bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Resting-State Electroencephalography Microstates in Idiopathic Generalized Epilepsy: A Prospective Case-Control Study
Authors: Jiang YuBao , Zhu MingYu , Hu Ying , Wang Kai
Published: November 2021

Objective: Idiopathic generalized epilepsy (IGE) involves aberrant organization and functioning of large-scale brain networks. This study aims to investigate whether the resting-state EEG microstate analysis could provide novel insights into the abnormal temporal and spatial properties of intrinsic brain activities in patients with IGE.

Methods: Three groups of participants were chosen for this study (namely IGE-Seizure, IGE-Seizure Free, and Healthy Controls). EEG microstate analysis on the resting-state EEG datasets was conducted for all participants. The average duration (“Duration”), the average number of microstates per second (“Frequency”), as well as the percentage of total analysis time occupied in that state (“Coverage”) of the EEG microstate were compared among the three groups.

Results: For microstate classes B and D, the differences in Duration, Frequency, and Coverage among the three groups were not statistically significant. Both Frequency and Coverage of microstate class A were statistically significantly larger in the IGE-Seizure group than in the other two groups. The Duration and Coverage of microstate class C were statistically significantly smaller in the IGE-Seizure group than those in the other two groups.

Conclusions: The Microstate class A was regarded as a sensorimotor network and Microstate class C was mainly related to the salience network, this study indicated an altered sensorimotor and salience network in patients with IGE, especially in those who had experienced seizures in the past 2 years, while the visual and attention networks seemed to be intact.

Significance: The temporal dynamics of resting-state networks were studied through EEG microstate analysis in patients with IGE, which is expected to generate indices that could be utilized in clinical researches of epilepsy.
Trends in Incidence and Mortality of Stroke in China From 1990 to 2019
Authors: Sun Tong , Chen Siyang , Wu Ke , Sun Min , Zhang Xianyan , You Chao
Published: November 2021

Objective: Stroke is a leading cause of mortality and morbidity globally. This study aimed to analyze the burden and 30-year trends of ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) in China.

Methods: Data that include incidence and mortality of stroke in China from January 1, 1990 to December 31, 2019 were derived from the Global Burden of Disease (GBD) study 2019. The absolute numbers of incident cases and deaths over the time, and age-standardized rates per 100,000, such as age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR), were analyzed.

Results: In 2019, there were 3.9 (95% uncertainty intervals (UI) 3.4–4.5) million incident cases and 2.1 (3.4–4.5) million deaths related to stroke in China. The ASIR and ASMR of stroke in China was 200 (176–230) and 127 (110–144). From 1990 to 2019, the ASIR of ischemic stroke had increased by 35.0% (29.0–40.0) while the ASIR of ICH and SAH had decreased by −53.0% (−56.0 to −50.0) and by −39.0% (−44.0 to −35.0), respectively. The ASMR of ischemic stroke had increased by 3.0% (−26.0 to 16.0) while the ASMR of ICH and SAH had decreased by −48.0% (−59.0 to −38.0) and by −84.0% (−89.0 to −69.0), respectively.

Conclusion: Although the incidence and mortality rates of stroke in China were decreased from 1990 to 2019, the number of incident cases and deaths nearly doubled. A sharp increase in the incidence rate of ischemic stroke was observed. A higher incidence rate of ischemic stroke in the women was also observed.
Comorbid Autoimmune Diseases in Patients With Myasthenia Gravis: A Retrospective Cross-Sectional Study of a Chinese Cohort
Authors: Shi Jianquan , Huan Xiao , Zhou Lei , Xi Jianying , Song Jie , Wang Ying , Luo Sushan , Zhao Chongbo
Published: November 2021

Introduction: The phenomenon of coexisting autoimmune diseases (ADs) in patients with myasthenia gravis (MG) has attracted considerable attention. However, few studies have investigated the burden and potential clinical associations of ADs in Chinese MG cohorts.

Methods: In this retrospective cross-sectional study, we reviewed the records of 1,132 patients with MG who were admitted to Huashan Hospital Fudan University from August 2013 to August 2020. Patients were excluded if they had incomplete medical records (n = 336).

Results: Comorbid ADs were found in 92 of 796 Chinese patients with MG (11.6%), among which, hyperthyroidism (6.7%), hypothyrosis (2.6%), and vitiligo (0.8%) were predominant. Patients with MG with ADs were predominantly female, younger at the onset of MG symptoms, and had a lower frequency of thymoma. Compared to the general population, we found a significantly higher percentage of hyperthyroidism (8.5-fold increase, p < 0.001), hypothyrosis (2.6-fold increase, p < 0.001), vitiligo (1.3-fold increase, p < 0.001), rheumatoid arthritis (1.4-fold increase, p < 0.001), immune thrombocytopenic purpura (193.1-fold increase, p < 0.001), autoimmune hemolytic anemia (7.4-fold increase, p < 0.001), autoimmune hepatitis (5.1-fold increase, p < 0.001), and polymyositis (11.5-fold increase, p < 0.001) in patients with MG with ADs. Patients with MG with ADs presented a lower proportion of previous history of MC (0 vs. 5.6%, p < 0.05) than those without ADs. The proportion of MGFA Class I at onset in patients with MG with ADs was significantly higher than that in patients with MG without ADs (77.0 vs. 52.7%, p < 0.05). The proportion of MuSK-positive in patients with MG with ADs was significantly lower than that in patients with MG without ADs (0 vs. 4.8%, p < 0.05).

Conclusion: In conclusion, we observed a higher frequency of concurrent ADs in a Chinese MG cohort. Furthermore, MG combined with ADs tended to have mild clinical presentation.
Associations Between Intake of Fermented Dairy Products and Blood Lipid Concentrations Are Affected by Fat Content and Dairy Matrix – The Tromsø Study: Tromsø7
Authors: Machlik Monika Lund , Hopstock Laila Arnesdatter , Wilsgaard Tom , Hansson Patrik
Published: November 2021

Introduction: Dairy fat is rich in saturated fatty acids known to increase serum low-density lipoprotein cholesterol (LDL-C) concentration, an important risk factor for cardiovascular disease (CVD). However, intake of fermented dairy products has been associated with reduced CVD risk in observational studies. How intakes of different fermented dairy products are associated with blood lipid concentrations may provide a possible explanation for the suggested reduced CVD risk.

Aim: To examine the associations between different types of fermented dairy products, with various fat contents and dairy matrix structures, and blood lipid concentrations in a general population.

Methods: In 11,377 women and men aged between 40-99 participating in the population-based Tromsø Study 2015-2016, multivariable linear regression was used to examine associations between total intake of fermented dairy products, intake of yogurt (including regular-fat, low-fat, and semi-solid yogurt), cheese (including regular-fat and low-fat), and liquid fermented dairy, and serum concentrations of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Dietary data was collected using a validated food frequency questionnaire. Analyses were adjusted for potential confounding factors, and cheese intake analyses were stratified by self-reported use of cholesterol-lowering drugs.

Results: Cheese intake was positively associated with HDL-C [regression coefficient 0.02 mmol/l (95 % CI 0.01, 0.03)], and inversely associated with LDL-C [regression coefficient−0.03 mmol/l (95 % CI−0.04,−0.01)] and triglycerides [relative change −1.34 % (95 % CI: −2.29 %, −0.37 %)] per 25 g/day among non-users of cholesterol-lowering drugs, while no associations were found among users. Total intake of fermented dairy was inversely associated with triglycerides [relative change −1.11 % (95 % CI: −1.96 %, −0.24 %)] per 250 g/day, while no associations were found for yogurt intake. Intake of low-fat cheese was more favorably associated with blood lipids compared to regular-fat cheese, and semi-solid yogurt was inversely associated with LDL-C and triglycerides, while intake of liquid fermented dairy was not associated with any of the blood lipids.

Conclusion: This study highlights the importance of investigating specific types of dairy products separately, based on fat content and dairy matrix, when examining effects on blood lipid concentrations, and stratifying statistical models by use of cholesterol-lowering drugs when relevant.
Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Carcinoma by Inhibiting IL-6 Signaling Pathway
Authors: Lu Yao , Xin Dao , Guan Lulu , Xu Mengli , Yang Yalan , Chen Yu , Yang Yuanyuan , Wang-Gillam Andrea , Wang Li , Zong Shanggang , Wang Feng
Published: November 2021

Purpose

To characterize the mechanism by which metformin inhibits PD-L1 expression in esophageal squamous cell carcinoma (ESCC) and to evaluate the effect of metformin on the antitumor immune response.

Methods

The Cancer Genome Atlas (TCGA) database was used to analyze the correlations between IL-6 and prognosis and between IL-6 and PD-L1 gene expression in esophageal cancer. Reverse transcription-quantitative polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence were used to study the mechanism by which metformin affects PD-L1 expression. Additionally, T cell function was assessed in a coculture system containing ESCC cells and peripheral blood mononuclear cells (PBMCs) treated with metformin or IL-6. In an in vivo assay, we used a model established with NPIdKO™ mice, which have a reconstituted immune system generated by transplanting PBMCs through intravenous injection, to evaluate the effect of metformin on tumors.

Results

The TCGA esophageal cancer data showed that IL-6 expression was positively correlated with PD-L1 expression and that patients with high IL-6 expression had a significantly lower overall survival rate than patients with low IL-6 expression. PD-L1 expression in ESCC cell lines was significantly inhibited by metformin via the IL-6/JAK2/STAT3 signaling pathway but was not correlated with the canonical AMPK pathway. In the coculture system, the metformin pretreatment group showed higher T cell activation and better T cell killing function than the control group. Animal experiments confirmed that metformin downregulated PD-L1 expression and that combination treatment with metformin and PD-1 inhibitors synergistically enhanced the antitumor response.

Conclusions

Metformin downregulated PD-L1 expression by blocking the IL-6/JAK2/STAT3 signaling pathway in ESCC, which enhanced the antitumor immune response.
The Quantitative Assessment of Using Multiparametric MRI for Prediction of Extraprostatic Extension in Patients Undergoing Radical Prostatectomy: A Systematic Review and Meta-Analysis
Authors: Li Wei , Sun Yuan , Wu Yiman , Lu Feng , Xu Hongtao
Published: November 2021

Purpose

To investigate the diagnostic performance of using quantitative assessment with multiparametric MRI (mpMRI) for prediction of extraprostatic extension (EPE) in patients with prostate cancer (PCa).

Methods

We performed a computerized search of MEDLINE, Embase, Cochrane Library, Web of Science, and Google Scholar from inception until July 31, 2021. Summary estimates of sensitivity and specificity were pooled with the bivariate model, and quality assessment of included studies was performed with the Quality Assessment of Diagnostic Accuracy Studies-2. We plotted forest plots to graphically present the results. Multiple subgroup analyses and meta-regression were performed to explore the variate clinical settings and heterogeneity.

Results

A total of 23 studies with 3,931 participants were included. The pooled sensitivity and specificity for length of capsular contact (LCC) were 0.79 (95% CI 0.75–0.83) and 0.77 (95% CI 0.73–0.80), for apparent diffusion coefficient (ADC) were 0.71 (95% CI 0.50–0.86) and 0.71 (95% CI 059–0.81), for tumor size were 0.62 (95% CI 0.57–0.67) and 0.75 (95% CI 0.67–0.82), and for tumor volume were 0.77 (95% CI 0.68–0.84) and 0.72 (95% CI 0.56–0.83), respectively. Substantial heterogeneity was presented among included studies, and meta-regression showed that publication year (≤2017 vs. >2017) was the significant factor in studies using LCC as the quantitative assessment (P=0.02).

Conclusion

Four quantitative assessments of LCC, ADC, tumor size, and tumor volume showed moderate to high diagnostic performance of predicting EPE. However, the optimal cutoff threshold varied widely among studies and needs further investigation to establish.
MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres
Authors: Tang Yongjian , Mukherjee Joydeep , Pieper Russell O.
Published: November 2021

TRF2 is part of the shelterin complex that hides telomeric DNA ends and prevents the activation of the cNHEJ pathway that can lead to chromosomal fusion. TRF2, however, also actively suppresses the cNHEJ pathway by recruiting two proteins, MRE11 and UBR5. MRE11 binds BRCC3, which in turn deubiquitinates γH2AX deposited at exposed telomeric DNA ends and limits RNF168 recruitment to the telomere. UBR5, in contrast directly ubiquitinates and destroys RNF168. The loss of telomeric RNF168 in turn blocks the subsequent recruitment of 53BP1 and prevents the cNHEJ-mediated fusion of chromosomes with exposed telomeric DNA ends. Although MRE11 and UBR5 are both involved in the control of telomeric RNF168 levels and the chromosome fusion process, their relative contributions have not been directly addressed. To do so we genetically suppressed MRE11 and UBR5 alone or in combination in glioma cell lines which we previously showed contained dysfunctional telomeres that were dependent on TRF2 for suppression of telomeric fusion and monitored the effects on events associated with telomere fusion. We here show that while suppression of either MRE11 or UBR5 alone had minimal effects on RNF168 telomeric accumulation, 53BP1 recruitment, and telomeric fusion, their combined suppression led to significant increases in RNF168 and 53BP1 telomeric recruitment and telomeric fusion and eventually cell death, all of which were reversible by suppression of RNF168 itself. These results show that MRE11 and UBR5 co-operate to suppress fusion at dysfunctional telomeres.
The Impact of Multidisciplinary Conferences on Healthcare Utilization in Chronic Pain Patients
Authors: Campwala Zahabiya , Davis Gregory , Khazen Olga , Trowbridge Rachel , Nabage Melisande , Bagchi Rohan , Argoff Charles , Pilitsis Julie G.
Published: November 2021

Approximately 100 million adults in the United States have chronic pain, though only a subset utilizes the vast majority of healthcare resources. Multidisciplinary care has been shown to improve outcomes in a variety of clinical conditions. There is concern that multidisciplinary care of chronic pain patients may overwhelm existing resources and increase healthcare utilization due to the volume of patients and the complexity of care. We report our findings on the use of multidisciplinary conferences (MDC) to facilitate care for the most complex patients seen at our tertiary center. Thirty-two of nearly 2,000 patients seen per year were discussed at the MDC, making up the top 2% of complex patients in our practice. We evaluated patients' numeric rating score (NRS) of pain, medication use, hospitalizations, emergency department visits, and visits to pain specialists prior to their enrollment in MDC and 1 year later. Matched samples were compared using Wilcoxon's signed rank test. Patients' NRS scores significantly decreased from 7.64 to 5.54 after inclusion in MDC (p < 0.001). A significant decrease in clinic visits (p < 0.001) and healthcare utilization (p < 0.05) was also observed. Opioid and non-opioid prescriptions did not change significantly (p = 0.43). 83% of providers agreed that MDC improved patient care. While previous studies have shown the effect of multi-disciplinary care, we show notable improvements with a team established around a once-a-month MDC.
Modalities and Determinants of Career Paths in Pediatrics: A Survey of Former Pediatric Residents From Lille University Medical Center
Authors: Héritier-Laffargue Charlotte , Takvorian Chloé , Kyheng Maeva , Nguyen Sylvie , Dubos François , Martinot Alain
Published: November 2021

There is currently a shortage of pediatricians in the Nord-Pas-de-Calais (NPC) area of France. The shortage affects both hospital positions (since many departures are not replaced) and private practice. The objectives of the present study were to (i) describe the career paths of former pediatric residents from Lille University Medical Center, (ii) identify factors associated with leaving NPC and leaving hospital-based practice, and (iii) compare the characteristics associated with the various types of practice.

Methods: Pediatric residents having started their residency at Lille University Medical Center between 1993 and 2013 were invited to fill out an online questionnaire. Main outcomes were leaving NPC and leaving hospital practice. The event rate at different times over a 10-year period was determined using the Kaplan-Meier method.

Results: The response rate was 92% (284 out of 310 invited respondents): 61% had changed their place or type of practice at least once, 54% had moved to a different city, and 41% had left NPC. Having trained elsewhere than in Lille and the lack of a chief assistant specialist position in NPC were independently associated with leaving NPC. 73% of the respondents were currently in hospital-based practice. Having started residency after 2003, taking a sabbatical during the residency and not training in a subspecialty (other than general pediatrics) were independently associated with leaving hospital-based practice. The stated reasons for leaving hospital-based practice were on-call duties (according to 71% of the respondents), overwork (46%), family reasons (34%), and a poor atmosphere at work (34%). Hospital-based pediatricians were more active in research and teaching. They worked an average of 13 h more per week than the other respondents, and were less satisfied with their choice of professional activity and their work-life balance.

Conclusion: Changes in the place or type of practice have become frequent. With the recent resurgence of interest in private practice, leaving hospital is reportedly associated with better working conditions, greater satisfaction, and a better work-life balance.
Regulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes
Authors: Kim Sangsoo Daniel , Morgan Larry , Hargreaves Elyse , Zhang Xiaoying , Jiang Zhihui , Antenos Monica , Li Ben , Kirby Gordon M.
Published: November 2021

Jaundice is a potentially fatal condition resulting from elevated serum bilirubin levels. For centuries, herbal remedies containing Artemisia capillaris Thunb. including the compound 6,7-dimethylesculetin (DE) have been used in Asia to prevent and treat jaundice in neonates. DE activates an important regulator of bilirubin metabolism, the constitutive androstane receptor (CAR), and increases bilirubin clearance. In addition, murine cytochrome P450 2a5 (Cyp2a5) is known to be involved in the oxidative metabolism of bilirubin. Moreover, treatment of mice with phenobarbital, a known inducer of both CAR and Cyp2a5, increases expression of Cyp2a5 suggesting a potential relationship between CAR and Cyp2a5 expression. The aim of this study is to investigate the influence of Artemisia capillaris and DE on the expression and regulatory control of Cyp2a5 and the potential involvement of CAR. Treatment of mouse hepatocytes in primary culture with DE (50 μM) significant increased Cyp2a5 mRNA and protein levels. In mice, Artemisia capillaris and DE treatment also increased levels of hepatic Cyp2a5 protein. Luciferase reporter assays showed that CAR increases Cyp2a5 gene transcription through a CAR response element in the Cyp2a5 gene promoter. Moreover, DE caused nuclear translocation of CAR in primary mouse hepatocytes and increased Cyp2a5 transcription in the presence of CAR. These results identify a potential CAR-mediated mechanism by which DE regulates Cyp2a5 gene expression and suggests that DE may enhance bilirubin clearance by increasing Cyp2a5 levels. Understanding this process could provide an opportunity for the development of novel therapies for neonatal and other forms of jaundice.
Cinacalcet Targets the Neurokinin-1 Receptor and Inhibits PKCδ/ERK/P65 Signaling to Alleviate Dextran Sulfate Sodium-Induced Colitis
Authors: Chen Yuehong , Liu Huan , Zhang Qiuping , Luo Yubin , Wu Liang , Zhong Yutong , Tang Zhigang , Pu Yaoyu , Lu Chenyang , Yin Geng , Xie Qibing
Published: November 2021

Objective: Inflammatory bowel disease is an immune-mediated chronic inflammatory disease of the gastrointestinal tract for which curative drugs are currently not available. This study was performed to assess the therapeutic effects of cinacalcet on dextran sulfate sodium (DSS)-induced colitis.

Methods: Primary macrophages obtained from bone marrow and the macrophage cell line RAW264.7 were used to examine the inhibitory effect of cinacalcet on cytokine production, the PKCδ/ERK/P65 signaling pathway, and NF-κB P65 translocation. Colitis was induced using DSS to assess the treatment effect of cinacalcet. Bioinformatics approaches were adopted to predict potential targets of cinacalcet, and a drug affinity responsive target stability (DARTs) assay was performed to confirm binding between cinacalcet and potential target.

Results:In vivo analysis showed that cinacalcet reduced the disease activity score, prevented shortening of the colon, diminished inflammatory cell infiltration, and protected the structural integrity of the intestinal wall. Cinacalcet also reduced production of the inflammatory cytokines TNFα, IL-1β, and IL-6 in the colon and sera of mice with DSS-induced colitis. In vitro studies revealed that cinacalcet suppressed the translocation of P65 and inhibited production of the inflammatory cytokines IL-1β and IL-6. Mechanistic studies revealed that the target of cinacalcet was neurokinin-1 receptor (NK1R) and their binding was confirmed by a DARTs assay. Furthermore, the inhibition of NK-κB P65 activation was found to occur via the suppression of PKCδ/ERK/P65 signaling mediated by cinacalcet.

Conclusion: Cinacalcet inhibits the activation of NF-κB and reduces the production of inflammatory cytokines by suppressing the PKCδ/ERK/P65 signaling pathway via targeting NK1R, suggesting that it can be used to treat inflammatory diseases, particularly colitis.
HR-MS Based Untargeted Lipidomics Reveals Characteristic Lipid Signatures of Wilson’s Disease
Authors: Zhi Yixiao , Sun Yujiao , Jiao Yonggeng , Pan Chen , Wu Zeming , Liu Chang , Su Jie , Zhou Jie , Shang Dong , Niu Junqi , Hua Rui , Yin Peiyuan
Published: November 2021

Background and Aims: The diagnosis of Wilson’s disease (WD) is challenging by clinical or genetic criteria. A typical early pathological change of WD is the increased liver lipid deposition and lowered serum triglyceride (TG). Therefore, the contents of serum lipids may provide evidence for screening of biomarkers for WD.

Methods: 34 WD patients, 31 WD relatives, and 65 normal controls were enrolled in this study. Serum lipidomics data was acquired by an ultra-high-performance liquid chromatography high-resolution mass spectrometry system, and the data were analyzed by multivariate statistical methods.

Results: Of all 510 identified lipids, there are 297 differential lipids between the WD and controls, 378 differential lipids between the relatives and controls, and 119 differential lipids between the patients and relatives. In WD, the abundances of most saturated TG were increased, whereas other unsaturated lipids decreased, including phosphatidylcholine (PC), sphingomyelin (SM), lysophosphatidylcholine (LPC), ceramide (Cer), and phosphatidylserine (PS). We also found many serum lipid species may be used as biomarkers for WD. The areas under the receiver operating characteristic curve (AUC) of PS (35:0), PS (38:5), and PS (34:0) were 0.919, 0.843, and 0.907. The AUCs of TG (38:0) and CerG1 (d42:2) were 0.948 and 0.915 and the AUCs of LPC (17:0) and LPC (15:0) were 0.980 and 0.960, respectively. The lipid biomarker panel exhibits good diagnostic performance for WD. The correlation networks were built among the different groups and the potential mechanisms of differential lipids were discussed. Interestingly, similar lipid profile of WD is also found in their relatives, which indicated the changes may also related to the mutation of the ATP7B gene.

Conclusions: Lipid deregulation is another important hallmark of WD besides the deposition of copper. Our lipidomic results provide new insights into the diagnostic and therapeutic targets of WD.
Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer
Authors: Colombo Giorgia , Gelardi Edoardo Luigi Maria , Balestrero Federica Carolina , Moro Marianna , Travelli Cristina , Genazzani Armando A.
Published: November 2021

Tumour cells modify their cellular metabolism with the aim to sustain uncontrolled proliferation. Cancer cells necessitate adequate amounts of NAD and NADPH to support several enzymes that are usually overexpressed and/or overactivated. Nicotinamide adenine dinucleotide (NAD) is an essential cofactor and substrate of several NAD-consuming enzymes, such as PARPs and sirtuins, while NADPH is important in the regulation of the redox status in cells. The present review explores the rationale for targeting the key enzymes that maintain the cellular NAD/NADPH pool in colorectal cancer and the enzymes that consume or use NADP(H).
Efficacy of Ligustrazine Injection as Adjunctive Therapy in Treating Acute Cerebral Infarction: A Systematic Review and Meta-Analysis
Authors: Shao Huikai , He Xia , Zhang Lijuan , Du Shan , Yi Xiaoqing , Cui Xiaojiao , Liu Xinxia , Huang Shengfeng , Tong Rongsheng
Published: November 2021

Background: Ligustrazine injection has been widely used as adjunctive therapy in the treatment of acute cerebral infarction (ACI) during the past decades in China, but its clinical efficacy is not yet well confirmed. This study aims to evaluate the efficacy of ligustrazine injection as adjunctive therapy for ACI.

Methods: Databases including China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), PubMed, Medline, Google Scholar, Chinese Biomedical Literature Database, Cochrane Library, Embase, Sino-Med, Wanfang Database, and Chinese Science Citation Database were systematically searched for the published randomized controlled trials (RCTs) on ligustrazine injection in the treatment of ACI until November 2020. Meta-analysis was performed on the primary outcome measure (i.e., clinical effective rate) and the secondary outcome measure [i.e., neurological deficit score (NDS), fibrinogen, low shear blood viscosity (LBV), and high shear blood viscosity (HBV)]. The quality of the included RCTs was assessed according to the M scoring system (the refined Jadad scale). Sensitivity analysis and subgroup analysis were conducted according to the methodological quality, years of publication, and sample size.

Results: Nineteen RCTs, containing 2022 patients, were included in this study. Meta-analysis indicated that ligustrazine injection combined with Western medicine could achieve a better effect in the treatment of ACI than using Western medicine alone in terms of clinical effective rate (RR = 1.24; 95% CI, 1.19–1.29), NDS (MD = −3.88; 95%CI, −4.51 to −3.61), fibrinogen (MD = −0.59; 95% CI, −0.76 to −0.42), LBV (MD = −2.11; 95% CI, −3.16 to −1.06), and HBV (MD = −0.88; 95% CI, −1.20 to −0.55).

Conclusions: This research indicated that ligustrazine injection as adjunctive therapy seemed to be more effective than using western medicine alone in treating ACI. However, more evidence is required to confirm the efficacy of ligustrazine injection due to the low methodological quality of the included RCTs.
Phenotype-Based HPLC-Q-TOF-MS/MS Coupled With Zebrafish Behavior Trajectory Analysis System for the Identification of the Antidepressant Components in Methanol Extract of Anshen Buxin Six Pills
Authors: Liu Jiani , Shang Yue , Xiao Juanlan , Fan Huirong , Jiang Min , Fan Saijun , Bai Gang
Published: November 2021

Phenotype screening has become an important tool for the discovery of active components in traditional Chinese medicine. Anshen Buxin Six Pills (ASBX) are a traditional Mongolian medicine used for the treatment of neurosis in clinical settings. However, its antidepressant components have not been explicitly identified and studied. Here, the antidepressant effect of ASBX was evaluated in adult zebrafish. High performance liquid chromatography-mass spectrometry (HPLC-Q-TOF-MS/MS) was combined with zebrafish behavior trajectory analysis to screen and identify the antidepressant-active extract fraction and active components of ASBX. Finally, the antidepressant effect of the active ingredients were verified by the behavior, pathology, biochemical indices and protein level of adult fish. The novel tank driving test (NTDT) showed that ASBX can effectively improve the depressive effect of reserpine on zebrafish. Petroleum ether and dichloromethane extracts of ASBX were screened as antidepressant active extracts. Costunolide (COS) and dehydrocostus lactone (DHE) were screened as the active components of ASBX. COS had been shown to significantly improve the depressive behavior, nerve injury and neurotransmitter levels (5-hydroxytryptamine (5-HT) and norepinephrine (NE)) of zebrafish by inhibiting the high expression of serotonin transporter and norepinephrine transporter induced by reserpine suggesting the antidepressant effect of COS may be related to its effect on 5-HT and NE pathways. This study provided a phenotype based screening method for antidepressant components of traditional Chinese medicines, so as to realize the separation, identification and activity screening of components at the same time.
A Zebrafish Model of Neurotoxicity by Binge-Like Methamphetamine Exposure
Authors: Bedrossiantz Juliette , Bellot Marina , Dominguez-García Pol , Faria Melissa , Prats Eva , Gómez-Canela Cristian , López-Arnau Raul , Escubedo Elena , Raldúa Demetrio
Published: November 2021

Hyperthermia is a common confounding factor for assessing the neurotoxic effects of methamphetamine (METH) in mammalian models. The development of new models of methamphetamine neurotoxicity using vertebrate poikilothermic animals should allow to overcome this problem. The aim of the present study was to develop a zebrafish model of neurotoxicity by binge-like methamphetamine exposure. After an initial testing at 20 and 40 mg/L for 48 h, the later METH concentration was selected for developing the model and the effects on the brain monoaminergic profile, locomotor, anxiety-like and social behaviors as well as on the expression of key genes of the catecholaminergic system were determined. A concentration- and time-dependent decrease in the brain levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) was found in METH-exposed fish. A significant hyperactivity was found during the first hour of exposure, followed 3 h after by a positive geotaxis and negative scototaxis in the novel tank and in the light/dark paradigm, respectively. Moreover, the behavioral phenotype in the treated fish was consistent with social isolation. At transcriptional level, th1 and slc18a2 (vmat2) exhibited a significant increase after 3 h of exposure, whereas the expression of gfap, a marker of astroglial response to neuronal injury, was strongly increased after 48 h exposure. However, no evidences of oxidative stress were found in the brain of the treated fish. Altogether, this study demonstrates the suitability of the adult zebrafish as a model of METH-induced neurotoxicity and provides more information about the biochemical and behavioral consequences of METH abuse.
Delanzomib, a Novel Proteasome Inhibitor, Combined With Adalimumab Drastically Ameliorates Collagen-Induced Arthritis in Rats by Improving and Prolonging the Anti-TNF-α Effect of Adalimumab
Authors: Wang Lei , Liu Lixiong , Hong Xiaoping , Liu Dongzhou , Cheng Zeneng
Published: November 2021

Delanzomib is a novel proteasome inhibitor initially developed for treating multiple myeloma. It was found to inhibit the expression of tumor necrosis factor alpha (TNF-α). This study aimed to investigate the ameliorating effect of delanzomib on collagen-induced arthritis (CIA) and to explore the pharmacodynamics and pharmacokinetics (PK) interactions between delanzomib and adalimumab. Rats with CIA were randomly assigned to receive the treatment with delanzomib, adalimumab, delanzomib combined with adalimumab, or placebo. Visual inspection and biochemical examinations including TNF-α, interleukin 6, and C-reactive protein were performed to assess arthritis severity during the treatment. The adalimumab concentration in rats was determined to evaluate the PK interaction between delanzomib and adalimumab. Also, the levels of neonatal Fc receptor (FcRn) and FcRn mRNA were measured to explore the role of FcRn in the PK interaction between delanzomib and adalimumab. As a result, delanzomib combined with adalimumab exhibited stronger anti-arthritis activity than a single drug because both drugs synergistically reduced TNF-α level in vivo. Delanzomib also decreased adalimumab elimination in rats by increasing the level of FcRn. The slower elimination of adalimumab in rats further prolonged the anti-TNF-α effect of adalimumab. Moreover, FcRn level was increased by delanzomib via suppressing FcRn degradation rather than promoting FcRn production. In conclusion, delanzomib combined with adalimumab may be a potential therapeutic approach for treating rheumatoid arthritis. The initial finding that the PK interaction occurred between delanzomib and adalimumab may have clinical relevance for patients who simultaneously take proteasome inhibitors and anti-TNF-α therapeutic proteins.
Mechanical Power Correlates With Lung Inflammation Assessed by Positron-Emission Tomography in Experimental Acute Lung Injury in Pigs
Authors: Scharffenberg Martin , Wittenstein Jakob , Ran Xi , Zhang Yingying , Braune Anja , Theilen Raphael , Maiello Lorenzo , Benzi Giulia , Bluth Thomas , Kiss Thomas , Pelosi Paolo , Rocco Patricia R. M. , Schultz Marcus J. , Kotzerke Jörg , Gama de Abreu Marcelo , Huhle Robert
Published: November 2021

Background:Mechanical ventilation (MV) may initiate or worsen lung injury, so-called ventilator-induced lung injury (VILI). Although different mechanisms of VILI have been identified, research mainly focused on single ventilator parameters. The mechanical power (MP) summarizes the potentially damaging effects of different parameters in one single variable and has been shown to be associated with lung damage. However, to date, the association of MP with pulmonary neutrophilic inflammation, as assessed by positron-emission tomography (PET), has not been prospectively investigated in a model of clinically relevant ventilation settings yet. We hypothesized that the degree of neutrophilic inflammation correlates with MP.

Methods:Eight female juvenile pigs were anesthetized and mechanically ventilated. Lung injury was induced by repetitive lung lavages followed by initial PET and computed tomography (CT) scans. Animals were then ventilated according to the acute respiratory distress syndrome (ARDS) network recommendations, using the lowest combinations of positive end-expiratory pressure and inspiratory oxygen fraction that allowed adequate oxygenation. Ventilator settings were checked and adjusted hourly. Physiological measurements were conducted every 6 h. Lung imaging was repeated 24 h after first PET/CT before animals were killed. Pulmonary neutrophilic inflammation was assessed by normalized uptake rate of 2-deoxy-2-[18F]fluoro-D-glucose (KiS), and its difference between the two PET/CT was calculated (ΔKiS). Lung aeration was assessed by lung CT scan. MP was calculated from the recorded pressure–volume curve. Statistics included the Wilcoxon tests and non-parametric Spearman correlation.

Results:Normalized18F-FDG uptake rate increased significantly from first to second PET/CT (p= 0.012). ΔKiSsignificantly correlated with median MP (ρ = 0.738,p= 0.037) and its elastic and resistive components, but neither with median peak, plateau, end-expiratory, driving, and transpulmonary driving pressures, nor respiratory rate (RR), elastance, or resistance. Lung mass and volume significantly decreased, whereas relative mass of hyper-aerated lung compartment increased after 24 h (p= 0.012,p= 0.036, andp= 0.025, respectively). Resistance and PaCO2were significantly higher (p= 0.012 andp= 0.017, respectively), whereas RR, end-expiratory pressure, and MP were lower at 18 h compared to start of intervention.

Conclusions:In this model of experimental acute lung injury in pigs, pulmonary neutrophilic inflammation evaluated by PET/CT increased after 24 h of MV, and correlated with MP.
Impact of Inter-Set Short Rest Interval Length on Inhibitory Control Improvements Following Low-Intensity Resistance Exercise in Healthy Young Males
Authors: Tomoo Keigo , Suga Tadashi , Dora Kento , Sugimoto Takeshi , Mok Ernest , Tsukamoto Hayato , Takada Shingo , Hashimoto Takeshi , Isaka Tadao
Published: November 2021

The length of rest interval between sets (i.e., inter-set rest interval) is an important variable for resistance exercise program. However, the impact of the inter-set rest interval on improvements in cognitive function following resistance exercise remains unknown. In this study, we compared the effect of short rest interval (SRI) vs. long rest interval (LRI) protocols on post-exercise cognitive inhibitory control (IC) improvements induced by low-intensity resistance exercise. Twenty healthy, young males completed both SRI and LRI sessions in a crossover design. The bilateral knee extensor low-intensity resistance exercise was programed for six sets with 10 repetitions per set using 40% of one-repetition maximum. The inter-set rest interval lengths for SRI and LRI protocols were set for 1 and 3min, respectively. The color-word Stroop task (CWST) was administrated at six time points: baseline, pre-exercise, immediate post-exercise, and every 10min during the 30-min post-exercise recovery period. The levels of blood lactate, which may be an important determinant for improving IC, throughout the 30-min post-exercise recovery period were significantly higher following SRI protocol than following LRI protocol (p=0.002 for interaction effect). In line with this result, large-sized decreases in the reverse-Stroop interference score, which represent improved IC, were observed immediately after SRI protocol (d=0.94 and 0.82, respectively, vs. baseline and pre-exercise) as opposed to the moderate-sized decreases immediately after LRI protocol (d=0.62 and 0.66, respectively, vs. baseline and pre-exercise). Moreover, significant decreases in the reverse-Stroop interference score were observed from 10 to 30min after SRI protocol (all ps<0.05 vs. baseline and/or pre-exercise), whereas no such decrease was observed after LRI protocol. Furthermore, the degree of decreases in the reverse-Stroop interference score throughout the 30-min post-exercise recovery period was significantly greater in SRI protocol than in LRI protocol (p=0.046 for interaction effect). We suggest that the SRI protocol is more useful in improving post-exercise IC, potentially via greater circulating lactate levels, compared to the LRI protocol. Therefore, the inter-set rest interval length may be an important variable for determining the degree of cognitive function improvements following resistance exercise in healthy young males.
Analysis of Pain and Analgesia Protocols in Acute Cerulein-Induced Pancreatitis in Male C57BL/6 Mice
Authors: Durst Mattea , Graf Theresia Reding , Graf Rolf , Kron Mareike , Arras Margarete , Zechner Dietmar , Palme Rupert , Talbot Steven R. , Jirkof Paulin
Published: November 2021

Pancreatitis is known to be painful in humans and companion animals. However, the extent of pain in experimental mouse models of acute pancreatitis is unknown. Consequently, the severity classification of acute pancreatitis in mice is controversially discussed and standardized pain management is missing. In this study, we investigated acute Cerulein-induced pancreatitis with pain-specific and well-being orientated parameters to detect its impact on mice. Male C57BL/6J male mice were injected with Cerulein; animals that received saline injections served as control group. The animals were observed for weight change and water intake. To assess pain, behaviors like stretch-and-press and reduced rearing, the Mouse Grimace Scale, and von Frey hypersensitivity were assessed. Fecal corticosterone metabolites and burrowing behavior were assessed to detect changes in the animal’s well-being. Pancreatitis severity was evaluated with amylase and lipase in the blood and pancreas histology. To investigate whether different analgesics can alleviate signs of pain, and if they influence pancreas inflammation, animals received Buprenorphine, Paracetamol in combination with Tramadol, or Metamizole in the drinking water. The calculated intake of these analgesics via drinking reached values stated to be efficient for pain alleviation. While pancreatitis did not seem to be painful, we detected acute pain from Cerulein injections that could not be alleviated by analgesics. The number of inflammatory cells in the pancreas did not differ with the analgesic administered. In conclusion: (1) Cerulein injections appear to be acutely painful but pain could not be alleviated by the tested analgesics, (2) acute pancreatitis induced by our protocol did not induce obvious signs of pain, (3) analgesic substances had no detectable influence on inflammation. Nevertheless, protocols inducing more severe or even chronic pancreatitis might evoke more pain and analgesic treatment might become imperative. Considering our results, we recommend the use of Buprenorphine via drinking water in these protocols. Further studies to search for efficient analgesics that can alleviate the acute pain induced by Cerulein injections are needed.
Myoelectric Activity and Fatigue in Low-Load Resistance Exercise With Different Pressure of Blood Flow Restriction: A Systematic Review and Meta-Analysis
Authors: de Queiros Victor Sabino , de França Ingrid Martins , Trybulski Robert , Vieira João Guilherme , dos Santos Isis Kelly , Neto Gabriel Rodrigues , Wilk Michal , Matos Dihogo Gama de , Vieira Wouber Hérickson de Brito , Novaes Jefferson da Silva , Makar Piotr , Cabral Breno Guilherme de Araújo Tinoco , Dantas Paulo Moreira Silva
Published: November 2021

Background: Low-load resistance exercise (LL-RE) with blood flow restriction (BFR) promotes increased metabolic response and fatigue, as well as more pronounced myoelectric activity than traditional LL-RE. Some studies have shown that the relative pressure applied during exercise may have an effect on these variables, but existing evidence is contradictory.

Purpose: The aim of this study was to systematically review and pool the available evidence on the differences in neuromuscular and metabolic responses at LL-RE with different pressure of BFR.

Methods: The systematic review and meta-analysis was reported according to PRISMA items. Searches were performed in the following databases: CINAHL, PubMed, Scopus, SPORTDiscus and Web of Science, until June 15, 2021. Randomized or non-randomized experimental studies that analyzed LL-RE, associated with at least two relative BFR pressures [arterial occlusion pressure (AOP)%], on myoelectric activity, fatigue, or metabolic responses were included. Random-effects meta-analyses were performed for MVC torque (fatigue measure) and myoelectric activity. The quality of evidence was assessed using the PEDro scale.

Results: Ten studies were included, all of moderate to high methodological quality. For MVC torque, there were no differences in the comparisons between exercise with 40–50% vs. 80–90% AOP. When analyzing the meta-analysis data, the results indicated differences in comparisons in exercise with 15–20% 1 repetition maximum (1RM), with higher restriction pressure evoking greater MVC torque decline (4 interventions, 73 participants; MD = −5.05 Nm [95%CI = −8.09; −2.01], p = 0.001, I2 = 0%). For myoelectric activity, meta-analyses indicated a difference between exercise with 40% vs. 60% AOP (3 interventions, 38 participants; SMD = 0.47 [95%CI = 0.02; 0.93], p = 0.04, I2 = 0%), with higher pressure of restriction causing greater myoelectric activity. This result was not identified in the comparisons between 40% vs. 80% AOP. In analysis of studies that adopted pre-defined repetition schemes, differences were found (4 interventions, 52 participants; SMD = 0.58 [95%CI = 0.11; 1.05], p = 0.02, I2 = 27%).

Conclusion: The BFR pressure applied during the LL-RE may affect the magnitude of muscle fatigue and excitability when loads between 15 and 20% of 1RM and predefined repetition protocols (not failure) are prescribed, respectively.

Systematic Review Registration: [http://www.crd.york.ac.uk/prospero], identifier [CRD42021229345].
Cassava Brown Streak Disease Response and Association With Agronomic Traits in Elite Nigerian Cassava Cultivars
Authors: Ano Chukwuka Ugochukwu , Ochwo-Ssemakula Mildred , Ibanda Angele , Ozimati Alfred , Gibson Paul , Onyeka Joseph , Njoku Damian , Egesi Chiedozie , S. Kawuki Robert
Published: November 2021

Cassava mosaic geminiviruses (CMGs) and cassava brown streak viruses (CBSVs) cause the highest yield losses in cassava production in Africa. In particular, cassava brown streak disease (CBSD) is and continues to be a significant constraint to optimal cassava production in Eastern and Southern Africa. While CBSD has not been reported in West Africa, its recent rapid spread and damage to cassava productivity in Eastern, and Southern Africa is alarming. The aim of this study was to evaluate Nigerian cassava genotypes in order to determine their responses to CBSD, in the event that it invades Nigeria, the world’s largest cassava producer. The study gathered information on whether useful CBSD resistance alleles are present in the elite Nigerian cassava accessions. A total of 1,980 full-sib cassava seedlings from 106 families were assessed in the field at the seedling stage for a year. A subset of 569 clones were selected and assessed for another year at the clonal stage in Namulonge, central Uganda, a known hotspot for CBSD screening. Results indicated that foliar and root incidences and severities varied significantly (p ≤ 0.01, p ≤ 0.001) except for CBSD foliar incidence at 6 months (CBSD6i). Highest and lowest plot-based heritability estimates for CBSD were registered for CBSD root severity (CBSDrs) (0.71) and CBSD6i (0.5). Positive and highly significant correlations were noted between CBSD root incidence (CBSDri) and CBSDrs (r = 0.90***). Significant positive correlations were also noted between CBSD foliar severity at 3 months (CBSD3s) and CBSD foliar incidence at 6 months (CBSD6i) (r = 0.77***), CBSD3s and CBSDrs (r = 0.35***). Fresh root weight (FreshRW) negatively correlated with CBSDri and CBSDrs, respectively (r = −0.21*** and r = −0.22***). Similarly, CBSD3s correlated negatively with cassava mosaic disease severity at 3 (CMD3s) and 6 months (CMD6s), respectively (r = −0.25*** and r = −0.21***). Fifteen clones were selected using a non-weighted summation selection index for further screening. In conclusion, results revealed that the elite Nigerian accessions exhibited significant susceptibility to CBSD within 2 years of evaluation period. It is expected that this information will aid future breeding decisions for the improvement of CBSD resistance among the Nigerian cassava varieties.