observed in 32 cases in the SC group as compared with 13 in the placebo control.China-made sildenafil citrate is an effective, safe and well-tolerated drug for ED of different etiologies in the Chinese population.目的: 评价国产枸橼酸西地那非（金戈）治疗男性勃起功能障碍（ED）的安全性、有效性和耐受性。方法： 采用多中心、随机、双盲、安慰剂对照研究方法 ，在国内5家医院泌尿外科或男科门诊纳入222例ED患者，随机分为西地那非组（111例）和安慰剂组（111例），进行为期8周的临床治疗观察。以国际勃起功能问卷（ IIEF）评分、性交成功率作为有效性评价指标，以不良事件发生率作为安全性评价指标。结果： 西地那非组和安慰剂组患者年龄分别为（47.20±11.32）岁和（ 46.67±13.08）岁（P0.05），ED病因分别为心理性（27.93% vs 23.42%）、器质性（21.62% vs 29.73%）和混合性ED（50.45% vs 46.85%）(P均0.05) ，其他流行病学数据如身高、体重、民族、吸烟、饮酒、药物过敏史等一般情况也均无统计学差异。对主要疗效指标的分析结果显示，西地那非组与安慰剂组对勃起 功能显著有效率分别为78.90%和29.91%（P0.01)；西地那非组性交成功率和总体疗效分别为63.87%和77.98%，均明显高于安慰剂组的29.16%和34.58%（P均0.01)。在对于不同种类ED的治疗上，西地那非对心理性、器质性和混合性ED的有效率分别为64.52%、83.33%和82.14%，明显高于安慰剂组的46.15%、21.21%和 25.00%（P均0.01)。安全性评价结果显示，共有45例（20.27%）受试者出现了各种不良事件（西地那非组有32例，安慰剂组有13例），所出现的不良事件大多数 为轻度、一过性的。结论： 国产枸橼酸西地那非是一种可治疗各种病因导致ED的安全有效的药物，且患者耐受性较好。.

Obese patients are more likely to encounter with difficult airway management, and supraglottic airway device has been adopted to facilitate tracheal intubation. The optimum anesthetic concentration for obese patients to insert a supraglottic airway device with spontaneous respiration has not been investigated. This study was designed to determine the end-tidal concentration of sevoflurane that would provide acceptable condition for supraglottic airway device insertion with propofol at induction in obese patients without using neuromuscular blockade. Thirty elective obese patients [body mass index (BMI) 30–50 kg/m2] scheduled for bariatric surgery were enrolled in this study. Sevoflurane was inhaled at a concentration of 5% after infusion of 1 mg/kg propofol (within 1 minute) according to lean body weight. The target concentration of sevoflurane was initiated at 2.5% with 0.5% as a step size using a modified Dixon up-and-down method. Five minutes after target concentration achieved, the insertion of supraglottic airway device was attempted. The minimum alveolar concentration of sevoflurane for successful insertion of supraglottic airway device calculated using up-and-down method were 2.25 (0.53) % for obese patients. The values of the effective concentration of sevoflurane for successful supraglottic airway device insertion in 50% (EC50) and 95% (EC95) of the obese patients obtained by probit regression analysis were 2.09% (95% confidence interval 1.48–2.68) and 3.31% (95% confidence interval 2.70–8.12), respectively. We conclude that sevoflurane at a minimum alveolar concentration of 2.25% can provide optimal conditions for insertion of supraglottic airway device with spontaneous respiration in obese patients with 1 mg/kg propofol at induction.

Diabetes mellitus (DM) is an important risk factor for increased vein graft failure after bypass surgery. The neuregulin-1 (NRG-1)/ErbB signaling system plays a critical role in neointimal formation after vascular injury as well as the proliferation and migration of mitogen-induced vascular smooth muscle cells; however, changes in NRG-1/ErbB signaling leading to vein grafts attrition in DM remain largely unexplored. Therefore, the aim of this study was to investigate changes in NRG-1/ErbB signaling in vein grafts in diabetic rats. To do this, a rat model of DM was established by streptozotocin injection followed by engraftment of autologous jugular veins to carotid arteries to induce intimal hyperplasia. After vein graft harvest, a pathohistological examination was performed; changes in NRG-1 and ErbB expression were also assessed. NRG-1 and ErbB expression localized to endothelial cells and vascular smooth muscle cells, which is consistent with the arterialization of vein grafts. NRG-1, ErbB2, and ErbB4 expression significantly decreased in vein grafts over time. Our findings show that NRG-1/ErbB signaling is impaired in vein grafts of diabetic rats, suggesting an important role for this pathway in the pathogenesis of intimal hyperplastic lesions in vein grafts of patients with DM.

Anxiety disorder is related to the pathophysiology of psychiatric diseases, including major depression, substance abuse, and schizophrenia. The amygdala is important for manifestation and modulation of anxiety. However, relatively little is known regarding the mechanisms that control the amygdala inhibitory activity that is involved in anxiety. We found that almost all ErbB4, which is the only autonomous receptor of neuregulin 1 (NRG1) in the basolateral amygdala (BLA), was expressed in GABAergic neurons. Endogenous NRG1-ErbB4 signaling pathway in the BLA could modulate anxiety-like behaviors and GABA release, whereas it had no effect on glutamatergic transmission. The administration of NRG1 into the BLA of high-anxiety mice alleviated their anxiety and enhanced GABAergic neurotransmission. Moreover, exogenous NRG1 also produced an anxiolytic effect in the stressed mice. Together, these observations indicated that NRG1-ErbB4 signaling is critical to maintaining GABAergic activity in the amygdala and thus to modulating anxiety-like behaviors. Because NRG1 and ErbB4 are susceptibility genes of schizophrenia, our findings might also help to explain the potential mechanism of emotional abnormality in schizophrenia.

Introduction: Although pneumonia is a major complication after acute ischaemic stroke (AIS), pneumonia prediction scores have not been extensively validated. This study aimed to compare the discrimination performance of 5 pneumonia prediction scores in AIS patients. Materials and Methods: We retrospectively reviewed all consecutive adult AIS patients whom presented to our emergency department within 4.5 hours of symptom-onset between January 2012 and February 2015. Diagnosis had to be made by a neurologist and infarcts confirmed by neuroimaging. We excluded patients with pneumonia on presentation. Pneumonia predictors were based on the 5 prediction scoring models: Kwon’s score, Chumbler’s score, Acute Ischaemic Stroke-Associated Pneumonia Score (AIS-APS), A2DS2 score and ISAN score. The definition of stroke-associated pneumonia was based on the criteria by the Pneumonia in Stroke Consensus Group. Analysis using area under receiver operating characteristics curve (AUROC) was performed. Results: Forty (5.5%) out of 731 patients analysed had stroke-associated pneumonia (SAP). A2DS2 score had the highest discrimination capacity (AUROC 0.88; 95% CI, 0.84 to 0.92), followed by AIS-APS (AUROC 0.87; 95% CI, 0.83 to 0.91), Kwon’s score (AUROC 0.86; 95% CI, 0.82 to 0.92), Prestroke Independence, Sex, Age and National Institutes of Health Stroke Scale (ISAN) score (AUROC 0.85; 95% CI, 0.80 to 0.90) and Chumbler’s score (AUROC 0.79; 95% CI, 0.74 to 0.84). However, there was no statistical difference of discrimination capacity among A2DS2 score, AIS-APS and Kwon’s score. Conclusion: A2DS2, AIS-APS and Kwon’s scores performed comparably in discriminating SAP in AIS patients. Key words: Prognosis, Epidemiology, Retrospective studies, Validation, Singapore, Brain ischaemia/complications

Implantation of electrical probes into the brain has been central to both neuroscience research and biomedical applications, although conventional probes induce gliosis in surrounding tissue. We recently reported ultraflexible open mesh electronics implanted into rodent brains by syringe injection that exhibit promising chronic tissue response and recording stability. Here we report time-dependent histology studies of the mesh electronics/brain-tissue interface obtained from sections perpendicular and parallel to probe long axis, as well as studies of conventional flexible thin-film probes. Confocal fluorescence microscopy images of the perpendicular and parallel brain slices containing mesh electronics showed that the distribution of astrocytes, microglia, and neurons became uniform from 2-12 wk, whereas flexible thin-film probes yield a marked accumulation of astrocytes and microglia and decrease of neurons for the same period. Quantitative analyses of 4- and 12-wk data showed that the signals for neurons, axons, astrocytes, and microglia are nearly the same from the mesh electronics surface to the baseline far from the probes, in contrast to flexible polymer probes, which show decreases in neuron and increases in astrocyte and microglia signals. Notably, images of sagittal brain slices containing nearly the entire mesh electronics probe showed that the tissue interface was uniform and neurons and neurofilaments penetrated through the mesh by 3 mo postimplantation. The minimal immune response and seamless interface with brain tissue postimplantation achieved by ultraflexible open mesh electronics probes provide substantial advantages and could enable a wide range of opportunities for in vivo chronic recording and modulation of brain activity in the future.

Cryptococcosis is a rare pediatric disease. The aim of the study is to describe clinical characteristics and prognosis of pediatric cryptococcosis from 2002 to 2014 in Beijing Children's Hospital. A total of 53 cases of cryptococcosis were identified, 69.8% of which were males. The mean age was 7 years. Forty-one (77.4%) patients had no underlying conditions. Fever, headache, and vomiting were the most common symptoms. The most common sites were the central nervous system (CNS), followed by the lungs. Most patients received a combination of amphotericin B and fluconazole with or without flucytosine as their initial regimen. Twenty-seven patients received a follow-up and six patients (22.2%) had died. The factors associated with neurological complications or death were headache (P = 0.008), seizures (P = 0.006), visual impairment (P = 0.011), neck stiffness (P = 0.008), low erythrocyte sedimentation rate (ESR) (P = 0.024), and a cerebral spinal fluid (CSF) cryptococcal antigen titer ≥ 1:1024 (P = 0.038).The majority of cryptococcosis cases in China occurred in children without underlying conditions, causing multiple organ damage. The CNS was the most common site. Patients who had headaches, seizures, or high CSF antigen titers experienced neurological complications or died. What is known: • Cryptococcosis is a rare cause of infection in children. What is new: • This review gives a brief overview over pediatric cryptococcosis in China.

Soluble epoxide hydrolase (sEH) inhibition has been demonstrated to have beneficial effects on various diseases, such as hypertension, diabetes, and brain ischemia. However, whether sEH inhibition has therapeutic potential in Parkinson's disease is still unknown. In this paper, we found that sEH expression is increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-treated mice, and sEH deficiency and inhibition significantly attenuated tyrosine hydroxylase (TH)-positive cell loss and improved rotarod performance. The substrate of sEH, 14,15-epoxyeicosatrienoic acid (14,15-EET), protected TH-positive cells and alleviated the rotarod performance deficits of wild-type mice but not sEH-knockout mice. Moreover, the 14,15-EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) abolished the neuronal protective effects of sEH deficiency. In primary cultured cortical neurons, MPP(+) induced significant Akt inactivation in neurons from sEH wild-type mice, and this effect was not observed in neurons from knockout mice. Our data indicate that sEH deficiency and inhibition increased 14,15-EET in MPTP-treated mice, which activated the Akt-mediated protection of TH-positive neurons and behavioral functioning. We also found that sEH deficiency attenuated TH-positive cell loss in a paraquat-induced mouse model of Parkinson's. Our data suggest that sEH inhibition might be a powerful tool to protect dopaminergic neurons in Parkinson's disease.