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Stroke-associated infection (SAI) is a major medical complication in acute ischemic stroke patients (AIS) treated with endovascular therapy (EVT). Three hundred thirty-three consecutive patients with AIS caused by a large vessel occlusion in the anterior circulation who received EVT (142 (42.6%) of them were given IV tPA as bridging therapy) and 337 AIS patients who received IV tPA only (non-EVT) were enrolled in the study and evaluated to determine the association of inflammatory factors on admission with SAI. Among the 333 AIS patients undergoing EVT, SAI occurred in 219 (65.8%) patients. Patients with SAI had higher baseline National Institutes of Health Stroke Scale (NIHSS) total scores, white blood cell (WBC) and neutrophil counts, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) than those without SAI (P < 0.05). The multivariable logistic regression analyses showed that older age in addition to higher diastolic blood pressure (DBP), NIHSS score, fasting blood glucose, WBC and neutrophil counts, NLR, and PLR were significantly associated with SAI (P < 0.05). However, these associations were not revealed in 337 non-EVT AIS patients. Furthermore, based on the inflammatory markers, we developed a nomogram that provided the opportunity for more accurate predictions (compared with conventional factors) and appeared a better prognostic tool for SAI according to the decision curve analysis. In summary, if proven externally valid, our nomogram that included WBC count, NLR, and PLR may be a useful tool for SAI prediction in clinical practice.

Akkermansia muciniphila, abbreviated as AKK and found in 2004, is an oval-shaped gram-negative bacterium isolated from a human feal. A. muciniphila is widely present in the intestinal tract of human. Its specialization in mucin degradation makes it a key organism at the mucosal interface between the lumen and host cells. More and more studies have shown that it can play the role of probiotics. Notably, declined levels of A. muciniphila have been observed in patients with diabetes, liver disease, cardiovascular disease, inflammatory bowel disease, neurodegenerative diseases, etc. In addition, A. muciniphila combined with traditional Chinese medicine, exhibited higher effect on regulating host functions, but the underlying mechanism was still unclear, requiring further in-depth research. Therefore, the aims of this review are to summarize the main effects of A. muciniphila on host health and its relationship with traditional Chinese medicine, summarize the main problems, and provide a reference for the further research of A. muciniphila and traditional Chinese medicine.

Purpose: To evaluate the relationship between obstructive sleep apnea (OSA) and diabetic macular edema (DME) and the effect of OSA on refractory DME in patients with type 2 diabetes (T2DM)., Design: Retrospective clinical cohort study., Methods: A population-based study was conducted at Chang Gung Memorial Hospital from March 1, 2009, to March 1, 2020. Among 14,152 patients who had undergone polysomnography (PSG) and whose data were registered on the sleep center's PSG database, 121 patients (242 eyes) with T2DM were enrolled according to the International Classification of Diseases, Ninth Revision (ICD-9) code 3620 for diabetic retinopathy (DR). Patients with a secondary cause of macular edema and those lacking medical records were excluded. All patients with T2DM enrolled in our study received both optical coherence tomography (OCT) and PSG. The prevalence of severe (apnea-hypopnea index [AHI] ≥30) and nonsevere (AHI <30) OSA was compared between patients with and without DME and refractory DME., Results: In total, 102 eyes (54 patients) were divided into groups of 40 eyes with DME or 62 eyes without DME. Severe OSA (odds ratio, 7.36; 95% confidence interval [CI]: 1.32-40.96; P = .023) was significantly associated with DME. Refractory DME was significantly more frequent in patients with severe OSA (27%) than in those with nonsevere OSA (0%; P = .009). Cox proportional hazards regression analysis revealed that OSA (hazard ratio, 2.97; CI, 1.08-8.16; P = .034) independently increased the DME risk after adjustment for age, sex, glycohemoglobin level, hypertension, and hypercholesterolemia., Conclusions: Severe OSA is a risk factor for DME and is associated with having refractory DME., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sustained elevation of corticosterone (CORT) is one of the common causes of aging and major depression disorder. However, the role of elevated CORT in late life depression (LLD) has not been elucidated. In this study, 18-month-old female rats were subjected to bilateral adrenalectomy or sham surgery. Their CORT levels in plasma were adjusted by CORT replacement and the rats were divided into high-level CORT (H-CORT), low-level CORT (L-CORT), and Sham group. We showed that L-CORT rats displayed attenuated depressive symptoms and memory defects in behavioral tests as compared with Sham or H-CORT rats. Furthermore, we showed that glutamatergic transmission was enhanced in L-CORT rats, evidenced by enhanced population spike amplitude (PSA) recorded from the dentate gyrus of hippocampus in vivo and increased glutamate release from hippocampal synaptosomes caused by high frequency stimulation or CORT exposure. Intracerebroventricular injection of an enzymatic glutamate scavenger system, glutamic-pyruvic transmine (GPT, 1 μM), significantly increased the PSA in Sham rats, suggesting that extracelluar accumulation of glutamate might be the culprit of impaired glutamatergic transmission, which was dependent on the uptake by Glt-1 in astrocytes. We revealed that hippocampal Glt-1 expression level in the L-CORT rats was much higher than in Sham and H-CORT rats. In a gradient neuron-astrocyte coculture, we found that the expression of Glt-1 was decreased with the increase of neural percentage, suggesting that impairment of Glt-1 might result from the high level of CORT contributed neural damage. In sham rats, administration of DHK that inhibited Glt-1 activity induced significant LLD symptoms, whereas administration of RIL that promoted glutamate uptake significantly attenuated LLD. All of these results suggest that glutamatergic transmission impairment is one of important pathogenesis in LLD induced by high level of CORT, which provide promising clues for the treatment of LLD.

The tonsil microbiome is associated with chronic tonsillitis and obstructive sleep apnea (OSA) in children, and the gut microbiome is associated with host weight status. In this study, we hypothesized that weight status may be associated with clinical profiles and the tonsil microbiome in children with OSA. We prospectively enrolled 33 non-healthy-weight (cases) and 33 healthy-weight (controls) pediatric OSA patients matched by the proportion of chronic tonsillitis. Differences in the tonsil microbiome between the non-healthy-weight and healthy-weight subgroups and relationships between the tonsil microbiome and clinical variables were investigated. Non-healthy weight was associated with significant intermittent hypoxemia (oxygen desaturation index, mean blood saturation (SpO 2 ), and minimal SpO 2 ) and higher systolic blood pressure percentile, but was not related to the tonsil microbiome. However, chronic tonsillitis was related to Acidobacteria in the non-healthy-weight subgroup, and oxygen desaturation index was associated with Bacteroidetes in the healthy-weight subgroup. In post hoc analysis, the children with mean SpO 2 ≤ 97% had reduced α and β diversities and a higher abundance of Bacteroidetes than those with mean SpO 2 > 97%. These preliminary findings are novel and provide insights into future research to understand the pathogenesis of the disease and develop personalized treatments for pediatric OSA.

Study Objectives: Patients with obstructive sleep apnea (OSA) exhibit heterogeneous heart rate variability (HRV) during wakefulness and sleep. We investigated the influence of OSA severity on HRV parameters during wakefulness in a large international clinical sample., Methods: 1247 subjects (426 without OSA and 821 patients with OSA) were enrolled from the Sleep Apnea Global Interdisciplinary Consortium. HRV parameters were calculated during a 5-minute wakefulness period with spontaneous breathing prior to the sleep study, using time-domain, frequency-domain and nonlinear methods. Differences in HRV were evaluated among groups using analysis of covariance, controlling for relevant covariates., Results: Patients with OSA showed significantly lower time-domain variations and less complexity of heartbeats compared to individuals without OSA. Those with severe OSA had remarkably reduced HRV compared to all other groups. Compared to non-OSA patients, those with severe OSA had lower HRV based on SDNN (adjusted mean: 37.4 vs. 46.2 ms; p < 0.0001), RMSSD (21.5 vs. 27.9 ms; p < 0.0001), ShanEn (1.83 vs. 2.01; p < 0.0001), and Forbword (36.7 vs. 33.0; p = 0.0001). While no differences were found in frequency-domain measures overall, among obese patients there was a shift to sympathetic dominance in severe OSA, with a higher LF/HF ratio compared to obese non-OSA patients (4.2 vs. 2.7; p = 0.009)., Conclusions: Time-domain and nonlinear HRV measures during wakefulness are associated with OSA severity, with severe patients having remarkably reduced and less complex HRV. Frequency-domain measures show a shift to sympathetic dominance only in obese OSA patients. Thus, HRV during wakefulness could provide additional information about cardiovascular physiology in OSA patients., Clinical Trial Information: A Prospective Observational Cohort to Study the Genetics of Obstructive Sleep Apnea and Associated Co-Morbidities (German Clinical Trials Register - DKRS, DRKS00003966) https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00003966., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Excitatory toxicity is still a hot topic in the study of ischemic stroke, and related research has focused mainly on neurons. Adenosine is an important neuromodulator that is known as a "biosignature" in the central nervous system (CNS). The protective effect of exogenous adenosine on neurons has been confirmed, but its mechanism remains elusive. In this study, astrocytes were pretreated with adenosine, and the effects of an A2a receptor (A2aR) inhibitor (SCH58261) and A2b receptor (A2bR) inhibitor (PSB1115) on excitatory glutamate were investigated. An oxygen glucose deprivation/reoxygenation (OGD/R) and glutamate model was generated in vitro. Post-model assessment included expression levels of glutamate transporters (glt-1), gap junction protein (Cx43) and glutamate receptor (AMPAR), Na + -K + -ATPase activity, and diffusion distance of dyes. Glutamate and glutamine contents were determined at different time points. The results showed that (1) adenosine could improve the function of Na + -K + -ATPase, upregulate the expression of glt-1, and enhance the synthesis of glutamine in astrocytes. This effect was associated with A2aR activation but not with A2bR activation. (2) Adenosine could inhibit the expression of gap junction protein (Cx43) and reduce glutamate diffusion. Inhibition of A2aR attenuated adenosine inhibition of gap junction intercellular communication (GJIC) in the OGD/R model, while it enhanced adenosine inhibition of GJIC in the glutamate model, depending on the glutamate concentration. (3) Adenosine could cause AMPAR gradually entered the nucleus from the cytoplasm, thereby reducing the expression of AMPAR on the cell membrane. Taken together, the results indicate that adenosine plays a role of anti-excitatory toxicity effect in protection against neuronal death and the functional recovery of ischemic stroke mainly by targeting astrocytes, which are closely related to A2aR. The present study provided a scientific basis for adenosine prevention and ischemic stroke treatment, thereby providing a new approach for alleviating ischemic stroke.

Background: Hepatic ischemia/reperfusion (I/R) injury is a major complication of liver resection or transplantation. However, the mechanism underlying hepatic I/R injury remains obscure. The aim of the present study was to investigate the role of Chemokine-like factor 1 (CKLF1) in hepatic I/R injury., Methods: Rats were subjected to 70% hepatic ischemia for 90 min, followed by 6, 12, 24, 48 and 96 h of reperfusion. The expression of CKLF1 was measured by real-time PCR and western blot. The effect of C19, an antagonism peptide of CKLF1, on hepatic I/R injury was investigated., Results: After subjected to 70% hepatic ischemia and reperfusion, the ALT and AST were increased. H&E results showed serious liver damage. The mRNA and protein levels of CKLF1 expression were upregulated during hepatic I/R. Immunohistochemistry staining results showed that neutrophil infiltration was increased in the ischemia lobe. MPO activity was significantly higher post reperfusion. TNF-α and IL-1β were upregulated during hepatic I/R. C19 administration significantly reduced the level of ALT and AST, decreased the necrosis area of liver tissue. Furthermore, C19 treatment inhibited neutrophil infiltration and reduced MPO activity. Meanwhile, C19 decreased the expression of TNF-α and IL-1β. The phosphorylation of P38, JNK were inhibited by C19 treatment., Conclusion: CKLF1 was upregulated during hepatic I/R. Inhibiting CKLF1 by C19, an antagonism peptide of CKLF1, could alleviate hepatic I/R injury, reduce neutrophil infiltration, decrease inflammatory response. The protective effect of C19 may related to MAPK signaling pathway., (Copyright © 2021. Published by Elsevier Ltd.)

Tetrahydroxy stilbene glycoside (TSG) is a main active compound in Polygonum multiflorum. Acetaminophen (APAP) is a well-known analgesic and antipyretic drug. It is considered to be safe within a therapeutic range, in case of acute intoxication hepatotoxicity occurs. This present study aims to observe TSG-provided alleviation on APAP-induced hepatoxicity in C57BL/6 mice. APAP performs extensive necrosis and dissolves nucleus suggesting liver damage from hepatic histopathology. Serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase analysis and liver histological evaluation showed that TSG reduced the hepatotoxicity induced by a toxic dose of APAP. Moreover, TSG alone had no hepatotoxicity. TSG eliminated hepatic glutathione depletion and cysteine adducts formation. It also reduced the expression of interleukin-10 and lowered the production of reactive oxygen species in liver tissues. Luminex was used to detect cytokine production in different groups. Herein, we used an untargeted metabolomics approach by performing ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry on treated mice to identify metabolic disruptions under APAP and TSG. Major alterations were observed for purine metabolism, amino acid metabolism, and fatty acid metabolism. These data provide metabolic evidence and biomarkers in the liver that the ABC transporters, Glycine serine and threonine metabolism, and Choline metabolism in cancer changed the most. These targets of metabolites have the potential to improve our understanding of homeostatic. Meanwhile, these metabolites revealed that TSG can alleviate inflammation caused by APAP and promote the activity of intrinsic antioxidants. In summary, TSG can regulate lipid metabolism, promote the production of antioxidant enzymes, and decrease the inflammatory response., (© 2020 Wiley Periodicals LLC.)

The critical role of mitochondrial dysfunction in the pathological mechanisms of neurodegenerative disorders, particularly Parkinson's disease (PD), is well established. Compelling evidence indicates that Parkinson's proteins (e.g., α-synuclein, Parkin, PINK1, DJ-1, and LRRK2) are associated with mitochondrial dysfunction and oxidative stress in PD. Significantly, there is a possible central role of alpha-synuclein (α-Syn) in the occurrence of mitochondrial dysfunction and oxidative stress by the mediation of different signaling pathways. Also, tau, traditionally considered as the main component of neurofibrillary tangles, aggregates and amplifies the neurotoxic effects on mitochondria by interacting with α-Syn. Moreover, oxidative stress caused by mitochondrial dysfunction favors assembly of both α-Syn and tau and also plays a key role in the formation of protein aggregates. In this review, we provide an overview of the relationship between these two pathological proteins and mitochondrial dysfunction in PD, and also summarize the underlying mechanisms in the interplay of α-Syn aggregation and phosphorylated tau targeting the mitochondria, to find new strategies to prevent PD processing., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Depression has become one of the most prevalent neuropsychiatric disorders characterized by anhedonia, anxiety, pessimism, or even suicidal thoughts. Receptor theory has been pointed out to explain the pathogenesis of depression, while it is still subject to debate. Additionally, gene abnormality accounts for nearly 40-50% of depression risk, which is a significant factor contributing to the onset of depression. Accordingly, studying on receptors and their gene abnormality are critical parts of the research on internal causes of depression. This review summarizes the pathogenesis of depression from six of the most related receptors and their associated genes, including N-methyl-D-aspartate receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, glucocorticoid receptor, 5-hydroxytryptamine receptor, GABA A receptor α2, and dopamine receptor; and several "non-classic" receptors, such as metabotropic glutamate receptor, opioid receptor, and insulin receptor. These receptors have received considerable critical attention and are highly implicated in the onset of depression. We begin by providing the biological mechanisms of action of these receptors on the pathogenesis of depression. Then we review the historical and social context about these receptors. Finally, we discuss the limitations of the current state of knowledge and outline insights on future research directions, aiming to provide more novel targets and theoretical basis for the early prevention, accurate diagnosis and prompt treatment of depression., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A new sesquiterpene pyridine alkaloid ( 1 ), along with four known compounds ( 2 - 5 ), were isolated from the stems and leaves of Euonymus fortunei . The new structure was determined by extensive spectroscopic analyses (IR, UV, NMR, HRESIMS and ECD). In addition, compound 3 showed a stronger anti-respiratory syncytial virus (RSV) activity with an IC 50 value of 1.20 ± 0.10 µM than the positive control ribavirin with an IC 50 value of 5.62 ± 0.49 µM.[Formula: see text].

Neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) commonly characterized by the gradual loss of neurons have a seriously bad impact on motor and cognitive abilities of affected humans and bring great inconvenience to their lives. Mitochondrial dysfunction has been considered the key and common factor for the pathologies of neurodegenerative diseases for that neurons are extremely energy-intensive due to their unique properties in structures and functions. Thus, mitophagy, as a central role of mitochondrial quality control and currently believed to be the most effective pathway to clear dysfunctional or unwanted mitochondria, is rather crucial in the preservation of neuronal health. In addition, mitophagy establishes an intimated link with several other pathways of mitochondrial quality control (e.g., mitochondrial biogenesis and mitochondrial dynamics), and they work together to preserve mitochondrial health. Therefore, in this review, we summarized the recent process on the mechanisms of mitophagy pathways in mammals, it's linking to mitochondrial quality control, its role in several major neurodegenerative diseases, and possible therapeutic interventions focusing on mitophagy pathways. And we expect that it can provide us with more understanding of the mitophagy pathways and more promising approaches for the treatment of neurodegenerative diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Current treatments for Parkinson's disease (PD) are mainly dopaminergic drugs. However, dopaminergic drugs are only symptomatic treatments and limited by several side effects. Recent studies into drug development focused on emerging new molecular mechanisms, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear receptor-related 1 (Nurr1), adenosine receptor A2, nicotine receptor, metabotropic glutamate receptors (mGluRs), and glucocerebrosidase (GCase). Also, immunotherapy and common pathological mechanisms shared with Alzheimer's Disease (AD) and diabetes have attracted much attention. In this review, we summarized the development of preclinical and clinical studies of novel drugs and the improvement of dopaminergic drugs to provide a prospect for PD treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The complexity of healthcare and concurrent advances in technology have promoted Interprofessional Education (IPE) in healthcare schools to prepare students to collaborate on interdisciplinary teams. Since 2016, healthcare curricula in Taiwan have incorporated IPE-based capstone courses to enhance creativity. To better understand the predictors of team creativity could help educators improve IPE and outcomes for nursing students and patients., Purpose: To determine whether nursing students' demographic characteristics, individual creativity, and perceived team interaction behaviors, team swift trust, team conflict, and team task interdependence may predict high perceived team creativity in IPE settings., Methods: A cross-sectional study design included nursing students (N = 99) at a science and technology university in Taiwan. Data from self-report questionnaires included variables for demographic characteristics, individual creativity, and perceived team characteristics. A hierarchical multiple regression analysis revealed predictors of high perceived team creativity., Results: Nursing students who perceived high team creativity also perceived higher interaction behaviors and lower process conflict than those who perceived less creativity. Spontaneous communication and team task conflict predicted high perceived team creativity., Conclusions: Nursing educators could increase team creativity in IPE by encouraging spontaneous communication and constructive task-oriented conflict management. This may benefit patient outcomes in the future., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Obstructive sleep apnoea (OSA) appears common in pregnancy. Complications of pregnancy such as gestational diabetes and hypertension predispose women to cardiometabolic disease in later life. It is unknown if snoring during pregnancy is a risk marker for later-life OSA., Methods: We analysed data from N = 897 women in the Sleep Apnea Global Interdisciplinary Consortium (SAGIC), which recruited patients attending sleep clinics at 11 sites. There were 577 cases with current OSA and 320 controls. Cases were further categorised into mild, moderate, and severe OSA based on apnoea-hypopnoea index. Retrospective self-report of snoring during pregnancy was the exposure of interest and was reported by 2.9% of cases and 3.4% of controls., Results: Multinomial regression demonstrated that snoring during a previous pregnancy was not significantly associated with mild (OR 0.34, 95% CI 0.09-1.25, p = 0.10), moderate (OR 0.69, 95% CI 0.21-2.19, p = 0.52), or severe OSA (OR 1.86, 95% CI 0.77-4.48, p = 0.17) compared to no snoring during pregnancy. Results were unchanged after adjustment for age, body mass index, and ethnicity. 79% of women reported current snoring but all who snored during pregnancy reported current snoring., Conclusions: Women who snore during pregnancy continue snoring in later-life but do not appear more likely to develop OSA. These findings are limited by self-reported data, recall bias, and small numbers of women who reported snoring during pregnancy. A prospective study with objective measurement of sleep and snoring during pregnancy is needed to examine the links between sleep disorders in pregnancy with health in later life., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disease with complicated pathogenesis. A novel bibenzyl compound 2-[4-hydroxy-3-(4-hydroxyphenyl)benzyl]-4-(4-hydroxyphenyl)phenol (20C) has been shown to have some neuroprotective effects, and its mechanism still needs further research. In this study, we used a 6-hydroxydopamine (6-OHDA)-induced PD rat model to evaluate the protective effect of 20C. Our study found that 20C could improve behavioral defects in 6-OHDA-lesion rats, decrease neuroinflammation and protect their DA neurons. It could inhibit the activity of inducible nitric oxide synthase (iNOS) induced by 6-OHDA, and lead to a decrease in the expression of nitrated-α-synuclein. When exposed to AMT-an inhibitor of iNOS, the nitrated-α-synuclein in PC12 decreased, and 20C demonstrated the same function on nitrated-α-synuclein as AMT. Besides, we also found that nitrated-α-synuclein was displayed in microglia. And 20C could decrease the expression of antigen-presenting molecule major histocompatibility complex I (MHC I) in dopamine (DA) neurons and MHC II in microglia induced by 6-OHDA. So, these imply that nitrated-α-synuclein might act as an endogenous antigen activating adaptive immunity, and the neuroprotection of 20C might be associated with inhibiting the activity of iNOS, decreasing the expression of the antigen molecule nitrated-α-synuclein and the antigen presenting molecule MHC. Our results indicated that inhibiting iNOS might be an effective strategy to protect neurons from oxidative stress., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Depression is a common neuropsychiatric symptom of Parkinson's disease (PD), resulting in a lower quality of life and cognitive impairment in PD patients. Traditional Chinese medicine (TCM) formulas have been widely used in neurodegenerative disease and neuropsychic disorders to improve life quality of patients in ethnomedicine. TCM formulas combined with selective serotonin reuptake inhibitors (SSRIs) also have a positive effect on depressed PD compared with SSRIs as reported by several clinical studies. However, the results are discordant and failed to be conclusive. We aim to evaluate the efficacy of TCM formulas combined with SSRIs for depressed PD in this systematic review. We searched literatures from PubMed, Web of Science, Medline, Embase, Google Scholar, Chinese National Knowledge Infrastructure, Wanfang Database, and VIP Information Database before July 2020. We included randomized controlled trials investigating the efficacy of TCM formulas combined with SSRIs on depressed PD patients. This analysis was according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Eleven randomized clinical trials involving 861 subjects were enrolled in this analysis. The overall results showed that TCM formulas combined with SSRIs significantly improved the depression score [weighted mean difference (WMD): -4.920, 95% confidence interval (CI): (-5.999, -3.840); [Formula: see text]¡ 0.001] and had a statistical significance on Unified Parkinson's Disease Rating Scale II score [WMD: -1.209, 95% CI: (-1.561, -0.857); [Formula: see text] < 0.001]. Furthermore, we observed that Chai-Hu-Shu-Gan Powder combined with SSRIs had a significant improvement on the depressive symptom in PD compared to the SSRIs alone [WMD: -5.390, 95% CI: (-7.66, -3.11); [Formula: see text] < 0.001]. No severe side events were reported in these included trials. This systematic review provided the evidences that TCM formulas combined with SSRIs might be helpful and safe in the treatment of depression of PD, including Chai-Hu-Shu-Gan Powder. Also, more randomized double-blinded trials with reliable design are required in the future.

The aim of this meta-analysis was to compare the pooled sensitivity and specificity of the Pediatric Sleep Questionnaire (PSQ), Obstructive Sleep Apnea Questionnaire (OSA-18), and pulse oximetry (PO) according to OSAS severity. Three electronic databases were searched for studies evaluating sensitivity and specificity of the three tools against the apnea-hypopnea index measured using overnight in-laboratory or in-home polysomnography in children and adolescents from inception until January 11, 2020. A random-effects bivariate model was used to estimate the summary sensitivity and specificity of the tools. We identified 39 studies involving 6131 clinical and community children (aged 2.9-16.7 y). The PSQ exhibited the highest sensitivity (74%) for detecting symptoms of mild pediatric OSAS. The PSQ and PO had comparable sensitivity in screening moderate and severe pediatric OSAS (0.82 and 0.89 vs 0.83 and 0.83, respectively). PO yielded superior specificity in detecting mild, moderate, and severe pediatric OSAS (86%, 75%, and 83%, respectively) than did the PSQ and OSA-18 (all p < 0.05). Age, percentage of girls, index test criteria, methodology quality, and sample size significantly moderated sensitivity and specificity. For early detection of pediatric OSAS, the combined use of PSQ and PO is recommended when polysomnography is not available. PROSPERO REGISTRATION NUMBER: CRD42018090571., Competing Interests: Conflicts of interest The authors do not have any conflicts of interest to disclose., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Stroke may cause severe death and disability but many clinical trials have failed in the past, partially because the lack of an effective method to regenerate new neurons after stroke. In this study, we report an in vivo neural regeneration approach through AAV NeuroD1-based gene therapy to repair damaged brains after ischemic stroke in adult non-human primates (NHPs). We demonstrate that ectopic expression of a neural transcription factor NeuroD1 in the reactive astrocytes after monkey cortical stroke can convert 90% of the infected astrocytes into neurons. Interestingly, astrocytes are not depleted in the NeuroD1-converted areas, consistent with the proliferative capability of astrocytes. Following ischemic stroke in monkey cortex, the NeuroD1-mediated astrocyte-to-neuron (AtN) conversion significantly increased local neuronal density, reduced microglia and macrophage, and surprisingly protected parvalbumin interneurons in the converted areas. Furthermore, the NeuroD1 gene therapy showed a broad time window in AtN conversion, from 10 to 30 days following ischemic stroke. The cortical astrocyte-converted neurons showed Tbr1 + cortical neuron identity, similar to our earlier findings in rodent animal models. Unexpectedly, NeuroD1 expression in converted neurons showed a significant decrease after 6 months of viral infection, indicating a downregulation of NeuroD1 after neuronal maturation in adult NHPs. These results suggest that in vivo cell conversion through NeuroD1-based gene therapy may be an effective approach to regenerate new neurons for tissue repair in adult primate brains., (Copyright © 2020 Ge, Yang, Li, Wang, Lin, Feng, Chen, Jiang, Wang, Hu and Chen.)

Background: Recently, empirical researchers have observed direct associations between conflict and interaction behaviors within organizational teams. However, research concerning indirect links between conflict and interaction behaviors on interdisciplinary teams in nursing school is scant, particularly in Taiwan., Objectives: The aim of this study was to explore the relationships among various types of conflict and interaction behaviors on interdisciplinary nursing education teams., Design, Setting, and Participants: This study utilized a cross-sectional, quantitative, descriptive design. The authors collected survey data from 99 nursing students who participated in 18-week capstone courses of small interdisciplinary groups collaborating to design healthcare products in Taiwan during 2018 and 2019., Methods: Questionnaires assessed the nursing students' perceptions about their teams' conflicts (of task, process, and relationship), and interaction behaviors (constructive controversy, helping behaviors, and spontaneous communication). The authors used descriptive statistics to compare demographics, conflict scores, and interaction behavior scores for collocated and distributed interdisciplinary teams. A Pearson's analysis identified correlations among the variables and their components, and the SPSS PROCESS macro showed moderating effects of spontaneous communication on the relationship between distributed team and conflict subscales., Results: After confirming the distributed team experienced significantly more conflict than the collocated team, we found significant negative correlations between constructive controversy and both process conflict and relationship conflict on the distributed team. Another interaction behavior, spontaneous communication, had a moderating effect on the relationships between the distributed team and both task conflict and relationship conflict., Conclusion: In interdisciplinary educational settings for nursing students, spontaneous communication may moderate the types of conflict that distributed teams are more likely than collocated teams to experience. Constructive controversy may be especially effective at mitigating conflict on distributed teams. Nursing educators may refer to these insights to improve outcomes for educational interdisciplinary healthcare teams., Competing Interests: Declaration of competing interest No competing interests are declared by the authors., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: The aims of this study are to examine the changes of tongue thickness and distance of two lingual arteries through drug-induced sleep ultrasound, and explore the relationship between sonographic measurements and clinical data., Materials and Methods: A total of 26 confirmed obstructive sleep apnea patients were recruited in this one-year study. All patients received ultrasound examination twice (wakefulness and drug-induced sleep) in sleep center under level 1 polysomnographic monitor. Drug-induced sleep was performed by administration of one Stilnox (Zolpidem, 2 mg/tablet) and ultrasound procedure commenced once stage 2 sleep shown in polysomnography. Ultrasound imaging was implemented via submental approach with transducer position at the sagittal midline of the submental area (sagittal view) to measure thickness of the tongue. Transducer was then moved at a transverse midpoint between the inferior border of the mandible and the hyoid bone (transverse view) to measure the distance between 2 lingual arteries., Results: The distance between 2 lingual arteries elongated significantly (p < .001) and thickness of tongue muscle became thinner during drug-induced sleep. The distance between 2 lingual arteries (sleep) had positive correlation with apnea/hypopnea index (AHI, r = 0.51, p = .008) and body mass index (BMI, r = 0.46, p = .018)., Conclusion: Drug-induced sleep ultrasound is feasible to measure changes of tongue in OSA patients. Ultrasound imaging showed that tongue muscle became thinner in conjunction with significant widening in distance between two lingual arteries during hypnotic-induced sleep and that was positively correlated with AHI and BMI. Drug-induced sleep ultrasound may be helpful to enhance safety in tongue surgery for OSA patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier B.V.)

The endocannabinoid system (ECS) has received extensive attention for its neuroprotective effect on the brain. This system comprises endocannabinoids, endocannabinoid receptors, and the corresponding ligands and proteins. The molecular players involved in their regulation and metabolism are potential therapeutic targets for neuropsychiatric diseases including anxiety, depression and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The inhibitors of two endocannabinoid hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), have the capacity to increase the level of endocannabinoids indirectly, causing fewer side effects than those associated with direct supplementation of cannabinoids. Their antidepressant and anxiolytic mechanisms are considered to modulate the hypothalamic-pituitary-adrenal axis and regulate synaptic and neural plasticity. In terms of AD/PD, treatment with FAAH/MAGL inhibitors leads to reduction in amyloid β-protein deposition and inhibition of the death of dopamine neurons, which are commonly accepted to underlie the pathogenesis of AD and PD, respectively. Inflammation as the cause of depression/anxiety and PD/AD is also the target of FAAH/MAGL inhibitors. In this review, we summarize the application and involvement of FAAH/MAGL inhibitors in related neurological diseases. Focus on the latest research progress using FAAH/MAGL inhibitors is expected to facilitate the development of novel approaches with therapeutic potential.

Phosphoinositide-3 kinase signaling modulates many cellular processes, including cell survival, proliferation, differentiation, and apoptosis. Currently, it is known that the establishment of respiratory syncytial virus infection requires phosphoinositide-3 kinase signaling. However, the regulatory pattern of phosphoinositide-3 kinase signaling or its corresponding molecular mechanism during respiratory syncytial virus entry remains unclear. Here, the involvement of phosphoinositide-3 kinase signaling in respiratory syncytial virus entry was studied. PIK-24, a novel compound designed with phosphoinositide-3 kinase as a target, had potent anti-respiratory syncytial virus activity both in vitro and in vivo PIK-24 significantly reduced viral entry into the host cell through blocking the late stage of the fusion process. In a mouse model, PIK-24 effectively reduced the viral load and alleviated inflammation in lung tissue. Subsequent studies on the antiviral mechanism of PIK-24 revealed that viral entry was accompanied by phosphoinositide-3 kinase signaling activation, downstream RhoA and cofilin upregulation, and actin cytoskeleton rearrangement. PIK-24 treatment significantly reversed all these effects. The disruption of actin cytoskeleton dynamics or the modulation of phosphoinositide-3 kinase activity by knockdown also affected viral entry efficacy. Altogether, it is reasonable to conclude that the antiviral activity of PIK-24 depends on the phosphoinositide-3 kinase signaling and that the use of phosphoinositide-3 kinase signaling to regulate actin cytoskeleton rearrangement plays a key role in respiratory syncytial virus entry., (Copyright © 2020 American Society for Microbiology.)

Pegaharines A-G ( 1 - 6 ), six novel β-carboline alkaloids representing three types of skeleton, were isolated from the seeds of Peganum harmala . Compound 1 is a peculiar β-carboline alkaloid characterized by the unprecedented carbon skeleton of an azepine-indole system. Compounds 3 - 6 represent the first examples of heterodimers constructed from rare tetracyclic β-carboline and classic tricyclic β-carboline alkaloids. Compounds 1 and 2 were characterized by X-ray crystallography. Compound 4 exhibited strong antiviral activity against HSV-2, with an IC 50 value of 2.12 ± 0.14 μM.

Studies have shown that the ginsenoside Rg1 can improve depressive symptoms in vitro and in vivo. However, the efficacy of Rg1on the hippocampal astrocyte gap junctions in depression are unclear. We mainly aimed to explore the relationship between Rg1, hippocampal astrocyte gap junctions and depression. Using primary cultured astrocytes, corticosterone (CORT) was used to induce stress. CORT (100 μM) significantly reduced the survival rate in astrocytes, and this effect was prevented by additional Rg1 administration. Interestingly, the gap junction blocker carbenoxolone (CBX) was able to revert this Rg1 effect. In in vivo models, one group was exposed to chronic unpredictable stress (CUS) for 47 days, while another group was bilaterally injected with CBX (100 μM) into the hippocampal CA1 region. Rats treated with Rg1 (20 mg/kg) showed an improvement in the sucrose preference and the forced swimming test in both models, indicating an antidepressive activity of Rg1. The levels of astrocyte gap junction connexin 43 (Cx43) were detected by immunofluorescence (IF) and western blotting. The levels of glial fibrillary acidic protein (GFAP) were detected by IF. The gap junctions in the hippocampal CA1 area were evaluated using dye transfer and electron microscopy. The reduction in Cx43 expression, the decrease in the Cx43 to GFAP ratio, the shorter dye diffusion distance, and the abnormal ultrastructure of gap junctions in rats exposed to CUS were markedly alleviated by concomitant Rg1 treatment. Taken together, the ginsenoside Rg1 could improve depression-like behavior in rats induced by astrocyte gap junction dysfunction in the hippocampus., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To assess the risk of Alzheimer's disease (AD) in patients with obstructive sleep apnea (OSA) with or without treatment based on real-world evidence., Study Design: Retrospective cohort study., Methods: Patients newly diagnosed with OSA during 1997-2012 were identified using the National Health Insurance Research Database of Taiwan. Patients without OSA were randomly selected and matched in a 1:4 ratio by age, sex, urbanization level, and income. All patients were followed up until death or the end of 2013. The primary outcome was AD occurrence., Results: This study included 3,978 OSA patients and 15,912 non-OSA patients. OSA was independently and significantly associated with a higher incidence of AD in an adjusted Cox proportional hazard model (adjusted hazard ratio: 2.12; 95% confidence interval [CI], 1.27-3.56). The average period of AD detection from the time of OSA occurrence was 5.44 years (standard deviation: 2.96). Subgroup analyses revealed that the effect of OSA remained significant in patients aged ≥60 years, male subgroups, patients without CPAP or surgical treatment, and patients without pharmacological therapies. Patients with OSA who received treatment (continuous positive airway pressure or surgery) exhibited a significantly reduced risk of AD compared with those without treatment (incidence rate ratio 0.23, 95% CI, 0.06-0.98)., Conclusion: OSA is independently associated with an increased risk of AD. Treatment for OSA reduces the AD risk in OSA patients. AD irreversibility renders OSA as a potential modifiable target for slowing or preventing the process of AD development., Level of Evidence: IV Laryngoscope, 130:2292-2298, 2020., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Extreme phenotypes of OSA have not been systematically defined., Research Question: This study developed objective definitions of extreme phenotypes of OSA by using a multivariate approach. The utility of these definitions for identifying characteristics that confer predisposition toward or protection against OSA is shown in a new prospective sample., Study Design and Methods: In a large international sample, race-specific liability scores were calculated from a weighted logistic regression that included age, sex, and BMI. Extreme cases were defined as individuals with an apnea-hypopnea index (AHI) ≥ 30 events/hour but low likelihood of OSA based on age, sex, and BMI (liability scores > 90th percentile). Similarly, extreme controls were individuals with an AHI < 5 events/hour but high likelihood of OSA (liability scores < 10th percentile). Definitions were applied to a prospective sample from the Sleep Apnea Global Interdisciplinary Consortium, and differences in photography-based craniofacial and intraoral phenotypes were evaluated., Results: This study included retrospective data from 81,338 individuals. A total of 4,168 extreme cases and 1,432 extreme controls were identified by using liability scores. Extreme cases were younger (43.1 ± 14.7 years), overweight (28.6 ± 6.8 kg/m 2 ), and predominantly female (71.1%). Extreme controls were older (53.8 ± 14.1 years), obese (34.0 ± 8.1 kg/m 2 ), and predominantly male (65.8%). These objective definitions identified 29 extreme cases and 87 extreme controls among 1,424 Sleep Apnea Global Interdisciplinary Consortium participants with photography-based phenotyping. Comparisons suggest that a greater cervicomental angle increases risk for OSA in the absence of clinical risk factors, and smaller facial widths are protective in the presence of clinical risk factors., Interpretation: This objective definition can be applied in sleep centers throughout the world to consistently define OSA extreme phenotypes for future studies on genetic, anatomic, and physiologic pathways to OSA., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Chemokine-like factor 1 (CKLF1) is a chemokine increased significantly in ischemic brain poststroke. It shows chemotaxis effects on various immune cells, but the mechanisms of CKLF1 migrating neutrophils are poorly understood. Recent studies have provided evidence that CC chemokine receptor 5 (CCR5), a receptor of CKLF1, is involved in ischemic stroke., Purposes: To investigate the effects of HIF-1α guided AAV in ischemic brain, investigating the outcome of stroke, and examining the involvement of CKLF1/CCR5 axis in recruitment of neutrophils., Results: HIF-1α guided AAV knocked down CKLF1 in ischemic area and alleviated brain damage of rats. CKLF1 migrated neutrophils through CCR5, worsening inflammatory responses. Akt/GSK-3β pathway may involve in CKLF1/CCR5 axis guided neutrophils chemotaxis., Conclusions: CKLF1/CCR5 axis is involved in neutrophils migration of rats with transient cerebral ischemia. CKLF1/CCR5 axis may be a useful target for stroke therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Study Objectives: OSA has been associated with increased cancer incidence and mortality. The aim of this study was to investigate cancer-related mortality, overall survival, and progression-free survival in patients with suspected OSA and lung cancer., Methods: This was a case series analysis of lung cancer from a sleep cohort with suspected OSA between 2009 and 2014. The AHI, hypoxia index, and survival outcome were recorded. Immunohistochemistry was used to analyze hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor expression in tumor pathology., Results: In the sleep cohort comprising 8,261 patients, a total of 23 patients had lung cancer. The incidence of lung cancer was significantly higher in the sleep cohort than in the entire adult population in Taiwan (crude incidence rate: 242.1 vs 51.5 per 10⁵ persons, P < .01). The 3-year cancer-related mortality was 25% in AHI < 15 events/h, 50% in AHI 15-29 events/h, and 80% in AHI ≥ 30 events/h (χ² test for trend, P = .03). In Kaplan-Meier survival analysis, patients with stage III-IV lung cancer and AHI < 30 events/h exhibited significantly better overall survival (P = .02) and progression-free survival (P = .02) than patients with severe OSA. Overexpression of HIF-1α and vascular endothelial growth factor was shown in 63% and 45% of lung tumor samples. Overexpression of HIF-1α was positively associated with AHI (P = .04)., Conclusions: In this preliminary case series, severe OSA is associated with an increased risk of cancer mortality in patients with stage III-IV lung cancer. AHI was significantly associated with HIF-1α overexpression., (© 2020 American Academy of Sleep Medicine.)

Pediatric obstructive sleep apnea (OSA) is associated with adverse health outcomes; however, little is known about the diversity of this population. This retrospective study aims to investigate age-related differences in the anthropometric and clinical features of this population. A total of 253 Taiwanese children (70 (27.7%) girls and 183 (72.3%) boys) with OSA were reviewed. Their median age, body mass index (BMI) z-score, and apnea-hypopnea index were 6.9 years, 0.87, and 9.5 events/h, respectively. The cohort was divided into three subgroups: 'preschoolers' (≥2 and <6 years), 'school-age children' (≥6 and <10 years), and 'adolescents (≥10 and <18 years)'. The percentage of the male sex, BMI z-score, neck circumference, systolic blood pressure z-score, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio tended to increase with age. Adenoid grades tended to decrease with age. Overall, disease severity was independently correlated with neck circumference, tonsil size, and adenoid grade. Increased neck circumference and tonsillar hypertrophy were the most influential factors for younger children, whereas adenoidal hypertrophy became more important at an older age. In conclusion, gender prevalence ratio, anthropometric measures, and clinical features varied with age, and the pathogenic drivers were not necessarily the same as the aggravating ones.

Our previous studies have shown that ginsenoside Rg1 (Rg1) exerts antidepressant-like effects in animal models of depression, accompanied by an improvement of astrocytic gap junction functions. However, whether connexin 43 (Cx43), the major connexin forming gap junctions between astrocytes, is the key regulator of Rg1-induced antidepressant-like effects is still unknown. In this study, we examine in vitro and in vivo the involvement of Cx43 in the antidepressant effects of Rg1. Corticosterone was used to establish an in vitro rat model of depression. Treatment with Rg1 1 h prior to corticosterone significantly improved the cell viability of astrocytes, which was significantly inhibited by carbenoxolone, a widely used gap junction inhibitor. Moreover, Rg1 treatment significantly ameliorated antidepressant-sensitive behaviours induced by infusion of carbenoxolone or Gap26, a selective inhibitor of Cx43, into the prefrontal cortex of the animals. Rg1 treatment increased the expression of Cx43 compared with Gap26 group. According to these results, the antidepressant-like effects of Rg1 were mainly mediated by Cx43-formed gap junctions., Competing Interests: Declaration of competing interest All the authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Obstructive sleep apnea (OSA) is a prevalent disease, which influences social relations and quality of life with major health impact. The etiology of OSA is multi-factorial involving both anatomical obstruction and physiological collapse of the upper airway during sleep with different proportion in individual patients. Continuous positive airway pressure (CPAP) is the gold standard and first-line treatment for OSA patients. The mechanism of CPAP is acting as air splint to avoid principal pharyngeal collapse during sleep. Consequently, extrapharyngeal collapse and significant pharyngeal obstructions can lower its compliance and lead to its failure. Adequate mask and pressure with thorough survey to eliminate side effects of CPAP from nasal, mask and flow-related problems are the prerequisite to improve CPAP compliance. For CPAP failure patients, multi-dimensional surgery is an alternative and salvage treatment that involves soft tissue surgery, skeletal surgery, and bariatric surgery. OSA patients with craniofacial anomaly are suggested to skeletal surgery. By contrast, OSA patients with pathological obesity are referred to bariatric surgery. Soft tissue surgery targets at the nose, soft palate, lateral pharyngeal wall, tongue and epiglottis that can be implemented by multi-level surgery with hybrid technique (mucosa-preservation, fat-ablation, muscle-suspension, tonsil-excision, cartilage-reconstruction) to maximize surgical outcomes and minimize complications. Some evolution in surgical concept and technique are noteworthy that include mini-invasive septoturbinoplasty, palatal suspension instead of excision, whole tongue treatment, and two-dimensional supraglottoplasty. Postoperative integrated treatment including myofunctional, positional therapy and body weight control reduces relapse of OSA and improves long-term treatment outcomes., (Copyright © 2020. Published by Elsevier B.V.)

Multiple sclerosis (MS) is a chronic inflammatory disease that is characterized by leukocyte infiltration and subsequent axonal damage, demyelinating inflammation, and formation of sclerosing plaques in brain tissue. The results of various studies in patients indicate that autoimmunity and inflammation make an important impact on the pathogenesis of MS. Chemokines are key mediators of inflammation development and cell migration, mediating various immune cell responses, including chemotaxis and immune activation, and are important in immunity and inflammation, therefore we focus on chemokines and their receptors in multiple sclerosis. In this article, we summarize the study of the role of prominent chemokines and their receptors in MS patients and MS animal modelsand discuss their potential significance in inflammatory injury and repair of MS. We have also summarized the progress in the treatment of multiple sclerosis antagonists in recent years with chemokine receptors as targets., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The mechanism of demyelinating diseases is controversial, while demyelination and remyeliantion disorder is the acknowledged etiology and therapeutic target. Untill now, there is no efficient therapy for these diseases. CZ-7, a new derivative of Claulansine F, which has been reported before, were investigated its pro-remyelination effect and its associated mechanism in cuprizone (CPZ)-induced demyelination model. In this study, male C57BL/6 mice were subjected to CPZ (300 mg/kg) through intragastric gavage and were orally administered CZ-7 (20 mg/kg) meanwhile. The results of weight monitoring and behavioral testing showed that CZ-7 can significantly improve behavior dysfunction in the demyelinating mice. Luxol-fast blue (LFB) staining, myelin basic protein (MBP) immunostaining, transmission electron microscopy (TEM) and QPCR results indicated the therapeutic effect of CZ-7 on CPZ mice model. Furthermore, degraded myelin basic protein (dMBP) immunofluorescent staining and oil red O staining showed that CZ-7 contributed to the clearance of degraded myelin debris. More microglia displayed phagocytic shape assembled in corpus callosum (CC) and there was an active process of phagocytosis in microglia after CZ-7 treatment. Immunofluorescent staining and QPCR analysis revealed the M2-polarized phenotype switch of microglia in the process of myelin debris removel, which demostrated the microenvironment improvement of CZ-7. Moreover, immunofluorescent staining of NG2 and O4 demonstated that more oligodendrocyte precursor cells (OPCs) existed in CC after CZ-7 treatment. In conclusion, our results demonstrated CZ-7 has a potential therapeutic effect for MS and other demyelinating diseases through enhancing myelin debris clearance to improve the microenvironment., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Similar to other types of neuronal degeneration, Parkinson's disease (PD) is characterized by the aggregation of a pathological protein, α-synuclein. The endoplasmic reticulum (ER) is the principal site of protein synthesis, quality control and degradation. Genetic mutants, environmental insults and other factors disturb ER balance and induce the accumulation of misfolded/unfolded proteins, which initiate ER stress and disturb normal cell function. ER stress perturbs Ca 2+ homeostasis and initiates the activation of autophagy and inflammasomes, which have been identified as risk factors for the development of PD. However, the mechanisms by which ER stress contributes to the processed of PD pathogenesis and development remain unclear. This review summarizes current knowledge of ER stress and highlights the principal role of ER stress in PD pathogenesis which may help reveal novel sight to illustrate the pathomechanism of PD., 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 © 2020. Published by Elsevier B.V.)

The aim of this study was to investigate the differences in volatile organic compounds (VOCs) obtained from the feces of a Baihe Jizihuang Tang (BHT)-treated rat depression model. Rats were subjected to chronic unpredictable mild stress (CUMS), and the differences in VOCs were analyzed by headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS), NIST software, principal component analysis, and orthogonal partial least squares discriminant analysis. Eleven biomarkers were identified on the basis of VOC migration time, and their relative peak intensities were analyzed. A metabonomic model was established using multivariate statistical analysis. The study demonstrated the metabonomics of CUMS rats and the intervention effect of BHT and also highlighted the potential therapeutic effects of the traditional Chinese medicine (TCM) Jingfang for the clinical treatment of complex diseases, which was in line with the holistic and systemic approaches of TCM. This study augments the use of metabonomics based on HS-GC-IMS in research studies. Using this method, there is no need to pre-process samples by extraction or derivatization, and the VOC component of the sample can be detected directly and rapidly. In conclusion, this study establishes a simple, convenient, and fast technique, which can help identify clinical biomarkers for rapid medical diagnosis., 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 © 2020 Elsevier B.V. All rights reserved.)

Background: Many nursing programs include a capstone project as part of the nursing curriculum. In Taiwan, these courses involve development of healthcare products. A student's success can depend on faculty's ability to employ creative teaching behaviors., Purpose: To examine the relationship between demographic and teaching characteristics, personality traits, and self-perceived levels of creative teaching behaviors for capstone nursing faculty., Methods: This study used a cross-sectional, descriptive, correlational study design. Faculty (N = 53) were recruited from healthcare schools in Taiwan. Data from self-report questionnaires included variables for demographic and teaching characteristics, perceived levels of creative personality traits (imagination, curiosity, adventure, challenge) and creative teaching behaviors (autonomous learning, creative thinking, characteristics/motivations, environment/opportunity). Hierarchical multiple regression identified predictors of creative teaching behaviors., Results: Mean total scores for creative teaching behaviors were high for nursing faculty; characteristics/motivations were the lowest subscale score. The creative personality trait of curiosity significantly and positively influenced the perception of high levels creative teaching behaviors., Conclusions: High scores for curiosity significantly predicted high scores for creative teaching behaviors for nursing faculty. These findings suggest faculty who perceive themselves as having low levels of creative teaching behaviors might benefit from training to increase levels of curiosity., Competing Interests: Declaration of competing interest No competing interests are declared by the authors, (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Vascular dementia (VD) is the second most common dementia disease after Alzheimer's diseases (AD) in the world. Donepezil is used to treat mild to moderate AD, and it has been shown to treat cognitive impairment and memory deficits caused by VD. However, the action mechanism of donepezil against VD has not been clarified. In this study, a bilateral common carotid artery occlusion (BCCAO) model was established in rats to simulate the pathology of VD. Two weeks after the surgery, the rats were administered donepezil (10 mg · kg -1  · d -1 , ig) for 3 weeks, and then subjected to behavioral tests. We showed that donepezil treatment significantly improved the performance of BCCAO rats in Morris Water Mazes test and Step-down test. Furthermore, we showed that donepezil treatment significantly attenuated neurodegeneration and restored the synapse dendritic spines density in cortex and hippocampus. We revealed that donepezil treatment significantly increased BDNF expression in cortex and hippocampus. Interestingly, donepezil treatment significantly decreased nuclear translocation of HDAC6 and the binding between HDAC6 and BDNF promoter IV in cortex, but not in the hippocampus. The attenuated neurodegeneration by donepezil in cortex and hippocampus might due to the reduced ROS levels and increased phosphorylation of AMPK, whereas increased phosphorylation of AKT was only detected in cortex. In conclusion, our results demonstrate that donepezil attenuates neurodegeneration in cortex and hippocampus via increasing BDNF expression; the regulation of donepezil on HDAC6 occurred in cortex, but not in the hippocampus. This study further clarifies the pharmacological mechanism of donepezil, while also emphasizes the promising epigenetic regulation of HDAC6.

Patients with sepsis frequently require mechanical ventilation (MV) to survive. However, MV has been shown to induce the production of proinflammatory cytokines, causing ventilator-induced lung injury (VILI). It has been demonstrated that hypoxia-inducible factor (HIF)-1α plays a crucial role in inducing both apoptotic and inflammatory processes. Low-molecular-weight heparin (LMWH) has been shown to have anti-inflammatory activities. However, the effects of HIF-1α and LMWH on sepsis-related acute lung injury (ALI) have not been fully delineated. We hypothesized that LMWH would reduce lung injury, production of free radicals and epithelial apoptosis through the HIF-1α pathway. Male C57BL/6 mice were exposed to 6-mL/kg or 30-mL/kg MV for 5 h. Enoxaparin, 4 mg/kg, was administered subcutaneously 30 min before MV. We observed that MV with endotoxemia induced microvascular permeability; interleukin-6, tumor necrosis factor-α, macrophage inflammatory protein-2 and vascular endothelial growth factor protein production; neutrophil infiltration; oxidative loads; HIF-1α mRNA activation; HIF-1α expression; bronchial epithelial apoptosis; and decreased respiratory function in mice ( p < 0.05). Endotoxin-induced augmentation of VILI and epithelial apoptosis were reduced in the HIF-1α-deficient mice and in the wild-type mice following enoxaparin administration ( p < 0.05). Our data suggest that enoxaparin reduces endotoxin-augmented MV-induced ALI, partially by inhibiting the HIF-1α pathway.

Depression is increasingly threatening human health as a serious psychological problem. However, it is remarkable that the precise mechanism underlying depression remains unelucidated. Recent studies have clarified that non-coding RNA, including but not limited to microRNA, long non-coding RNA, and circular RNA, plays an important role in the pathogenesis of depression. The research results cited in this paper reveal the origin, expression, distribution, function, and mechanism of microRNA in the nervous system. MicroRNA is involved in regulation of life activities, including growth, immune reaction, haematopoiesis, and metabolism, which are significant for maintaining normal physiological functions. Moreover, microRNA plays an important role in cell death and proliferation, development of cancer, and disease prognosis. Here, we also introduce the general research status of long non-coding RNA and circular RNA. Next, descriptive study methods, including fluorescence quantitative polymerase chain reaction, northern blot, microarray technology, RNA-seq, and fluorescent in situ hybridization are discussed. Functional study methods are also summarized and divided into gain- and loss-of-function studies. Moreover, the roles of non-coding RNA in the pathogenesis of depression, including neurogenesis, synaptic plasticity, brain-derived neurotrophic factor expression, HPA axis regulation, neurotransmission, neuropeptide expression, neuro-inflammation, and polyamine synthesis are discussed. Nevertheless, many unknown associations between non-coding RNA and depression remain to be clarified., 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 © 2019. Published by Elsevier B.V.)

Ginsenoside Rg1 is one of the most active ingredients in ginseng, which has been reported to protect dopaminergic neurons and improve behavioral defects in MPTP model, 6-OHDA model and rotenone model. However, it is unclear whether Rg1 exerted neuroprotection in LPS-induced sub-acute PD model. In this study, we investigated the neuroprotective effect of Rg1 in the sub-acute PD mouse model and explored the related mechanisms. Rg1 (10, 20, 40 mg·kg -1 ·d -1 ) was orally administered to mice for 18 days. A sub-acute PD model was established in the mice through LPS microinjection into the substantia nigra (SN) from D8 to D13. We found that Rg1 administration dose-dependently inhibited LPS-induced damage of dopaminergic neurons and activation of glial cells in the substantia nigra pars compacta (SNpc). The neuroprotective effects of Rg1 were associated with the reduction of pro-inflammatory cytokines and the improvement of anti-inflammatory cytokines and neurotrophin in the midbrain. Rg1 shifted the polarization of microglia towards the M2 phenotype from M1, evidenced by decreased M1 markers (inducible NO synthase, CD16, etc.) and increased M2 markers (arginase 1 (Arg1), CD206, etc) in the midbrain. Furthermore, Rg1 administration markedly inhibited nuclear translocation of NF-κB in midbrain microglia. In conclusion, Rg1 protects PD mice induced by continuous LPS injection by inhibiting the nuclear entry of NF-κB and regulating the polarization balance of microglia, shedding new light on a disease-modifying therapy of PD.

Study Objectives: Obstructive sleep apnea (OSA) has been associated with increased cancer incidence and mortality. The aim of this study was to investigate cancer-related mortality, overall survival and progression free survival in patients with suspected OSA and lung cancer., Methods: This was a case series analysis of lung cancer from a sleep cohort with suspected OSA between 2009 and 2014. The apnea- hypopnea index (AHI), Tsat90% (hypoxia index) and survival outcome were recorded. Immunohistochemistry was used to analyze HIF-1α and VEGF expression in tumor pathology., Results: In the sleep cohort comprising 8261 patients, a total of 23 patients had lung cancer. The incidence of lung cancer was significantly higher in the sleep cohort than in the entire adult population in Taiwan (242.1 vs 51.5 per 10⁵ persons, P< 0.01). The 3-year cancer-related mortality was 25% in AHI < 15, 50% in AHI 15 to 29 and 80% in AHI ≥ 30 (chi-squared test for trend P =0.03). In Kaplan-Meier survival analysis, patients with stage III-IV lung cancer and AHI< 30 exhibited significantly better overall survival (P = 0.02) and progression free survival (P = 0.02) than patients with severe OSA. Overexpression of HIF-1α and VEGF was shown in 63 % and 45 % of lung tumor samples. Overexpression of HIF-1α was positively associated with AHI (P = 0.04)., Conclusions: In this preliminary case series, severe OSA is associated with an increased risk of cancer mortality in patients with stage III-IV lung cancer. AHI was significantly associated with HIF-1α overexpression., (© 2020 American Academy of Sleep Medicine.)

Both obstructive sleep apnea (OSA) and obesity are major health issues that contribute to increased systemic inflammation in children. To date, adenotonsillectomy (AT) is still the first-line treatment for childhood OSA. However, the relationships among and predictive values of obesity, inflammation, and OSA severity have not been comprehensively investigated. This prospective study investigated body mass index (BMI), serum inflammatory markers, and OSA severity before and after AT in 60 pediatric patients with OSA. At baseline, differences in levels of interleukin-6, interleukin-9, basic fibroblast growth factor, platelet-derived growth factor-BB, as well as regulated on activation, normal T cell expressed and secreted (RANTES) were significant among the various weight status and OSA severity subgroups. After 3 months postoperatively, the differences in these inflammatory markers diminished along with a decrease in OSA severity while obesity persisted. The rate of surgical cure (defined as postoperative obstructive apnea-hypopnea index < 2.0 and obstructive apnea index < 1.0) was 62%. Multivariate analysis revealed that age, BMI z-score, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein-1, and RANTES independently predicted surgical cure. Despite the significant reductions in inflammatory markers and OSA severity after AT, an inter-dependent relationship between obesity and OSA persisted. In addition to age and BMI, several inflammatory markers helped to precisely predict surgical cure.

Background: Creativity and innovation are considered important core competencies in Taiwan for nursing students. Teachers play a critical role in the development of student creativity. Although studies have investigated creativity training, there is no consensus on how best to evaluate the effectiveness of the training., Objective: To evaluate whether a teaching for creativity module (TCM) can enhance teaching behaviors and self-efficacy of teaching creativity for capstone course nursing faculty. The TCM intervention was taught in two stages by experts in diverse areas of industrial design. A 2-day teaching creativity workshop was followed by reinforcement of creativity skills in the classroom with nursing and design faculties teaching side-by-side for 6 h of the 18-week capstone course., Design: This quasi-experimental study employed a pretest-posttest design to compare an intervention and control group., Participants and Setting: Capstone course nursing faculties were recruited from five science and technology universities in Taiwan., Results: Forty-two capstone faculty members participated; 21 completed the TCM intervention and 21 were in the control group. Analysis of covariance (ANCOVA) demonstrated the TCM intervention group had significantly better post-test mean scores for creative teaching behaviors and self-efficacy of teaching creativity than the control group. Our findings suggest participation in a creativity workshop and reinforcement of teaching skills with classroom interdisciplinary teacher training can augment teaching for creativity of nursing faculty., Conclusion: The findings of this study indicate that an intervention program in creativity can increase teaching behaviors as well as perceptions of self-efficacy regarding teaching for creativity, which could foster student creativity. These findings have important implications for educational settings, as they suggest that the workshop and reinforcement of learning with hands-on guidance in creativity with interdisciplinary teaching should be integrated into the curriculum, which could facilitate student creativity by increasing teaching behaviors and improving self-confidence regarding teaching creativity., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

L-lactate is an abundant metabolite in a number of niches in host organisms and represents an important carbon source for bacterial pathogens such as Neisseria gonorrhoeae. In this study, we describe an alternative, iron-sulfur cluster-containing L-lactate dehydrogenase (LutACB), that is distinct from the flavoprotein L-lactate dehydrogenase (LldD). Expression of lutACB was found to be positively regulated by iron, whereas lldD was more highly expressed under conditions of iron-limitation. The functional role of LutACB and LldD was reflected in in vitro studies of growth and in the survival of N gonorrhoeae in primary cervical epithelial cells., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Parkinson's disease (PD) is a neurodegenerative disease and its characteristic is the progressive degeneration of dopaminergic neurons within the substantia nigra (SN) of the midbrain. There is hardly any clinically proven efficient therapeutics for its cure in several recent preclinical advances proposed to treat PD. Recent studies have found that the endocannabinoid signaling system in particular the comprised two receptors, CB1 and CB2 receptors, has a significant regulatory function in basal ganglia and is involved in the pathogenesis of PD. Therefore, adding new insights into the biochemical interactions between cannabinoids and other signaling pathways may help develop new pharmacological strategies. Factors of the endocannabinoid system (ECS) are abundantly expressed in the neural circuits of basal ganglia, where they interact interactively with glutamatergic, γ-aminobutyric acid-ergic (GABAergic), and dopaminergic signaling systems. Although preclinical studies on PD are promising, the use of cannabinoids at the clinical level has not been thoroughly studied. In this review, we evaluated the available evidence and reviewed the involvement of ECS in etiologies, symptoms and treatments related to PD. Since CB1 and CB2 receptors are the two main receptors of endocannabinoids, we primarily put the focus on the therapeutic role of CB1 and CB2 receptors in PD. We will try to determine future research clues that will help understand the potential therapeutic benefits of the ECS in the treatment of PD, aiming to open up new strategies and ideas for the treatment of PD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) that afflicts millions of individuals worldwide is associated with deposits of aggregate-prone proteins (e.g., α-synuclein) and with mitochondrial dysfunction in neuronal cells. Mitochondria are the main source of reactive oxygen species, provide energy for neuronal cells, and are regarded as dynamic organelles that are determined by mitochondrial fission, fusion, and mitophagy to maintain mitochondrial homeostasis. Growing evidence reveals that several dynamics-related proteins, such as dynamin-related protein 1 (Drp1), mediate mitochondrial fission, fusion, and mitophagy, to protect against neurodegeneration in PD. More importantly, not only is Drp1-mediated fission required for mitophagy that exerts a protective effect on neurons, but abnormal mitochondrial fission and mitophagy can drive neuronal survival or cell death (i.e., autophagy, apoptosis, and necroptosis), suggesting that Drp1 may play a pivotal role in the pathogenesis of PD. Also, PD-related proteins such as α-synuclein, leucine-rich repeat kinase-2, PTEN-induced putative kinase 1, and Parkin have been proven to interact with Drp1, thus contributing to mitochondrial dynamics and clearance, as well as neuronal fate. Here, we review the roles of Drp1 in mitochondrial fission, dynamics, mitophagy, bulk autophagy, apoptosis, and necroptosis for a better understanding of mitochondrial disturbances in PD-associated neurodegeneration and summarize the advances of novel chemical compounds targeting Drp1 to provide new insight into potential PD therapies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)