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Background: Previous findings have revealed that disorders of lipid metabolism may be a risk factor for pulmonary function damage; however, the combined effect of dyslipidemia and central obesity on pulmonary function is unclear. The cardiometabolic index (CMI) is a composite of serum lipids (triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C)) and visceral fat parameters (waist-to-height ratio (WHtR)). This research aimed to investigate the link between CMI and pulmonary function, employing large-scale demographic data sourced from the National Health and Nutrition Examination Survey (NHANES) database., Methods: This cross-sectional study used data involving 4125 adults aged 20 and above collected by NHANES between 2007 and 2012. We defined CMI as the exposure variable and measured outcomes using forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC to evaluate pulmonary function. Weighted multiple linear regression models and subgroup analyses were employed to investigate separate relationships between CMI and pulmonary function. In addition, to investigate variations across different strata and evaluate the robustness of the findings, interaction tests and sensitivity analyses were conducted., Results: Results from the weighted multiple linear regression analysis indicated a unit increase in log2-CMI was associated with a reduction of 82.63 mL in FEV1 and 112.92 mL in FVC. The negative association remained significant after transforming log2-CMI by quartile (Q). When the log2-CMI level reached Q4, β coefficients (β) were -128.49 (95% CI: -205.85, -51.13), -169.01 (95% CI: -266.72, -71.30), respectively. According to the interaction test findings, the negative association linking log2-CMI with FEV1 and FVC persists regardless of confounding factors including age, gender, BMI, physical activity (PA), and smoking status. A subsequent sensitivity analysis provided additional confirmation of the stability and reliability of the results. For females, the inflection points for the nonlinear relationships between log2-CMI and FEV1, as well as log2-CMI and FVC, were identified at 2.33 and 2.11, respectively. While in males, a consistent negative association was observed., Conclusions: Our findings suggest that higher CMI is associated with lower FEV1 and FVC. CMI may serve as a complementary consideration to the assessment and management of pulmonary function in clinical practice., (© 2024. The Author(s).)

Background and Purpose: Intestinal inflammation and gut microbiota dysbiosis contribute to Parkinson disease (PD) pathogenesis, and growing evidence suggests associations between inflammatory bowel diseases (IBD) and PD. Considered as markers of chronic gastrointestinal inflammation, elevated serum anti-Saccharomyces cerevisiae antibody (ASCA) levels, against certain gut fungal components, are related to IBD, but their effect on PD is yet to be investigated., Methods: Serum ASCA IgG and IgA levels were measured using an enzyme-linked immunosorbent assay, and the gut mycobiota communities were investigated using ITS2 sequencing and analyzed using the Qiime pipeline., Results: The study included 393 subjects (148 healthy controls [HCs], 140 with PD, and 105 with essential tremor [ET]). Both serum ASCA IgG and IgA levels were significantly higher in the PD group than in the ET and HC groups. Combining serum ASCA levels and the occurrence of constipation could discriminate patients with PD from controls (area under the curve [AUC] = 0.81, 95% confidence interval [CI] = 0.76-0.86) and from patients with ET (AUC = 0.85, 95% CI = 0.79-0.89). Furthermore, the composition of the gut fungal community differed between the PD and HC groups. The relative abundances of Saccharomyces cerevisiae, Aspergillus, Candida solani, Aspergillus flavus, ASV601_Fungi, ASV866_Fungi, and ASV755_Fungi were significantly higher in the PD group, and enriched Malassezia restricta was found in the HC group., Conclusions: Our study identified elevated serum ASCA levels and enriched gut Saccharomyces cerevisiae in de novo PD., (© 2023 European Academy of Neurology.)

Objectives: Hepatocellular carcinoma (HCC) is a common indication for hepatectomy that is often complicated by postoperative complication. The authors sought to investigate the relationship between the open with laparoscopic approach of hepatectomy and incidences of postoperative infectious complications., Patients and Methods: Using a multicenter database, HCC patients who underwent laparoscopic hepatectomy (LH) or open hepatectomy (OH) were reviewed and analyzed. Propensity score matching (PSM), inverse probability of treatment weight (IPTW), and multivariate logistic regression analyses were utilized to assess the association of the operative approach with postoperative infectious complications, including incisional surgical site infection (SSI), organ/space SSI, and remote infection (RI)., Results: Among 3876 patients, 845 (21.8%) and 3031 (78.2%) patients underwent LH and OH, respectively. The overall incidence of infection was 6.9 versus 14.6% among patients who underwent LH versus OH, respectively ( P <0.001). Of note, the incidences of incisional SSI (1.8 vs. 6.3%, P <0.001), organ/space SSI (1.8 vs. 4.6%, P <0.001), and RI (3.8 vs. 9.8%, P <0.001) were all significantly lower among patients who underwent LH versus OH. After PSM (6.9, 1.8, 1.8, and 3.8% vs. 18.5, 8.4, 5.2, and 12.8%, respectively) and IPTW (9.5, 2.3, 2.1, and 5.5% vs. 14.3, 6.3, 4.5, and 9.8%, respectively), LH remained associated with statistically lower incidences of all types of infectious complications. After adjustment for other confounding factors on multivariate analyses, LH remained independently associated with lower incidences of overall infection, incisional SSI, organ/space SSI, and RI in the overall, PSM, and IPTW cohorts, respectively., Conclusion: Compared with open approach, laparoscopic approach was independently associated with lower incidences of postoperative infectious complications following hepatectomy for HCC., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Peripheral immune cells play a vital role in the development of Parkinson's disease (PD). However, their cytokine and chemokine secretion functions remain unclear. Therefore, we aimed to explore the cytokine and chemokine secretion functions of specific immune cell subtypes in drug-naïve patients with PD at different ages of onset. We included 10 early-onset and 10 late-onset patients with PD and age-matched healthy controls (HCs). We used mass cytometry to select specific immune cell subsets and evaluate intracellular cytokine and chemokine expression. Statistical tests included t-tests, analysis of variance, bivariate correlation analysis, and linear regression analysis. Compared with HCs, patients with PD exhibited significantly decreased intracellular pro-inflammatory cytokines and chemokines in selected clusters (e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-1β, and CC-chemokine ligand (CCL)17). Specific cytokines and cell clusters were associated with clinical symptoms. TNF-α played an important role in cognitive impairment. Intracellular TNF-α levels in the naïve CD8 + T-cell cluster C16 (CD57 - naïve CD8 + T) and natural killer (NK) cell cluster C32 (CD57 - CD28 - NK) were negatively correlated with Montreal Cognitive Assessment scores. The C16 cluster affected cognitive function and motor symptoms. Increased TNF-α and decreased interferon-γ expression in C16 correlated with increased Unified Parkinson's Disease Rating Scale III scores in patients with PD. In summary, we developed a more detailed cytokine and chemokine map of peripheral specific CD8 + T cell and NK cell subsets, which revealed disrupted secretory function in patients with PD and provided unique clues for further mechanistic exploration., (© 2023. The Author(s).)

Microglial hyperactivation of the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome contributes to the pathogenesis of Parkinson's disease (PD). Recently, neuronally expressed NLRP3 was demonstrated to be a Parkin polyubiquitination substrate and a driver of neurodegeneration in PD. However, the role of Parkin in NLRP3 inflammasome activation in microglia remains unclear. Thus, we aimed to investigate whether Parkin regulates NLRP3 in microglia. We investigated the role of Parkin in NLRP3 inflammasome activation through the overexpression of Parkin in BV2 microglial cells and knockout of Parkin in primary microglia after lipopolysaccharide (LPS) treatment. Immunoprecipitation experiments were conducted to quantify the ubiquitination levels of NLRP3 under various conditions and to assess the interaction between Parkin and NLRP3. In vivo experiments were conducted by administering intraperitoneal injections of LPS in wild-type and Parkin knockout mice. The Rotarod test, pole test, and open field test were performed to evaluate motor functions. Immunofluorescence was performed for pathological detection of key proteins. Overexpression of Parkin mediated NLRP3 degradation via K48-linked polyubiquitination in microglia. The loss of Parkin activity in LPS-induced mice resulted in excessive microglial NLRP3 inflammasome assembly, facilitating motor impairment, and dopaminergic neuron loss in the substantia nigra. Accelerating Parkin-induced NLRP3 degradation by administration of a heat shock protein (HSP90) inhibitor reduced the inflammatory response. Parkin regulates microglial NLRP3 inflammasome activation through polyubiquitination and alleviates neurodegeneration in PD. These results suggest that targeting Parkin-mediated microglial NLRP3 inflammasome activity could be a potential therapeutic strategy for PD., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

DNA damage and defective DNA repair are extensively linked to neurodegeneration in Parkinson's disease (PD), but the underlying molecular mechanisms remain poorly understood. Here, we determined that the PD-associated protein DJ-1 plays an essential role in modulating DNA double-strand break (DSB) repair. Specifically, DJ-1 is a DNA damage response (DDR) protein that can be recruited to DNA damage sites, where it promotes DSB repair through both homologous recombination and nonhomologous end joining. Mechanistically, DJ-1 interacts directly with PARP1, a nuclear enzyme essential for genomic stability, and stimulates its enzymatic activity during DNA repair. Importantly, cells from PD patients with the DJ-1 mutation also have defective PARP1 activity and impaired repair of DSBs. In summary, our findings uncover a novel function of nuclear DJ-1 in DNA repair and genome stability maintenance, and suggest that defective DNA repair may contribute to the pathogenesis of PD linked to DJ-1 mutations.

Multiple single nucleotide polymorphisms may contribute to cognitive decline in Parkinson's disease. However, the mechanism by which these single nucleotide polymorphisms modify brain imaging phenotype remains unclear. The aim of this study was to investigate the potential effects of multiple single nucleotide polymorphisms on brain imaging phenotype in Parkinson's disease. Forty-eight Parkinson's disease patients and 39 matched healthy controls underwent genotyping and 7T magnetic resonance imaging. A cognitive-weighted polygenic risk score model was designed, in which the effect sizes were determined individually for 36 single nucleotide polymorphisms. The correlations between polygenic risk score, neuroimaging features, and clinical data were analyzed. Furthermore, individual single nucleotide polymorphism analysis was performed to explore the main effects of genotypes and their interactive effects with Parkinson's disease diagnosis. We found that, in Parkinson's disease, the polygenic risk score was correlated with the neural activity of the hippocampus, parahippocampus, and fusiform gyrus, and with hippocampal-prefrontal and fusiform-temporal connectivity, as well as with gray matter alterations in the orbitofrontal cortex. In addition, we found that single nucleotide polymorphisms in α-synuclein (SNCA) were associated with white matter microstructural changes in the superior corona radiata, corpus callosum, and external capsule. A single nucleotide polymorphism in catechol-O-methyltransferase was associated with the neural activities of the lingual, fusiform, and occipital gyri, which are involved in visual cognitive dysfunction. Furthermore, DRD3 was associated with frontal and temporal lobe function and structure. In conclusion, imaging genetics is useful for providing a better understanding of the genetic pathways involved in the pathophysiologic processes underlying Parkinson's disease. This study provides evidence of an association between genetic factors, cognitive functions, and multi-modality neuroimaging biomarkers in Parkinson's disease., Competing Interests: None

Parkinson's disease (PD) is the second most common neurodegenerative disease around the world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in the pathophysiology of PD. There is growing evidence suggesting that DNA damage is involved in the propagation of cellular damage in PD, leading to neuropathology under different conditions. Here, we reviewed the current work on DNA damage repair in PD. First, we outlined the evidence and causes of DNA damage in PD. Second, we described the potential pathways by which DNA damage mediates neurotoxicity in PD and discussed the precise mechanisms that drive these processes by DNA damage. In addition, we looked ahead to the potential interventions targeting DNA damage and repair. Finally, based on the current status of research, key problems that need to be addressed in future research were proposed.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease with a significant public health burden. It is characterized by the gradual degeneration of dopamine neurons in the central nervous system. Although symptomatic pharmacological management remains the primary therapeutic method for PD, clinical experience reveals significant inter-individual heterogeneity in treatment effectiveness and adverse medication responses. The mechanisms behind the observed interindividual variability may be elucidated by investigating the role of genetic variation in human-to-human variances in medication responses and adverse effects., Objective: This review aims to explore the impact of gene polymorphism on the efficacy of antiparkinsonian drugs. The identification of factors associated with treatment effectiveness variability might assist the creation of a more tailored pharmacological therapy with higher efficacy, fewer side outcomes, and cheaper costs., Methods: In this review, we conducted a thorough search in databases such as PubMed, Web of Science, and Google Scholar, and critically examined current discoveries on Parkinson's disease pharmacogenetics. The ethnicity of the individuals, research methodologies, and potential bias of these studies were thoroughly compared, with the primary focus on consistent conclusions., Results: This review provides a summary of the existing data on PD pharmacogenetics, identifies its limitations, and offers insights that may be beneficial for future research. Previous studies have investigated the impact of gene polymorphism on the effectiveness and adverse effects of levodopa. The trendiest genes are the COMT gene, DAT gene, and DRD2 gene. However, limited study on other anti-Parkinson's drugs has been conducted., Conclusion: Therefore, In order to develop an individualized precision treatment for PD, it is an inevitable trend to carry out multi-center, prospective, randomized controlled clinical trials of PD pharmacogenomics covering common clinical anti-PD drugs in large, homogeneous cohorts., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Brain radiomics can reflect the characteristics of brain pathophysiology. However, the value of T1-weighted images, quantitative susceptibility mapping, and R2* mapping in the diagnosis of Parkinson's disease (PD) was underestimated in previous studies. In this prospective study to establish a model for PD diagnosis based on brain imaging information, we collected high-resolution T1-weighted images, R2* mapping, and quantitative susceptibility imaging data from 171 patients with PD and 179 healthy controls recruited from August 2014 to August 2019. According to the inclusion time, 123 PD patients and 121 healthy controls were assigned to train the diagnostic model, while the remaining 106 subjects were assigned to the external validation dataset. We extracted 1408 radiomics features, and then used data-driven feature selection to identify informative features that were significant for discriminating patients with PD from normal controls on the training dataset. The informative features so identified were then used to construct a diagnostic model for PD. The constructed model contained 36 informative radiomics features, mainly representing abnormal subcortical iron distribution (especially in the substantia nigra), structural disorganization (e.g., in the inferior temporal, paracentral, precuneus, insula, and precentral gyri), and texture misalignment in the subcortical nuclei (e.g., caudate, globus pallidus, and thalamus). The predictive accuracy of the established model was 81.1 ± 8.0% in the training dataset. On the external validation dataset, the established model showed predictive accuracy of 78.5 ± 2.1%. In the tests of identifying early and drug-naïve PD patients from healthy controls, the accuracies of the model constructed on the same 36 informative features were 80.3 ± 7.1% and 79.1 ± 6.5%, respectively, while the accuracies were 80.4 ± 6.3% and 82.9 ± 5.8% for diagnosing middle-to-late PD and those receiving drug management, respectively. The accuracies for predicting tremor-dominant and non-tremor-dominant PD were 79.8 ± 6.9% and 79.1 ± 6.5%, respectively. In conclusion, the multiple-tissue-specific brain radiomics model constructed from magnetic resonance imaging has the ability to discriminate PD and exhibits the advantages for improving PD diagnosis., Competing Interests: None

Background and Purpose: The insidious onset of Parkinson's disease (PD) makes early diagnosis difficult. Notably, idiopathic rapid eye movement sleep behavior disorder (iRBD) was reported as a prodrome of PD, which may represent a breakthrough for the early diagnosis of PD. However, currently there is no reliable biomarker for PD diagnosis. Considering that α-synuclein (α-Syn) and neuroinflammation are known to develop prior to the onset of clinical symptoms in PD, it was hypothesized that plasma total exosomal α-Syn (t-exo α-Syn), neural-derived exosomal α-Syn (n-exo α-Syn) and exosomal apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) may be potential biomarkers of PD., Methods: In this study, 78 PD patients, 153 probable iRBD patients (pRBD) and 63 healthy controls (HCs) were recruited. α-Syn concentrations were measured using a one-step paramagnetic particle-based chemiluminescence immunoassay, and ASC levels were measured using the Ella system., Results: It was found that t-exo α-Syn was significantly increased in the PD group compared to the pRBD and HC groups (p &lt; 0.0001), whilst n-exo α-Syn levels were significantly increased in both the PD and pRBD groups compared to HCs (p &lt; 0.0001). Furthermore, although no difference was found in ASC levels between the PD and pRBD groups, there was a positive correlation between ASC and α-Syn in exosomes., Conclusions: Our results suggest that both t-exo α-Syn and n-exo α-Syn were elevated in the PD group, whilst only n-exo α-Syn was elevated in the pRBD group. Additionally, the adaptor protein of inflammasome ASC is correlated with α-Syn and may facilitate synucleinopathy., (© 2022 European Academy of Neurology.)

Objective: This study aimed to investigate the utility of inflammatory markers of hemogram parameters as objective indicators of disease severity in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis., Methods: A total of 98 patients were retrospectively reviewed. Inflammatory markers of hemogram parameters, including neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio, were acquired within 24 h of admission. We then analyzed their utility as predictive factors for disease severity at different time points assessing with the modified Rankin Scale (mRS)., Results: There were 49 patients in the mild group (mRS ≤ 2) and 49 patients in the moderate-to-severe (mRS > 2) group at admission. The moderate-to-severe group presented more frequently with psychiatric symptoms and central hypoventilation, as well as a lower lymphocyte count, a higher neutrophil count, a higher NLR and a higher MLR (all p < 0.05) when compared with the mild group. NLR and MLR showed similar positive correlations with mRS scores (r = 0.40, r = 0.40, both p < 0.001). Further multivariate logistic regression analyses indicated that NLR > 4.232 was an independent risk factor for moderate-to-severe status at admission. Meanwhile, NLR and MLR were associated with disease severity at different stages of follow-up but showed no independent predictive value., Conclusion: Our findings suggested that NLR was an independent risk factor for moderate-to-severe status in the initial stage of anti-NMDAR encephalitis with a cut-off value of > 4.232., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Mutations in the PRKN gene are the major cause of autosomal recessive Parkinson's disease (PD). However, studies of parkin-/- mice did not show the loss of dopaminergic neurons and motor phenotypes at a young age. Whether pathological changes are associated with nonmotor symptoms of PD remains unclear. Visual impairment is one common nonmotor symptom in patients with PD. This study aimed to examine the effects of parkin-/- on mitochondria and synaptic structures in the retina of 6-month-old mice. Compared with wild-type mice, parkin-/- mice exhibited a slightly thickened retina. Also, the number of normal mitochondria (mito-5 grade) in rod spherules (RSs) significantly decreased (p &lt; 0.01), the average area of mitochondria was significantly larger (p &lt; 0.001), and the number of ribbons in RSs significantly decreased (p = 0.02). The RSs of parkin-/- mice showed severe swelling after flicker stimulation. Our study implicated that parkin-/- led to the impairment of mitochondria and abnormality of the synaptic structure in mouse retina at a young age, which damaged the synaptic transmission between photoreceptors and second-order retinal neurons and resulted in visual impairment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of midbrain substantia nigra pars compacta dopaminergic neurons and the formation of Lewy bodies. Over the years, researchers have gained extensive knowledge about dopaminergic neuron degeneration from the perspective of the environmental and disease-causing genetic factors; however, there is still no disease-modifying therapy. Aging has long been recognized as a major risk factor for PD; however, little is known about how aging contributes to the disease development. Genome instability is the main driving force behind aging, and has been poorly studied in patients with PD. Here, we summarize the evidence for nuclear DNA damage in PD. We also discuss the molecular mechanisms of nuclear DNA damage and repair in PD, especially from the perspective of familial PD-related mutant genes. Understanding the significance of DNA damage and repair may provide new potential intervention targets for treating PD., Competing Interests: Conflicts of interest All authors claim that there are no conflicts of interest., (copyright: © 2022 Li et al.)

Background: Increased life expectancy and improved perioperative management have resulted in increased utilization of hepatectomy for hepatocellular carcinoma (HCC) among elderly patients. However, individualized model for predicting the surgical safety and efficacy is lacking. The present study aimed to develop a safety and efficacy-associated risk calculator for HCC in the elderly after resection (SEARCHER)., Methods: From an international multicenter database, elderly patients who underwent curative-intent hepatectomy for HCC were stratified by patient age: 65-69 years, 70-74 years, 75-79 years, and ≥80 years. Short- and long-term outcomes among the 4 groups were compared. Univariate and multivariate analyses of risk factors of postoperative major morbidity, cancer-specific survival (CSS) and overall survival (OS) were performed in the training cohort. A nomogram-based online calculator was then constructed and validated in the validation cohort., Results: With increasing age, the risk of postoperative major morbidity and worse OS increased (P = 0.001 and 0.020), but not postoperative mortality and CSS (P = 0.577 and 0.890) among patients across the 4 groups. Based on three nomograms to predict major morbidity, CSS and OS, the SEARCHER model was constructed and made available at https://elderlyhcc.shinyapps.io/SEARCHER. The model demonstrated excellent calibration and optimal performance in both the training and validation cohorts, and performed better than the several commonly-used conventional scoring and staging systems of HCC., Conclusions: With higher potential postoperative major morbidity and worse OS as patients age, the decision of whether to perform a hepatectomy for HCC needs to be comprehensively considered in the elderly. The proposed SEARCHER model demonstrated good performance to individually predict safety and efficacy of hepatectomy in elderly patients with HCC., Competing Interests: Declaration of competing interest None reported., (Copyright © 2022 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: The identification of patients at high risk of developing postoperative complications is important to improve surgical safety. We sought to develop an individualized tool to predict post-hepatectomy major complications in hepatitis B virus (HBV)-infected patients with hepatocellular carcinoma (HCC)., Methods: A multicenter database of patients undergoing hepatectomy for HCC were analyzed; 2/3 and 1/3 of patients were assigned to the training and validation cohorts, respectively. Independent risks of postoperative 30-day major complications (Clavien-Dindo grades III-V) were identified and used to construct a web-based prediction model, which predictive accuracy was assessed using C-index and calibration curves, which was further validated by the validation cohort and compared with conventional scores., Results: Among 2762 patients, 391 (14.2%) developed major complications after hepatectomy. Diabetes mellitus, concurrent hepatitis C virus infection, HCC beyond the Milan criteria, cirrhosis, preoperative HBV-DNA level, albumin-bilirubin (ALBI), and aspartate transaminase to platelet ratio index (APRI) were identified as independent predictors of developing major complications, which were used to construct the online calculator ( http://www.asapcalculate.top/Cal11&#95;en.html ). This model demonstrated good calibration and discrimination, with the C-indexes of 0.752 and 0.743 in the training and validation cohorts, respectively, which were significantly higher than those conventional scores (the training and validation cohorts: 0.565 ~ 0.650 and 0.568 ~ 0.614, all P < 0.001)., Conclusions: A web-based prediction model was developed to predict the probability of post-hepatectomy major complications in an individual HBV-infected patient with HCC. It can be used easily in the real-world clinical setting to help management-related decision-making and early warning, especially in areas with endemic HBV infection., (© 2022. The Society for Surgery of the Alimentary Tract.)

Ferroptosis, a novel form of regulated cell death, is caused by accumulation of lipid peroxides and excessive iron deposition. This process has been linked to the death of dopaminergic neurons in substantia nigra compacta (SNc) of Parkinson's disease (PD) patients. Quercetin (QCT), a natural flavonoid, has multiple pharmacological activities. However, it has not been established whether QCT can protect against dopaminergic neuron death by inhibiting ferroptosis. In this study, we investigated the potential antiferroptotic effects of QCT in cellular models established using specific ferroptosis inducers (Erastin and RSL-3) and MPP + . The effects were also explored using MPTP-induced PD mouse models. The cell counting kit-8 (CCK-8) assay was performed to assess cell viability. Variations in mitochondrial morphology were evaluated by transmission electron microscopy (TEM) while the mitochondrial membrane potential, mass, and ROS were measured by fluorescent probes. Lipid peroxidation levels were assayed through measurement of lipid ROS, MDA, GSH, and SOD levels. The effects of QCT on MPTP-induced behavioral disorders were examined by rotarod and open field tests. In vitro and in vivo , QCT significantly inhibited ferroptosis by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein. Additionally, QCT ameliorated motor behavioral impairments and protected against the loss of dopaminergic neurons in MPTP-induced PD models. Interestingly, Nrf2 knockdown alleviated the protective effects of QCT against ferroptosis. In conclusion, these results demonstrate that ferroptosis is involved in MPP + /MPTP-induced PD, and QCT inhibits ferroptosis by activating the Nrf2 protein. Therefore, QCT is a potential agent for preventing the loss of dopaminergic neurons by targeting ferroptosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Zhi-Hao Lin et al.)

Background: Parkinson's disease (PD), with either rapid eye movement sleep behavior disorder (RBD) or olfactory dysfunction (OD), has been associated with disease progression. However, there is currently heterogeneity in predicting prognosis., Objectives: To identify whether the concurrent presence of OD and probable RBD (pRBD) in PD (Dual hit in PD, PD-DH) is associated with disease progression., Methods: We included 420 patients with de novo PD from the Parkinson's Progression Markers Initiative: 180 PD only (PD), 82 PD with OD (PD-OD), 94 PD with pRBD (PD-pRBD), and 64 PD with both OD and pRBD (PD-DH). Participants underwent motor and nonmotor evaluations, dopamine transporter imaging, and cerebrospinal fluid (CSF) assessment. Data were analyzed with generalized estimating equations and Cox proportional hazards analysis., Results: The PD-DH subtype was associated with higher scores and faster progression rates in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Parts II and III. Also, patients in PD-DH group had faster deterioration in nonmotor symptoms, including MDS-UPDRS Part I score, Montreal Cognitive Assessment, Hopkins Verbal Learning Test-Revised, Wechsler Memory Scale-Third edition (WMS-III) Letter Number Sequencing score, Symbol Digit Modalities Test, and Scales for Outcomes in PD-Autonomic scores, with all P values <0.002. Moreover, the PD-DH subtype had a higher mild cognitive impairment risk (hazard ratio = 1.756, 95% confidence interval [CI] = 1.132-2.722; P  = 0.012), faster decline in caudate standard uptake values (β = -0.03, 95% CI = -0.06 to -0.008, P  = 0.012), and CSF α-synuclein levels (β = -77, 95% CI = -149 to -5, P  = 0.034) than the PD group., Conclusion: Coexisting pRBD and OD in patients with PD may be associated with faster progressions in motor measurements and in cognitive and autonomic symptoms, indicating PD-DH as a more aggressive subtype for PD., (© 2022 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.)

Purpose: Portal hypertension due to cirrhosis is common among patients with hepatocellular carcinoma (HCC). This study aimed to compare the outcomes of partial hepatectomy in patients with HCC and clinically significant portal hypertension (CSPH) with or without concurrent splenectomy and esophagogastric devascularization (CSED)., Patients and Methods: From a multicenter database, patients with HCC and CSPH who underwent curative-intent hepatectomy were identified. Postoperative morbidity and mortality, and long-term overall survival (OS) were compared in patients with and without CSED before and after propensity score matching (PSM)., Results: Of the 358 enrolled patients, 86 patients underwent CSED. Before PSM, the postoperative 30-day morbidity and mortality rates were comparable between the CSED and non-CSED group (both P > 0.05). Using PSM, 81 pairs of patients were created. In the PSM cohort, the 5-year OS rate of the CSED group were significantly better than the non-CSED group (52.9% vs. 36.5%, P= 0.046). The former group had a significantly lower rate of variceal bleeding on follow-up (7.4% vs. 21.7%, P= 0.014). On multivariate analysis, CSED was associated with significantly better OS (HR: 0.39, P < 0.001)., Conclusion: Hepatectomy and CSED can safely be performed in selected patients with HCC and CSPH, which could improve postoperative prognosis by preventing variceal bleeding, and prolonging long-term survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Cognitive flexibility enables effective switching between mental processes to generate appropriate responses. Cholinergic neurons (CNs) within the pedunculopontine nucleus (PPN) are associated with many functions, but their contribution to cognitive flexibility remains poorly understood. Here we measure PPN cholinergic activities using calcium indicators during the attentional set-shifting task. We find that PPN CNs exhibit increasing activities correlated with rewards during each stage and error trials in reversal stages, indicating sensitivity to rule switching. Inhibition of PPN cholinergic activity selectively impairs reversal learning, which improves with PPN CN activation. Activation of PPN CNs projecting to the substantia nigra pars compacta, mediodorsal thalamus, and parafascicular nucleus in a time-locked manner with reward improves reversal learning. Therefore, PPN CNs may encode not only reward signals but also the information of changing reward contingency that contributes to guiding reversal learning through output projections to multiple nuclei that participate in flexibility., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Parkinson's disease (PD) and dystonia are closely related in terms of pathophysiology and clinical manifestations, but their common genetic characteristics remain unclear. Some genome-wide association studies (GWASs) and replication studies have revealed correlations between single nucleotide polymorphisms (SNPs) of the ARSG, BDNF, NALCN, OR4X2, KIAA1715, and OR4B1 genes and dystonia. This study was conducted to assess the association between these genetic loci and PD in a population from Eastern China., Methods: We genotyped the SNPs (rs11655081 of ARSG ; rs6265 of BDNF ; rs61973742, rs1338051, rs9518384, and rs9518385 of NALCN ; rs67863238 of OR4X2 ; rs10930717 of KIAA1715 ; and rs35875350 of OR4B1 ) in a cohort of 474 patients with PD and 439 healthy controls from East China. To determine the genotypes of these SNPs, we used an Agena MassARRAY Typer 4.0. Odds ratios ( OR s) and 95% CI s were computed to evaluate the correlations between these SNPs and the risk of PD., Results: There were significant differences in the genotype distribution ( OR = 0.649, 95% CI = 0.478-0.880) and minor allele frequency (MAF) ( OR = 0.703, 95% CI = 0.533-0.929) of SNP rs61973742 ( NALCN ) between patients with PD and healthy controls. A significant difference was detected in the genotype distribution of rs11655081 ( ARSG ) ( OR = 1.486, 95% CI = 1.080-2.045)., Conclusion: Single nucleotide polymorphisms rs11655081 ( ARSG ) and rs61973742 ( NALCN ) may be associated with PD. The C allele of rs11655081 may increase the risk of PD, whereas the G allele of rs61973742 may be a protective factor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Jiang, Pu, Jin, Gao, Zheng, Tian and Zhang.)

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., (© 2022. The Author(s).)

Background: Hepatocellular carcinoma (HCC) is the most common malignancy in the elderly worldwide, but it is also common among younger individuals in areas with endemic hepatitis B virus infection. The differences in long-term oncological prognosis of young versus elderly patients after R0 liver resection for HCC were explored in this study., Methods: Using a Chinese multicentre database, consecutive patients who underwent R0 liver resection for HCC between 2007 and 2019 were analysed retrospectively. After excluding middle-aged (36-69 years old) patients, overall survival (OS), cancer-specific survival (CSS), and recurrence were compared between young (35 years or younger) and elderly (70 years or older) patients using propensity score matching (PSM)., Results: Among 531 enrolled patients, there were 192 (36.2 per cent) and 339 (63.8 per cent) patients categorized as young and elderly respectively. PSM created 140 pairs of matched patients. In the PSM cohort, 5-year OS was comparable for young versus elderly patients (51.7 versus 52.3 per cent, P = 0.533). Young patients, however, had a higher 5-year cumulative recurrence rate (62.1 versus 51.6 per cent, P = 0.011) and a worse 5-year CSS rate (54.0 versus 64.3 per cent, P = 0.034) than elderly patients. On multivariable Cox regression analyses, young patient age remained independently associated with an increased recurrence rate (hazard ratio 1.62, P = 0.016) and a decreased CSS rate (hazard ratio 1.69, P = 0.021) compared with older age., Conclusion: Following R0 liver resection for HCC, younger patients were at a higher risk of recurrence, and elderly patients had a better CSS rate. Thus, enhanced surveillance for HCC recurrence should be implemented for young patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

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 Aβ42 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., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background: Emerging evidence indicates that the apolipoprotein E (APOE) ε4 exacerbates α-synuclein pathology., Objective: To determine whether APOE ε4 contributes to motor progression in early Parkinson's disease (PD)., Methods: Longitudinal data were obtained from 384 patients with PD divided into APOE ε4 carriers (n = 85) and noncarriers (n = 299) in the Parkinson's Progression Marker Initiative. Participants underwent yearly motor assessments over a mean follow-up period of 78.9 months. Repeated measures and linear mixed models were used to test the effects of APOE ε4., Results: The motor progression was significantly more rapid in patients with PD carrying APOE ε4 than in noncarriers (β = 0.283, P = 0.026, 95% confidence interval: 0.033-0.532). Through subgroup analysis, we found that the effect of APOE ε4 was significant only in patients with high amyloid β burden (β = 0.761, P < 0.001, 95% confidence interval: 0.0356-1.167)., Conclusions: APOE ε4 may be associated with rapid motor progression in PD. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: Hepatic ischemia-reperfusion (I/R) injury (IRI) represents a crucial challenge in liver transplantation. Fisetin has anti-inflammatory, anti-aging and anti-oxidative properties. This study aimed to examine whether fisetin mitigates hepatic IRI and examine its underlying mechanisms., Methods: Sham or warm hepatic I/R operated mice were pretreated with fisetin (5, 10 or 20 mg/kg). Hepatic histological assessments, TUNEL assays and serum aminotransferase measurements were performed. An in vitro hypoxia/reoxygenation (H/R) model using RAW264.7 macrophages pretreated with fisetin (2.5, 5 or 10 µmol/L) was also used. Serum and cell supernatant concentrations of interleukin-1β (IL-1β), IL-18 and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). Protein levels of p-GSK3β, p-AMPK and NLR family pyrin domain-containing 3 (NLRP3)-associated proteins were detected by Western blotting., Results: Compared with the I/R group, fisetin pretreatment reduced pathological liver damage, serum aminotransferase levels, serum concentrations of IL-1β, IL-18 and TNF-α in the murine IRI model. Fisetin also reduced the expression of NLRP3 inflammasome-associated proteins (NLRP3, cleaved caspase-1, IL-1β and IL-18) in I/R-operated liver. The experiments in vitro showed that fisetin decreased the release of IL-1β, IL-18 and TNF-α, and reduced the expression of NLRP3 inflammasome-associated proteins in H/R-treated RAW264.7 cells. Moreover, fisetin increased the expressions of p-GSK3β and p-AMPK in both models, indicating that its anti-inflammatory effects were dependent on GSK3β/AMPK signaling. The anti-inflammatory effects of fisetin were partially inhibited by the AMPK specific inhibitor compound C., Conclusions: Fisetin showed protective effects against hepatic IRI, countering inflammatory responses through mediating the GSK3β/AMPK/NLRP3 inflammasome pathway., (Copyright © 2021. Published by Elsevier B.V.)

Background: To date, the genetic contribution to Parkinson's disease (PD) remains unclear. Mutations in the collagen type VI alpha 3 (COL6A3) gene were recently identified as a cause of isolated dystonia. Since PD and dystonia are closely related disorders with shared clinical and genetic characteristics, we explored the association between COL6A3 and PD in a Chinese cohort., Methods: We performed genetic screening of COL6A3 in a Chinese cohort of 173 patients with sporadic PD and 200 healthy controls. We identified variants that are likely to have pathogenic effects based on: 1) a minor allele frequency of < 0.01; and 2) the variant being recognized as deleterious by at least 15 different in silico predicting tools. Finally, we tested the aggregate burden of COL6A3 on PD via SKAT-O analysis., Results: First, we found compound heterozygous COL6A3 gene mutations in one early-onset PD patients. Then, we explored whether COL6A3 variants contributed to increased risk of developing PD in a Chinese population. We detected 21 rare non-synonymous variants. Pathogenicity predictions identified 7 novel non-synonymous variants as likely to be pathogenic. SKAT-O analysis further revealed that an aggregate burden of variants in COL6A3 contributes to PD (p = 0.038)., Conclusion: An increased aggregate burden of the COL6A3 gene was detected in patients with PD.

A pivotal neuropathological manifestation of synucleinopathies, like Parkinson's disease (PD), is the aggregation of α-synuclein. In a recent cell-to-cell transmission model of α-synuclein, α-synuclein propagation was demonstrated to resemble that of prion proteins in the central nervous system. Furthermore, exosomes, as biomolecule carriers, have been shown to transmit α-synuclein from neuron to neuron. However, the mechanisms underlying exosomal α-synuclein transmission have not been well understood. The NLR family pyrin domain containing 3 protein (NLRP3) inflammasome activation in microglia, and the subsequent release of proinflammatory cytokines, are two crucial pathological events involved in neuroinflammation and PD progression. Research has revealed that the NLRP3 inflammasome may facilitate the secretion of extracellular vesicles, as well as exosomal transmission of proteins like aggregated α-synuclein. However, only a few reports have evaluated these pathogenic mechanisms. Herein we evaluate for the first time the current evidence for the involvement of the NLRP3 inflammasome in microvesicle generation by microglial cells, and the various mechanisms regarding the production, shedding, and content of exosomes in relation to α-synuclein transmission from neuron to neuron. Furthermore, we propose a model of microglial NLRP3 inflammasome-dependent exosome secretion and exosomal α-synuclein transmission in PD. This knowledge may lead to the identification of novel potential targets for drug development and stimulate further research in PD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Mutations in the teneurin transmembrane protein 4 ( TENM4 ) gene, known to be involved in neuropsychiatric disorders, have been identified in three pedigree of essential tremor (ET) from Spain. ET has overlapping clinical manifestations and epidemiological symptoms with Parkinson's disease (PD), suggesting these two disorders may reflect common genetic risk factors. In this study, we investigated clinical and genetic manifestations in four unrelated pedigrees with both ET and PD in which TENM4 variants were identified., Methods: We subsequently explored whether TENM4 variants contributed to the risk of developing PD. The frequency of TENM4 variants was evaluated from four PD pedigrees and other 407 subjects., Results: The results revealed 12 different novel heterozygous variants, all at low frequency. A clear general enrichment of TENM4 variants was detected in early onset PD patients ( p < 0.001, OR = 5.264, 95% CI = 1.957-14.158)., Conclusion: The results indicate that rare TENM4 variants may be associated with an increased risk of PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Pu, Gao, Si, Zheng, Jin, Ruan, Fang, Chen, Song, Yin, Yan, Tian and Zhang.)

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.

Background: Excessive aggregation of α-synuclein is the key pathophysiological feature of Parkinson's disease (PD). Rapid eye movement sleep behavior disorder (RBD) is also associated with synucleinopathies and considered as a powerful predictor of PD. Growing evidence suggests the diminished clearance of α-synuclein may be partly attributable to poor interstitial fluid drainage, which can be reflected by magnetic resonance imaging (MRI)-visible enlarged perivascular space (EPVS). However, the effect of MRI-visible EPVS on iRBD and PD, and their correlation with clinical characteristics remain unclear., Objective: To evaluate the clinical and neuroimaging significance of MRI-visible EPVS in iRBD and PD patients., Methods: We enrolled 33 iRBD patients, 82 PD (with and without RBD) patients, and 35 healthy controls (HCs), who underwent clinical evaluation and 3.0 Tesla MRI. Two neurologists assessed MRI-visible EPVS in centrum semiovale (CSO), basal ganglia (BG), substantia nigra (SN), and brainstem (BS). Independent risk factors for iRBD and PD were investigated using multivariable logistic regression analysis. Spearman analysis was used to test the correlation of MRI-visible EPVS with clinical characteristics of patients., Results: iRBD patients had significantly higher EPVS burdens (CSO, BG, SN, and BS) than PD patients. Higher CSO-EPVS and BS-EPVS burdens were independent risk factors for iRBD. Furthermore, higher CSO-EPVS and SN-EPVS burdens were positively correlated with the severity of clinical symptom in iRBD patients, and higher BG-EPVS burden was positively correlated with the severity of cognitive impairment in PD patients., Conclusion: iRBD and PD patients have different MRI-visible EPVS burdens, which may be related with a compensatory mechanism in glymphatic system. Lower MRI-visible EPVS burden in PD patients may be a manifestation of severe brain waste drainage dysfunction. These findings shed light on the pathophysiologic relationship between iRBD and PD with respect to neuroimaging marker of PD., (Copyright © 2020 Si, Gu, Song, Zhou, Fang, Jin, Wu, Gao, Guo, Guan, Xu, Yin, Yan, Zhang and Pu.)

Chronic inflammation might correlate with the formation of α-synuclein oligomers, subsequently leading to dopaminergic (DA) neuronal death in Parkinson's disease (PD). As major components of chronic inflammation, NOD-like receptor protein 3 (NLRP3) inflammasomes play a crucial role in PD via caspase 1 activation, primarily induced by mitochondrial damage. NLRP3 binds to apoptosis-associated speck-like protein containing a CARD (PYCARD/ASC), and forms inflammasomes in the brain. Inflammasomes act as a platform for caspase 1 to induce interleukin 1 Beta (IL1β) maturation, leading to neuronal pyroptosis. Furthermore, alpha-synuclein, whose abnormal aggregation is the main pathogenesis of PD, also activates NLRP3 inflammasomes. Mutations to PRKN (encoding Parkin) are the most common cause of autosomal recessive familial and sporadic early-onset PD. Evidence has confirmed a relationship between Parkin and NLRP3 inflammasomes. In this review, we summarize the current understanding of NLRP3 inflammasomes and their role in PD progression, and discuss their regulation by Parkin., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: To date, several studies have suggested that genes involved in monogenic forms of Parkinson's disease (PD) contribute to unrelated sporadic cases, but there is limited evidence in the Chinese population., Methods: We performed a systematic analysis of 12 autosomal-dominant PD (AD-PD) genes (SNCA, LRRK2, GIGYF2, VPS35, EIF4G1, DNAJC13, CHCHD2, HTRA2, NR4A2, RIC3, TMEM230, and UCHL1) using panel sequencing and database filtration in a case-control study of a cohort of 391 Chinese sporadic PD patients and unrelated controls. We evaluated the association between candidate variants and sporadic PD using gene-based analysis., Results: Overall, 18 rare variants were discovered in 18.8% (36/191) of the index patients. In addition to previously reported pathogenic mutations (LRRK2 p.Arg1441His and p.Ala419Val), another four unknown variants were found in LRRK2, which also contribute to PD risk (p = 0.002; odds ratio (OR) = 7.83, 95% confidence intervals (CI) = 1.76-34.93). The cumulative frequency of undetermined rare variants was significantly higher in PD patients (14.1%) than in controls (3.5%) (p = 0.0002; OR=4.54, 95% CI = 1.93-10.69)., Conclusion: Our results confirm the strong impact of LRRK2 on the risk of sporadic PD, and also provide considerable evidence of the existence of additional undetermined rare variants in AD-PD genes that contribute to the genetic etiology of sporadic PD in a Chinese cohort., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Recently, the arylsulfatase A (ARSA) variant c.899 T > C (p.L300S) was identified to be segregated with Parkinson's disease (PD) in one family of Japanese descent. And the variant c.1055A > G (p.N352S) of ARSA was reported as a risk reduction factor for PD in a Japanese population. To further investigate the relationship between ARSA and PD, we screened these two loci of the ARSA gene in 407 sporadic PD patients and 471 healthy controls from a Chinese Han population. However, we did not detect the ARSA p.L300S variant in either PD patients or healthy controls. Moreover, in case-control association analysis, the p.N325S variant showed no significant association with PD. Therefore, these results suggested that these ARSA variants may not be common genetic factors for sporadic PD in Chinese Han population., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Essential tremor (ET) is one of the most prevalent movement disorders. The genetic etiology of ET has not been well defined although a significant proportion (≥50%) are familial cases. Linkage analysis and genome-wide association studies (GWASs) have identified several risk variants. In recent years, whole-exome sequencing of ET has revealed several specific causal variants in FUS (p.Q290X), HTRA2 (p.G399S), and TENM4 (c.4324 G>A, c.4100C>A, and c.3412G>A) genes., Objective: To investigate the genetic contribution of these three genes to ET, the protein-coding sequences of FUS, HTRA2, and TENM4 were analyzed in a total of 238 ET patients and 272 controls from eastern China using direct Sanger sequencing., Results: We identified two synonymous coding single nucleotide polymorphisms (SNPs), rs741810 and rs1052352 in FUS, and three previously reported synonymous SNPs, rs11237621, rs689369, and rs2277277 in TENM4. No nonsynonymous exonic variants were identified in these subjects. We found that the frequency of the rs1052352C allele was significantly higher (P = .001) in the ET group than in the control group., Conclusion: Overall, our findings suggest that rs1052352 of FUS might contribute to ET risk in Chinese population., (© 2020 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Objective: The aim of this study was to investigate potential genetic overlap between essential tremor and Parkinson's disease in a cohort of 825 subjects from an Eastern Chinese population., Methods: A total of 441 Parkinson's disease patients and 384 healthy controls were recruited. The MassARRAY System was used to detect three essential tremor-related single nucleotide polymorphisms. Odds ratio (OR) and 95% confidential interval (CI) were calculated to assess the relationship between polymorphisms and Parkinson's disease susceptibility., Results: Our results demonstrated that the odds ratios of rs3794087 of SLC1A2, rs9652490 of LINGO1, and rs17590046 of PPARGC1A were 0.71 (95% CI = 0.55-0.91), 0.99 (95% CI = 0.78-1.26), and 0.88 (95% CI = 0.62-1.25), respectively., Conclusion: An essential tremor SNP (rs3794087 of SLC1A2) is associated with a decreased risk of PD in the Eastern Han Chinese population, while rs9652490 (LINGO1) and rs17590046 (PPARGC1A) do not show an association., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Background: Small-for-size graft (SFSG) has emerged as one of the very contentions in adult-to-adult living donor liver transplantation (LDLT) as a certain graft size is related to recipients' prognosis. Graft-to-recipient weight ratio (GRWR) ≥0.8% was considered as a threshold to conduct LDLT. However, this also has been challenged over decades as a result of technique refinements. For a better understanding of SFSG in practice, we conducted this meta-analysis to compare the perioperative outcomes and long-term outcomes between patients adopting the grafts with a lower volume (GRWR < 0.8%, SFSG group) and sufficient volume (GRWR ≥ 0.8%, non-SFSG group) in adult-to-adult LDLT., Data Sources: The studies comparing recipients adopting graft with a GRWR < 0.8% and ≥ 0.8% were searched by three authors independently in PubMed, Web of Science, Embase, the Cochrane Library, MEDLINE and Google Scholar databases until September 2018 and data were analyzed by RevMan 5.3.5., Results: Sixteen studies with a total of 3272 subjects were included in this meta-analysis. In terms of small-for-size syndrome (SFSS), no significant difference was found in subjects enrolled after year 2010 (before 2010, OR=3.00, 95% CI: 1.69-5.35, P = 0.0002; after 2010, OR=1.23, 95% CI: 0.79-1.90, P = 0.36; P for interaction: 0.02). There was no significant difference in operative duration, blood loss, cold ischemia time, biliary complications, acute rejection, postoperative bleeding, hospitalization time, perioperative mortality, and 1-, 3- and 5-year overall survival rates between two groups., Conclusions: This meta-analysis suggested that adopting SFSG in adult LDLT has comparable outcomes to those with non-SFSG counterparts since 2010., (Copyright © 2019. Published by Elsevier B.V.)

Differentiation of human fibroblasts into functional neurons depends on the introduction of viral-mediated transcription factors, which present risks of viral gene integration and tumorigenicity. In recent years, although some studies have been successful in directly inducing neurons through sustained expression of small molecule compounds, they have only been shown to be effective on mouse-derived cells. Thus, herein we delivered vectors containing Epstein-Barr virus-derived oriP/Epstein-Barr nuclear antigen 1 encoding the neuronal transcription factor, Ascl1, the neuron-specific microRNA, miR124, and a small hairpin directed against p53, into human fibroblasts. Cells were incubated in a neuron-inducing culture medium. Immunofluorescence staining was used to detect Tuj-1, microtubule-associated protein 2, neuron-specific nucleoprotein NeuN and nerve cell adhesion molecules in the induced cells. The proportion of Tuj1-positive cells was up to 36.7% after induction for 11 days. From day 21, these induced neurons showed neuron-specific expression patterns of microtubule-associated protein 2, NeuN and neural cell adhesion molecule. Our approach is a simple, plasmid-based process that enables direct reprogramming of human fibroblasts into neurons, and provides alternative avenues for disease modeling and neurodegenerative medicine., Competing Interests: None

Dopa-responsive dystonia (DRD) comprises a heterogeneous group of movement disorders. A limited number of studies of Chinese patients with DRD have been reported. In the present study, we investigated the clinical and genetic features of 12 Chinese DRD families. Point mutation analysis of the GTP-cyclohydrolase I (GCH1), tyrosine hydroxylase (TH) and sepiapterin reductase (SPR) genes was conducted by direct sequencing. In addition, multiplex ligation-dependent probe amplification targeting GCH1 and TH was performed in "mutation-free" patients. Three reported mutations (IVS2-2A>G, c.293C>T, c.550C>T) were detected in GCH1, whereas two compound heterozygous variants were identified in TH, one of which was novel (c.1083C>A). Furthermore, this novel variant was not detected in any of the 250 ethnicity-matched, healthy controls. No exon deletions or duplicate mutations in the two genes were found in patients with DRD. No mutation in SPR was found. In addition, one patient with the IVS2-2A>G mutation in GCH1 showed signs of Parkinsonism. In conclusion, we here identified a novel heterozygous variant in TH (c.1083C>A). It is important to perform routine screening of GCH1 and TH for patients with DRD. While for patients with Parkinsonism, GCH1 mutation analysis should be performed after screening of genes like PARKIN, PARK7 (DJ-1) and PINK1.

Autophagy is an intracellular "self-eating" process that is closely related to inflammation and cellular immunity. New studies indicate that autophagy is also involved in tumor suppression. The anti-inflammatory cytokine interleukin-37 (IL-37) has been shown to have tumor-suppressive abilities in hepatocellular carcinoma (HCC). Notably, autophagy appears to play a dual role in the development of HCC and may be involved in both tumorigenesis and tumor suppression. However, the potential role of IL-37 in autophagy is currently unknown. In this study, we investigated the effect of IL-37 on autophagy in multiple HCC cell lines. In doing so, we found that IL-37 inhibits proliferation in HCC cells and also induces autophagy and apoptosis in the SMMC-7721 and Huh-7 cell lines. Further experiments revealed that IL-37 treatment reduced the levels of phosphorylated protein kinase B (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), phosphorylated p70 ribosomal protein s6 kinase (p-p70S6K) and phosphorylated 4E-binding protein 1 (4E-BP1). Moreover, treatment with an AKT agonist, insulin-like growth factor 1 (IGF-1), reversed these IL-37-mediated effects on autophagy, and treatment with an phosphoinositide-3-kinase (PI3K)/AKT inhibitor, LY294002, mimicked the effects of IL-37. Taken together, these results indicate that IL-37 regulates autophagy in SMMC-7721 and Huh-7 cells via inhibition of the PI3K/AKT/mTOR signaling pathway., (Copyright © 2017. Published by Elsevier Ltd.)

Background: The molecular mechanisms of Shenxianshengmai (SXSM), a traditional Chinese medicine, on bradycardia have been incompletely understood. The study tried to investigate the gene expression profile and proteomics of bradycardia rabbits' hearts after SXSM treatment., Methods: Twenty-four adult rabbits were randomly assigned in four groups: sham, model, model plus SXSM treatment, and sham plus SXSM treatment groups. Heart rate was recorded in all rabbits. Then, total RNA of atria and proteins of ventricle were isolated and quantified, respectively. Gene expression profiling was conducted by gene expression chip, and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed to confirm the results of gene expression chip. We used isobaric tags for elative and absolute quantitation and Western blotting to identify altered proteins after SXSM treatment., Results: There was a constant decrease in the mean heart rate (32%, from 238 ± 6 beats/min to 149 ± 12 beats/min) after six weeks in model compared with that in sham group. This effect was partially reversed by 4-week SXSM treatment. Complementary DNA microarray demonstrated that the increased acetylcholinesterase and reduced nicotinic receptor were take responsibility for the increased heart rate. In addition, proteins involved in calcium handling and signaling were affected by SXSM treatment. Real-time RT-PCR verified the results from gene chip. Results from proteomics demonstrated that SXSM enhanced oxidative phosphorylation and tricarboxylic acid (TCA) cycle in ventricular myocardium to improve ATP generation., Conclusions: Long-term SXSM stimulates sympathetic transmission by increasing the expression of acetylcholinesterase and reduces the expression of nicotinic receptor to increase heart rate. SXSM also restored the calcium handling genes and altered genes involved in signaling. In addition, SXSM improves the ATP supply of ventricular myocardium by increasing proteins involved in TCA cycle and oxidation-respiratory chain., Competing Interests: There are no conflicts of interest.

Data on the risk of ischemic stroke and systemic embolism (iSSE) events in patients with nonvalvular atrial fibrillation (NVAF), a CHA2DS2-VASc score of ≤1, hypertrophic cardiomyopathy (HCM), and without anticoagulant therapy are still lacking. The aim of this study was to investigate the incidence of iSSE events in these patients. We consecutively screened medical records of patients with HCM and NVAF referred to Fuwai Hospital between January 1994 and March 2014. The primary end point was iSSE events, defined as a composite of ischemic stroke and systemic embolism. Follow-up was carried out to ascertain end point status. Medical records of 522 patients with NVAF and HCM were screened. A total of 108 patients (20.7 %) with a CHA2DS2-VASc score of ≤1 and without anticoagulant therapy were enrolled and constituted our study population. After a median follow-up of 2.4 years (range 0.6-14.1 years; 376.2 patient-years), ischemic stroke occurred in 2 patients, resulting in death of 1 patient in the first year and paralysis of the other patient in the fourth year. No other iSSE events occurred. The incidence of iSSE was 0.9 % [95 % confidence interval (CI) 0.0-5.0 %] in the first year, and 0.5 % per 100 patient-years (95 % CI 0.1-1.9 %). The risk of iSSE events seems low in patients with NVAF, a CHA2DS2-VASc score of ≤1, HCM, and without anticoagulant therapy. Multicenter studies with sizeable study populations are needed to validate the risk of iSSE events in these patients.