bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic Screening for Deep Vein Thrombosis in Critically Ill Inpatients With COVID-19: Impact on the Incidence of Venous Thromboembolism
Authors: Lapébie François-Xavier , Minville Vincent , Ribes Agnès , Combis Bertrand , Thery Arthur , Geeraerts Thomas , Silva Stein , Bura-Rivière Alessandra , Vardon-Bounes Fanny
Published: January 2021

Background: Several studies suggest an increased incidence of thrombosis in COVID-19 patients. However, evidence on how to prevent and even treat it is scarce. The aim of this study was to compare the cumulative incidence of venous thromboembolism (VTE) of two different methods for lower extremity deep vein thrombosis (LE-DVT) diagnosis: systematic vs. clinically guided complete compression venous ultrasonography (CCUS). We conducted a monocentric, prospective, open-label, non-randomized study. All consecutive patients admitted in three intensive care units (ICUs) of University Hospital of Toulouse for COVID-19 pneumonia were included: one performed systematic screening for LE-DVT, the others did not. The primary outcome was the 21-day cumulative incidence of VTE. The secondary end points were the 21-day cumulative incidences of major bleeding and death.

Results: Among the 78 patients included, 27 (34.6%) underwent systematic screening for DVT 7 ± 2 days after ICU admission. Thirty-two patients (41.0%) were diagnosed with VTE, with a 21-day cumulative incidence of 42.3% (95% CI, 31.4–55.2), without difference between screened and non-screened patients (hazard ratio 1.45, 95% CI, 0.72–2.93). In the screened group, the frequency of isolated DVT was higher (25.9 vs. 5.9%, p-value = 0.027), but the frequency of pulmonary embolism was not reduced (25.9 vs. 29.4%, p-value = 0.745). The 21-day cumulative incidences of major bleeding and death were 9.6% (95% CI, 4.7–19.2) and 10.3% (95% CI, 5.0–20.8), respectively, without difference between the two groups.

Conclusions: A systematic screening for DVT in patients hospitalized in ICU was not associated with a higher diagnosis of VTE or a reduced diagnosis of PE.
Exploring the Association Between Sialic Acid and SARS-CoV-2 Spike Protein Through a Molecular Dynamics-Based Approach
Authors: Bò Leonardo , Miotto Mattia , Di Rienzo Lorenzo , Milanetti Edoardo , Ruocco Giancarlo
Published: January 2021

Recent experimental evidence demonstrated the capability of SARS-CoV-2 Spike protein to bind sialic acid molecules, which was a trait not present in SARS-CoV and could shed light on the molecular mechanism used by the virus for the cell invasion. This peculiar feature has been successfully predicted by in-silico studies comparing the sequence and structural characteristics that SARS-CoV-2 shares with other sialic acid-binding viruses, like MERS-CoV. Even if the region of the binding has been identified in the N-terminal domain of Spike protein, so far no comprehensive analyses have been carried out on the spike-sialic acid conformations once in the complex. Here, we addressed this aspect performing an extensive molecular dynamics simulation of a system composed of the N-terminal domain of the spike protein and a sialic acid molecule. We observed several short-lived binding events, reconnecting to the avidic nature of the binding, interestingly occurring in the surface Spike region where several insertions are present with respect to the SARS-CoV sequence. Characterizing the bound configurations via a clustering analysis on the Principal Component of the motion, we identified different possible binding conformations and discussed their dynamic and structural properties. In particular, we analyze the correlated motion between the binding residues and the binding effect on the stability of atomic fluctuation, thus proposing regions with high binding propensity with sialic acid.
The Therapeutic Efficacy of Curcumin vs. Metformin in Modulating the Gut Microbiota in NAFLD Rats: A Comparative Study
Authors: Li Ruifang , Yao Yurong , Gao Pengfei , Bu Shurui
Published: January 2021

Structural disruption of gut microbiota is closely related to the occurrence of non-alcoholic fatty liver disease (NAFLD). Previous research has demonstrated that both curcumin (CUR) and metformin (MET) have a therapeutic effect against NAFLD and play a role in modulating the gut microbiota. However, there is a lack of direct comparison between the two medications in terms of the therapeutic efficacy and the regulatory effect on gut microbiota. In this study, we administered either CUR or MET to rats with high-fat diet (HFD)-induced obesity to observe changes in body parameters, biochemical parameters, liver, and ileum pathology and gut microbiota, and used next generation sequencing and multivariate analysis to evaluate the structural changes of gut microbiota in a NAFLD rat model before and after CUR and MET intervention. It was found that both CUR and MET attenuated hepatic ectopic fat deposition, alleviated inflammatory factors, and improved intestinal barrier integrity in HFD-fed rats. More importantly, CUR and MET reduced the Firmicutes/Bacteroidetes ratio and reverted the composition of the HFD-disrupted gut microbiota. Both CUR and MET treatments effectively modified the gut microbiome, enriched the abundance of beneficial bacteria and reduced opportunistic pathogens in obese rats. The abundance of Butyricicoccus was increased while the abundance of Dorea was decreased in HFD + CUR group. Besides, some beneficial bacteria such as Prevotella were increased in MET-treated animals. Spearman’s correlation analysis showed that Helicobacter, Akkermansia, Desulfovibrio, Romboutsia, Corynebacterium, Lactobacillus, Ruminococcaceae_unclassified, Lachnospiraceae_unclassified, and Clostridiales_unclassified showed significantly positive correlations with TG, TC, LDL-C, GLU, IL-6, IL-1β, and TNF-α, and negative correlations with HDL-C (both p < 0.05). However, Prevotella and Stomatobaculum showed an opposite trend. In summary, CUR and MET showed similar effects in alleviating hepatic steatosis, improving intestinal barrier integrity and modulating gut microbiota in HFD-induced obesity rats, and therefore may prove to be a novel adjunctive therapy for NAFLD.
Ethanol-Enriched Substrate Facilitates Ambrosia Beetle Fungi, but Inhibits Their Pathogens and Fungal Symbionts of Bark Beetles
Authors: Lehenberger Maximilian , Benkert Markus , Biedermann Peter H. W.
Published: January 2021

Bark beetles (sensu lato) colonize woody tissues like phloem or xylem and are associated with a broad range of micro-organisms. Specific fungi in the ascomycete orders Hypocreales, Microascales and Ophistomatales as well as the basidiomycete Russulales have been found to be of high importance for successful tree colonization and reproduction in many species. While fungal mutualisms are facultative for most phloem-colonizing bark beetles (sensu stricto), xylem-colonizing ambrosia beetles are long known to obligatorily depend on mutualistic fungi for nutrition of adults and larvae. Recently, a defensive role of fungal mutualists for their ambrosia beetle hosts was revealed: Few tested mutualists outcompeted other beetle-antagonistic fungi by their ability to produce, detoxify and metabolize ethanol, which is naturally occurring in stressed and/or dying trees that many ambrosia beetle species preferentially colonize. Here, we aim to test (i) how widespread beneficial effects of ethanol are among the independently evolved lineages of ambrosia beetle fungal mutualists and (ii) whether it is also present in common fungal symbionts of two bark beetle species (Ips typographus,Dendroctonus ponderosae) and some general fungal antagonists of bark and ambrosia beetle species. The majority of mutualistic ambrosia beetle fungi tested benefited (or at least were not harmed) by the presence of ethanol in terms of growth parameters (e.g., biomass), whereas fungal antagonists were inhibited. This confirms the competitive advantage of nutritional mutualists in the beetle’s preferred, ethanol-containing host material. Even though most bark beetle fungi are found in the same phylogenetic lineages and ancestral to the ambrosia beetle (sensu stricto) fungi, most of them were highly negatively affected by ethanol and only a nutritional mutualist ofDendroctonus ponderosaebenefited, however. This suggests that ethanol tolerance is a derived trait in nutritional fungal mutualists, particularly in ambrosia beetles that show cooperative farming of their fungi.
Induction of the Stringent Response Underlies the Antimicrobial Action of Aliphatic Isothiocyanates
Authors: Nowicki Dariusz , Krause Klaudyna , Szamborska Patrycja , Żukowska Adrianna , Cech Grzegorz M. , Szalewska-Pałasz Agnieszka
Published: January 2021

Bacterial resistance to known antibiotics comprises a serious threat to public health. Propagation of multidrug-resistant pathogenic strains is a reason for undertaking a search for new therapeutic strategies, based on newly developed chemical compounds and the agents present in nature. Moreover, antibiotic treatment of infections caused by enterotoxin toxin-bearing strain—enterohemorrhagic Escherichia coli (EHEC) is considered hazardous and controversial due to the possibility of induction of bacteriophage-encoded toxin production by the antibiotic-mediated stress. The important source of potentially beneficial compounds are secondary plant metabolites, isothiocyanates (ITC), and phytoncides from the Brassicaceae family. We reported previously that sulforaphane and phenethyl isothiocyanate, already known for their chemopreventive and anticancer features, exhibit significant antibacterial effects against various pathogenic bacteria. The mechanism of their action is based on the induction of the stringent response and accumulation of its alarmones, the guanosine penta- and tetraphosphate. In this process, the amino acid starvation path is employed via the RelA protein, however, the precise mechanism of amino acid limitation in the presence of ITCs is yet unknown. In this work, we asked whether ITCs could act synergistically with each other to increase the antibacterial effect. A set of aliphatic ITCs, such as iberin, iberverin, alyssin, erucin, sulforaphen, erysolin, and cheirolin was tested in combination with sulforaphane against E. coli. Our experiments show that all tested ITCs exhibit strong antimicrobial effect individually, and this effect involves the stringent response caused by induction of the amino acid starvation. Interestingly, excess of specific amino acids reversed the antimicrobial effects of ITCs, where the common amino acid for all tested compounds was glycine. The synergistic action observed for iberin, iberverin, and alyssin also led to accumulation of (p)ppGpp, and the minimal inhibitory concentration necessary for the antibacterial effect was four- to eightfold lower than for individual ITCs. Moreover, the unique mode of ITC action is responsible for inhibition of prophage induction and toxin production, in addition to growth inhibition of EHEC strains. Thus, the antimicrobial effect of plant secondary metabolites by the stringent response induction could be employed in potential therapeutic strategies.
Butylated Hydroxytoluene Induced Resistance Against Botryosphaeria dothidea in Apple Fruit
Authors: Huang Yan , Sun Cuicui , Guan Xiangnan , Lian Sen , Li Baohua , Wang Caixia
Published: January 2021

Apple ring rot caused by Botryosphaeria dothidea is an important disease in China, which leads to serious economic losses during storage. Plant activators are compounds that induce resistance against pathogen infection and are considered as a promising alternative strategy to traditional chemical treatment. In the present study, butylated hydroxytoluene (BHT), a potential plant activator, was evaluated for its induced resistance against B. dothidea in postharvest apple fruits. The physiological and molecular mechanisms involved in induced resistance were also explored. The results showed that BHT treatment could trigger strong resistance in apple fruits against B. dothidea, and the optimum concentration was 200 μmol L–1 by immersion of fruits. BHT treatment significantly increased the activities of four defensive enzymes and alleviated lipid peroxidation by increasing antioxidant enzyme activities. In addition, salicylic acid (SA) content was enhanced by BHT treatment as well as the expression of three SA biosynthesis-related genes (MdSID2, MdPAD4, and MdEDS1) and two defense genes (MdPR1 and MdPR5). Our results suggest that BHT-conferred resistance against B. dothidea might be mainly through increasing the activities of defense-related enzymes and activating SA signaling pathway, which may provide an alternative strategy to control apple ring rot in postharvest fruits.
Variable Release of Lipoteichoic Acid From Staphylococcus aureus Bloodstream Isolates Relates to Distinct Clinical Phenotypes, Strain Background, and Antibiotic Exposure
Authors: Algorri Marquerita , Jorth Peter , Wong-Beringer Annie
Published: January 2021

Background

Staphylococcus aureus is a leading cause of bacterial bloodstream infections. The heterogeneity in patient outcomes in S. aureus bacteremia (SAB) can be attributed in part to strain characteristics, which may influence host response to infection. We specifically examined the relationship between lipoteichoic acid (LTA) release from S. aureus and disease phenotype, strain background, and antibiotic exposure.

Methods

Seven strains of S. aureus causing different clinical phenotypes of bacteremia and two reference strains (LAC USA 300 and Mu3) were analyzed for LTA release at baseline and following exposure to antibiotics from different pharmacologic classes (vancomycin, ceftaroline, and tedizolid). LTA release was quantified by LTA-specific ELISA. Whole genome sequencing was performed on the clinical strains and analyzed using open-source bioinformatics tools.

Results

Lipoteichoic acid release varied by 4-fold amongst the clinical strains and appeared to be related to duration of bacteremia, independent of MLST type. Low LTA releasing strains were isolated from patients who had prolonged duration of bacteremia and died. Antibiotic-mediated differences in LTA release appeared to be associated with MLST type, as ST8 strains released maximal LTA in response to tedizolid while other non-ST8 strains demonstrated high LTA release with vancomycin. Genetic variations related to the LTA biosynthesis pathway were detected in all non-ST8 strains, though ST8 strains showed no variations despite demonstrating differential LTA release.

Conclusion

Our findings provide the basis for future studies to evaluate the relationship between LTA release-mediated host immune response and clinical outcomes as well as the potential for antibiotic modulation of LTA release as a therapeutic strategy and deserve confirmation with larger number of strains with known clinical phenotypes.
Virus and Viroid-Derived Small RNAs as Modulators of Host Gene Expression: Molecular Insights Into Pathogenesis
Authors: Ramesh S. V. , Yogindran Sneha , Gnanasekaran Prabu , Chakraborty Supriya , Winter Stephan , Pappu Hanu R.
Published: January 2021

Virus-derived siRNAs (vsiRNAs) generated by the host RNA silencing mechanism are effectors of plant’s defense response and act by targeting the viral RNA and DNA in post-transcriptional gene silencing (PTGS) and transcriptional gene silencing (TGS) pathways, respectively. Contrarily, viral suppressors of RNA silencing (VSRs) compromise the host RNA silencing pathways and also cause disease-associated symptoms. In this backdrop, reports describing the modulation of plant gene(s) expression by vsiRNAs via sequence complementarity between viral small RNAs (sRNAs) and host mRNAs have emerged. In some cases, silencing of host mRNAs by vsiRNAs has been implicated to cause characteristic symptoms of the viral diseases. Similarly, viroid infection results in generation of sRNAs, originating from viroid genomic RNAs, that potentially target host mRNAs causing typical disease-associated symptoms. Pathogen-derived sRNAs have been demonstrated to have the propensity to target wide range of genes including host defense-related genes, genes involved in flowering and reproductive pathways. Recent evidence indicates that vsiRNAs inhibit host RNA silencing to promote viral infection by acting as decoy sRNAs. Nevertheless, it remains unclear if the silencing of host transcripts by viral genome-derived sRNAs are inadvertent effects due to fortuitous pairing between vsiRNA and host mRNA or the result of genuine counter-defense strategy employed by viruses to enhance its survival inside the plant cell. In this review, we analyze the instances of such cross reaction between pathogen-derived vsiRNAs and host mRNAs and discuss the molecular insights regarding the process of pathogenesis.
Organic Acids as Alternatives for Antibiotic Growth Promoters Alter the Intestinal Structure and Microbiota and Improve the Growth Performance in Broilers
Authors: Dai Dong , Qiu Kai , Zhang Hai-jun , Wu Shu-geng , Han Yan-ming , Wu Yuan-yuan , Qi Guang-hai , Wang Jing
Published: January 2021

The present study aimed to investigate the effects of organic acids (OA) as alternatives for antibiotic growth promoters (AGP) on growth performance, intestinal structure, as well as intestinal microbial composition and short-chain fatty acids (SCFAs) profiles in broilers. A total of 336 newly hatched male Arbor Acres broiler chicks were randomly allocated into 3 dietary treatments including the basal diet [negative control (NC)], the basal diet supplemented with 5 mg/kg flavomycin, and the basal diet supplemented with OA feed additives. Each treatment had eight replicates with 14 birds each. The results showed that AGP and OA promoted growth during day 22–42 compared with the NC group (P < 0.05). OA significantly increased the jejunal goblet cell density and ileal villus height on day 42 compared with the NC group (P < 0.05). Meanwhile, OA up-regulated the mRNA expression of jejunal barrier genes (Claudin-3 and ZO-1) relative to the NC group (P < 0.05). Significant changes of microbiota induced by the OA were also found on day 42 (P < 0.05). Several SCFAs-producing bacteria like Ruminococcaceae, Christensenellaceae, and Peptococcaceae affiliated to the order Clostridiales were identified as biomarkers of the OA group. Higher concentrations of SCFAs including formic acid and butyric acid were observed in the cecum of OA group (P < 0.05). Simultaneously, the abundance of family Ruminococcaceae showed highly positive correlations with the body weight and mRNA level of ZO-1 on day 42 (P < 0.05). However, AGP supplementation had the higher mRNA expression of Claudin-2, lower goblet cell density of jejunum, and decreased Firmicutes to Bacteroidetes ratio, suggesting that AGP might have a negative impact on intestinal immune and microbiota homeostasis. In conclusion, the OA improved growth performance, intestinal morphology and barrier function in broilers, which might be attributed to the changes of intestinal microbiota, particularly the enrichment of SCFAs-producing bacteria, providing a more homeostatic and healthy intestinal microecology.
A Clofazimine-Containing Regimen Confers Improved Treatment Outcomes in Macrophages and in a Murine Model of Chronic Progressive Pulmonary Infection Caused by the Mycobacterium avium Complex
Authors: Lee Ju Mi , Park Jiyun , Choi Sangwon , Jhun Byung Woo , Kim Su-Young , Jo Kyung-Wook , Hong Jung Joo , Kim Lee-Han , Shin Sung Jae
Published: January 2021

Treatment outcomes using the standard regimen (a macrolide, ethambutol, and rifampicin) for Mycobacterium avium complex-pulmonary disease (MAC-PD) remain unsatisfactory. Thus, improved treatment regimens for MAC-PD are required. Clofazimine has recently been revisited as an effective drug against mycobacterial infection. We performed a comparison between the standard regimen and an alternative regimen (replacing the rifampicin of the standard regimen with clofazimine) based on the intracellular anti-MAC activities of the individual drugs in a murine model of chronic progressive MAC-pulmonary infection (MAC-PI). The intracellular anti-MAC activities of the individual drugs and their combinations in murine bone marrow-derived macrophages (BMDMs) were determined. The treatment efficacies of the standard and clofazimine-containing regimens were evaluated in mice chronically infected with M. avium by initiating 2- and 4-week treatment at 8 weeks post-infection. Bacterial loads in the lung, spleen, and liver were assessed along with lung inflammation. Insufficient intracellular anti-MAC activity of rifampicin in BMDMs was recorded despite its low in vitro minimum inhibitory concentrations (MICs), whereas optimal intracellular killing activity against all tested MAC strains was achieved with clofazimine. Compared to the standard regimen, the clofazimine-containing regimen significantly reduced CFUs in all organs and achieved marked reductions in lung inflammation. The replacement of rifampicin with clofazimine in the treatment regimen resulted in more favorable outcomes in an animal model of chronic progressive MAC-PI. Intriguingly, 2 weeks of treatment with the clofazimine-containing regimen reduced bacterial loads more effectively than 4 weeks of treatment with the standard regimen in M. avium-infected mice. Thus, the clofazimine-containing regimen also had a treatment-shortening effect.
Unveiling Tumor Microenvironment Interactions Using Zebrafish Models
Authors: Loveless Reid , Shay Chloe , Teng Yong
Published: January 2021

The tumor microenvironment (TME) is a rich and active arena that is strategically evolved overtime by tumors to promote their survival and dissemination. Over the years, attention has been focused to characterize and identify the tumor-supporting roles and subsequent targeting potentials of TME components. Nevertheless, recapitulating the human TME has proved inherently challenging, leaving much to be explored. In this regard, in vivo model systems like zebrafish, with its optical clarity, ease of genetic manipulation, and high engraftment, have proven to be indispensable for TME modeling and investigation. In this review, we discuss the recent ways by which zebrafish models have lent their utility to provide new insights into the various cellular and molecular mechanisms driving TME dynamics and tumor support. Specifically, we report on innate immune cell interactions, cytokine signaling, metastatic plasticity, and other processes within the metastatic cascade. In addition, we reflect on the arrival of adult zebrafish models and the potential of patient-derived xenografts.
Multi-Scale Extension in an Entorhinal-Hippocampal Model for Cognitive Map Building
Authors: Wang Jiru , Yan Rui , Tang Huajin
Published: January 2021

Neuroscience research shows that, by relying on internal spatial representations provided by the hippocampus and entorhinal cortex, mammals are able to build topological maps of environments and navigate. Taking inspiration from mammals' spatial cognition mechanism, entorhinal-hippocampal cognitive systems have been proposed for robots to build cognitive maps. However, path integration and vision processing are time-consuming, and the existing model of grid cells is hard to achieve in terms of adaptive multi-scale extension for different environments, resulting in the lack of viability for real environments. In this work, an optimized dynamical model of grid cells is built for path integration in which recurrent weight connections between grid cells are parameterized in a more optimized way and the non-linearity of sigmoidal neural transfer function is utilized to enhance grid cell activity packets. Grid firing patterns with specific spatial scales can thus be accurately achieved for the multi-scale extension of grid cells. In addition, a hierarchical vision processing mechanism is proposed for speeding up loop closure detection. Experiment results on the robotic platform demonstrate that our proposed entorhinal-hippocampal model can successfully build cognitive maps, reflecting the robot's spatial experience and environmental topological structures.
Extrinsic Factors Regulating Dendritic Patterning
Authors: Lin Tzu-Yang , Chen Pei-Ju , Yu Hung-Hsiang , Hsu Chao-Ping , Lee Chi-Hon
Published: January 2021

Stereotypic dendrite arborizations are key morphological features of neuronal identity, as the size, shape and location of dendritic trees determine the synaptic input fields and how information is integrated within developed neural circuits. In this review, we focus on the actions of extrinsic intercellular communication factors and their effects on intrinsic developmental processes that lead to dendrite patterning. Surrounding neurons or supporting cells express adhesion receptors and secreted proteins that respectively, act via direct contact or over short distances to shape, size, and localize dendrites during specific developmental stages. The different ligand-receptor interactions and downstream signaling events appear to direct dendrite morphogenesis by converging on two categorical mechanisms: local cytoskeletal and adhesion modulation and global transcriptional regulation of key dendritic growth components, such as lipid synthesis enzymes. Recent work has begun to uncover how the coordinated signaling of multiple extrinsic factors promotes complexity in dendritic trees and ensures robust dendritic patterning.
Is Guillain–Barré Syndrome Associated With COVID-19 Infection? A Systemic Review of the Evidence
Authors: Abdullahi Auwal , Candan Sevim Acaroz , Soysal Tomruk Melda , Elibol Nuray , Dada Olumide , Truijen Steven , Saeys Wim
Published: January 2021

Background: There is emerging evidence that Guillain–Barré syndrome (GBS) may be associated with coronavirus disease 2019 (COVID-19) infection. The aim of this review was to investigate the strength of the evidence.

Method: The review was registered in PROSPERO (CDR42020184822). Three electronic databases, MEDLINE, PubMed, and Web of Science, and three preprint servers, MedRvix, ChemRvix, and BioRvix, were searched from December 2019 to 24th September 2020. Studies were included if they were on COVID-19 and of any design. Articles that are reviews or opinion were excluded. The selection process was carried out using EndNote and Rayyan software. The main outcomes in the study were study design, sample size, sex, age, overall GBS symptoms, other COVID-19 symptoms, comorbidity, timing between infection and the onset of neurological symptoms, CT, MRI, and EMG results. Methodological quality of the studies was assessed using the McMaster Critical Review Form. The collected data was analyzed using qualitative synthesis.

Findings: Fifty-one high-quality studies (mostly) consisting of 83 patients were included in the study. All of the patients (except in a very few) in the included studies had confirmed diagnosis of COVID-19. Similarly, the diagnosis of GBS was based on standard clinical, electrophysiological, and cerebrospinal fluid (CSF) criteria.

Conclusion: GBS may be associated with COVID-19, and therefore, testing for COVID-19 is recommended in patients presenting with GBS during this pandemic.
Operation Brain Trauma Therapy: An Exploratory Study of Levetiracetam Treatment Following Mild Traumatic Brain Injury in the Micro Pig
Authors: Lafrenaye Audrey , Mondello Stefania , Povlishock John , Gorse Karen , Walker Susan , Hayes Ronald , Wang Kevin , Kochanek Patrick M.
Published: January 2021

Operation brain trauma therapy (OBTT) is a drug- and biomarker-screening consortium intended to improve the quality of preclinical studies and provide a rigorous framework to increase the translational potential of experimental traumatic brain injury (TBI) treatments. Levetiracetam (LEV) is an antiepileptic agent that was the fifth drug tested by OBTT in three independent rodent models of moderate to severe TBI. To date, LEV has been the most promising drug tested by OBTT and was therefore advanced to testing in the pig. Adult male micro pigs were subjected to a mild central fluid percussion brain injury followed by a post-injury intravenous infusion of either 170 mg/kg LEV or vehicle. Systemic physiology was assessed throughout the post-injury period. Serial serum samples were obtained pre-injury as well as at 1 min, 30 min, 1 h, 3 h, and 6 h post-injury for a detailed analysis of the astroglial biomarker glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1. Tissue was collected 6 h following injury for histological assessment of diffuse axonal injury using antibodies against the amyloid precursor protein (APP). The animals showed significant increases in circulating GFAP levels from baseline to 6 h post-injury; however, LEV treatment was associated with greater GFAP increases compared to the vehicle. There were no differences in the numbers of APP+ axonal swellings within the pig thalamus with LEV treatment; however, significant alterations in the morphological properties of the APP+ axonal swellings, including reduced swelling area and increased swelling roundness, were observed. Additionally, expression of the neurite outgrowth marker, growth-associated protein 43, was reduced in axonal swellings following LEV treatment, suggesting potential effects on axonal outgrowth that warrant further investigation.
Learning Curve for Endovascular Treatment of Anterior Circulation Large Vessel Occlusion at a Single Center
Authors: Cai Qiankun , Zhu Yuyou , Huang Xianjun , Xiao Lulu , Gu Mengmeng , Wang Peng , Zhang Chao , Chen Jixing , Hu Wei , Wang Guoping , Sun Wen
Published: January 2021

Background and purpose: Data concerning the learning curve for endovascular treatment (EVT) of anterior circulation large vessel occlusion are scarce. This study aimed to investigate the relationship between operator experience and the outcome of EVT and to further identify the number of cases needed to acquire the ability to perform successful reperfusion.

Materials and methods: Four hundred and thirty-four patients who underwent EVT by seven operators at a single center from January 2016 to September 2019 were enrolled. Procedural experience was defined by the number of cases performed by each operator. Multivariable backward regression analyses were used to investigate the association between procedural experience and functional independence (defined as a modified Rankin Scale score of 0–2), 90-days mortality, successful reperfusion (defined as a modified Thrombolysis in Cerebral Infarction score of 2b-3), and puncture-to-reperfusion time after adjusting for covariates. A risk-adjusted cumulative sum (RA-CUSUM) chart was utilized to identify the number of caseloads needed to overcome the learning curve effect.

Results: Procedural experience was independently associated with functional independence, 90-days mortality, successful reperfusion, and puncture-to-reperfusion time reduction (per 10-case increment: OR 1.219, 95% CI: 1.079–1.383, P < 0.001; OR 0.847, 95% CI: 0.738–0.968, P = 0.016; OR 1.553, 95% CI: 1.332–1.830, P < 0.001 and β 8.087 min, 95% CI: 6.184–9.991, P < 0.001, respectively). The RA-CUSUM chart indicated that at least 29 cases were required to overcome the learning curve effect.

Conclusions: There was a dose-response relationship between operator case volume and clinical outcome, procedure time, and successful reperfusion. The experience needed for successful EVT was at least 29 cases.
Glucose Metabolism Characteristics of Extra-Hypothalamic Cortex in Patients With Hypothalamic Hamartomas (HH) Undergoing Epilepsy Evaluation: A Retrospective Study of 16 Cases
Authors: Yang Yan-Feng , Wei Peng-Hu , Meng Fei , An Yang , Fan Xiao-Tong , Wang Yi-He , Wang Di , Ren Lian-Kun , Shan Yong-Zhi , Zhao Guo-Guang
Published: January 2021

Purpose:There are few studies on the glucose metabolic characteristics of the extra-hypothalamic cortex in the hypothalamic hamartomas (HH). A comprehensive understanding of pathogenic progression of the disease is required from the perspective of cortical metabolism; therefore, we aimed to characterize metabolic characteristics of extra-hypothalamic in HH patients.

Methods:We investigated the metabolic characteristics of 16 HH patients, all of whom underwent epilepsy evaluation at Xuan Wu Hospital between 2017 and 2019. The lateralization and cortical distribution pattern of hypometabolism was assessed and related to HH mass neuroanatomy on magnetic resonance imaging (MRI) as well as scalp-electroencephalogram (scalp-EEG) abnormalities. Furthermore, asymmetry measurements of region of interest (ROI) in the temporal cortex (hippocampal formation, amygdala, and lateral temporal neocortex) were quantitatively assessed based on the normalized average positron emission tomography (PET) voxel values. The surgery prognosis was assessed using the International League Against Epilepsy (ILAE) classification system.

Results:The lateralization of hypometabolism in global visual ratings was consistent with the HH mass lateralization seen on MRI. Cortical hypometabolism showed three patterns depending whether the HH mass involved mammillary bodies, middle hypothalamus nucleus, or both. The three patterns were hypometabolism of the mesial temporal cortex with symptom of mesial temporal epilepsy (3/16, pattern I), lateral temporal, and extratemporal (frontal or parietal) cortex with symptom of neocortex temporal or frontal epilepsy (5/16, pattern II), and mesial and lateral temporal cortex and extratemporal (frontal or parietal) cortex with varied symptoms (8/16, pattern III), respectively. A significant difference in PET voxel values was found between bilateral hippocampal formation (P= 0.001) and lateral temporal neocortex in the third group (P= 0.005). We suggest that the hypometabolic characteristics of the extra-hypothalamic cortex in HH patients have three patterns. The final cortical hypometabolic pattern depends on the neuroanatomic location of the HH mass and was consistent with the main involved cortex of the interictal and ictal discharges. The third hypometabolic pattern with the most extensive cortical hypometabolism has a poorer prognosis.
Cerebral Vessels: An Overview of Anatomy, Physiology, and Role in the Drainage of Fluids and Solutes
Authors: Agarwal Nivedita , Carare Roxana Octavia
Published: January 2021

The cerebral vasculature is made up of highly specialized structures that assure constant brain perfusion necessary to meet the very high demand for oxygen and glucose by neurons and glial cells. A dense, redundant network of arteries is spread over the entire pial surface from which penetrating arteries dive into the cortex to reach the neurovascular units. Besides providing blood to the brain parenchyma, cerebral arteries are key in the drainage of interstitial fluid (ISF) and solutes such as amyloid-beta. This occurs along the basement membranes surrounding vascular smooth muscle cells, toward leptomeningeal arteries and deep cervical lymph nodes. The dense microvasculature is made up of fine capillaries. Capillary walls contain pericytes that have contractile properties and are lined by a highly specialized blood–brain barrier that regulates the entry of solutes and ions and maintains the integrity of the composition of ISF. They are also important for the production of ISF. Capillaries drain into venules that course centrifugally toward the cortex to reach cortical veins and empty into dural venous sinuses. The walls of the venous sinuses are also home to meningeal lymphatic vessels that support the drainage of cerebrospinal fluid, although such pathways are still poorly understood. Damage to macro- and microvasculature will compromise cerebral perfusion, hamper the highly synchronized movement of neurofluids, and affect the drainage of waste products leading to neuronal and glial degeneration. This review will present vascular anatomy, their role in fluid dynamics, and a summary of how their dysfunction can lead to neurodegeneration.
Continuity of Care During COVID-19 Lockdown: A Survey on Stakeholders' Experience With Telerehabilitation
Authors: Assenza Carla , Catania Hilenia , Antenore Clementina , Gobbetti Tiziana , Gentili Paola , Paolucci Stefano , Morelli Daniela
Published: January 2021

Objective: To explore professionals', adult patients', and children's caregivers' perception and satisfaction with telerehabilitation during COVID-19 lockdown.

Design: An observational transversal study on a web-based survey was conducted in order to explore participants' perception and satisfaction of telerehabilitation during COVID-19 lockdown.

Setting: The study was conducted at our Outpatient Neurorehabilitation Service.

Subjects: All rehabilitation professionals, adult patients, and children's caregivers who accepted telerehabilitation were recruited.

Interventions: Participants had to respond to the Client Satisfaction Questionnaire-8 and to a purpose-built questionnaire on their perception and satisfaction of the service provided.

Main Measures: Data were analyzed by qualitative statistics and logistic regression models.

Results: All 144 caregivers, 25 adult patients, and 50 professionals reported a medium-high level of perception and a high level of satisfaction. Results showed a correlation among caregivers of children aged 0–3 and feeling overwhelmed with remote care (OR = 3.27), a low perception of telerehabilitation for enhancing goals (OR = 6.51), and a high perception of feeling helped in organizing daily activity (OR = 2.96). For caregivers of children aged over 6 years, changes in the therapy plan were related to a low perception of feeling in line with the in-person therapy (OR = 2.61 and OR = 9.61) and a low satisfaction (OR = 5.54 and OR = 4.97). Changes in therapy were related to concern (OR = 4.20). Caregivers under 40 and professionals showed a high probability to perceive telerehabilitation as supportive (OR = 2.27 and OR = 5.68). Level of experience with remote media was shown to influence perception and satisfaction.

Interpretation: Telerehabilitation can be a useful practice both during a health emergency and in addition to in-presence therapy.
International Legal Approaches to Neurosurgery for Psychiatric Disorders
Authors: Chandler Jennifer A. , Cabrera Laura Y. , Doshi Paresh , Fecteau Shirley , Fins Joseph J. , Guinjoan Salvador , Hamani Clement , Herrera-Ferrá Karen , Honey C. Michael , Illes Judy , Kopell Brian H. , Lipsman Nir , McDonald Patrick J. , Mayberg Helen S. , Nadler Roland , Nuttin Bart , Oliveira-Maia Albino J. , Rangel Cristian , Ribeiro Raphael , Salles Arleen , Wu Hemmings
Published: January 2021

Neurosurgery for psychiatric disorders (NPD), also sometimes referred to as psychosurgery, is rapidly evolving, with new techniques and indications being investigated actively. Many within the field have suggested that some form of guidelines or regulations are needed to help ensure that a promising field develops safely. Multiple countries have enacted specific laws regulating NPD. This article reviews NPD-specific laws drawn from North and South America, Asia and Europe, in order to identify the typical form and contents of these laws and to set the groundwork for the design of an optimal regulation for the field. Key challenges for this design that are revealed by the review are how to define the scope of the law (what should be regulated), what types of regulations are required (eligibility criteria, approval procedures, data collection, and oversight mechanisms), and how to approach international harmonization given the potential migration of researchers and patients.
Olanzapine-Induced Activation of Hypothalamic Astrocytes and Toll-Like Receptor-4 Signaling via Endoplasmic Reticulum Stress Were Related to Olanzapine-Induced Weight Gain
Authors: He Meng , Qian Kun , Zhang Ying , Huang Xu-Feng , Deng Chao , Zhang Baohua , Gao Guanbin , Li Jing , Xie Hao , Sun Taolei
Published: January 2021

The antipsychotic drug olanzapine is associated with serious obesity side effects. Hypothalamic astrocytes and associated toll-like receptor-4 (TLR4) signaling play an essential role in obesity pathogenesis. This study investigated the effect of olanzapine on astrocytes and TLR4 signaling both in vitro and in the rat hypothalamus and their potential role in olanzapine-induced weight gain. We found that olanzapine treatment for 24 h dose-dependently increased cell viability, increased the protein expression of astrocyte markers including glial fibrillary acidic protein (GFAP) and S100 calcium binding protein B (S100B), and activated TLR4 signaling in vitro. In rats, 8- and 36-day olanzapine treatment caused weight gain accompanied by increased GFAP and S100B protein expression and activated TLR4 signaling in the hypothalamus. These effects still existed in pair-fed rats, suggesting that these effects were not secondary effects of olanzapine-induced hyperphagia. Moreover, treatment with an endoplasmic reticulum (ER) stress inhibitor, 4-phenylbutyrate, inhibited olanzapine-induced weight gain and ameliorated olanzapine-induced changes in hypothalamic GFAP, S100B, and TLR4 signaling. The expression of GFAP, S100B, and TLR4 correlated with food intake and weight gain. These findings suggested that olanzapine-induced increase in hypothalamic astrocytes and activation of TLR4 signaling were related to ER stress, and these effects may be related to olanzapine-induced obesity.
Inflamm-Aging and Brain Insulin Resistance: New Insights and Role of Life-style Strategies on Cognitive and Social Determinants in Aging and Neurodegeneration
Authors: Komleva Yulia , Chernykh Anatoly , Lopatina Olga , Gorina Yana , Lokteva Irina , Salmina Alla , Gollasch Maik
Published: January 2021

Over the past decades, the human life span has dramatically increased, and therefore, a steady increase in diseases associated with age (such as Alzheimer’s disease and Parkinson’s disease) is expected. In these neurodegenerative diseases, there is a cognitive decline and memory loss, which accompany increased systemic inflammation, the inflamm-aging, and the insulin resistance. Despite numerous studies of age-related pathologies, data on the contribution of brain insulin resistance and innate immunity components to aging are insufficient. Recently, much research has been focused on the consequences of nutrients and adiposity- and nutrient-related signals in brain aging and cognitive decline. Moreover, given the role of metainflammation in neurodegeneration, lifestyle interventions such as calorie restriction may be an effective way to break the vicious cycle of metainflammation and have a role in social behavior. The various effects of calorie restriction on metainflammation, insulin resistance, and neurodegeneration have been described. Less attention has been paid to the social determinants of aging and the possible mechanism by which calorie restriction might influence social behavior. The purpose of this review is to discuss current knowledge in the interdisciplinary field of geroscience—immunosenescence, inflamm-aging, and metainflammation—which makes a significant contribution to aging. A substantial part of the review is devoted to frontiers in the brain insulin resistance in relation to neuroinflammation. In addition, we summarize new data on potential mechanisms of calorie restriction that influence as a lifestyle intervention on the social brain. This knowledge can be used to initiate successful aging and slow the onset of neurodegenerative diseases.
Implications of Glycosylation in Alzheimer’s Disease
Authors: Haukedal Henriette , Freude Kristine K.
Published: January 2021

Alzheimer’s disease (AD) is the most common cause of dementia, affecting millions of people worldwide, and no cure is currently available. The major pathological hallmarks of AD are considered to be amyloid beta plaques and neurofibrillary tangles, generated by respectively APP processing and Tau phosphorylation. Recent evidence imply that glycosylation of these proteins, and a number of other AD-related molecules is altered in AD, suggesting a potential implication of this process in disease pathology. In this review we summarize the understanding of glycans in AD pathogenesis, and discuss how glycobiology can contribute to early diagnosis and treatment of AD, serving as potential biomarkers and therapeutic targets. Furthermore, we look into the potential link between the emerging topic neuroinflammation and glycosylation, combining two interesting, and until recent years, understudied topics in the scope of AD. Lastly, we discuss how new model platforms such as induced pluripotent stem cells can be exploited and contribute to a better understanding of a rather unexplored area in AD.
The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation
Authors: Cieślik Magdalena , Gassowska-Dobrowolska Magdalena , Zawadzka Aleksandra , Frontczak-Baniewicz Małgorzata , Gewartowska Magdalena , Dominiak Agnieszka , Czapski Grzegorz A. , Adamczyk Agata
Published: January 2021

Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders in offspring, but the pathomechanism is largely unknown. The aim of our study was to analyse the molecular mechanisms contributing to synaptic alterations in hippocampi of adolescent rats exposed prenatally to MIA. MIA was evoked in pregnant female rats by i.p. administration of lipopolysaccharide at gestation day 9.5. Hippocampi of offspring (52–53-days-old rats) were analysed using transmission electron microscopy (TEM), qPCR and Western blotting. Moreover, mitochondrial membrane potential, activity of respiratory complexes, and changes in glutathione system were measured. It was found that MIA induced changes in hippocampi morphology, especially in the ultrastructure of synapses, including synaptic mitochondria, which were accompanied by impairment of mitochondrial electron transport chain and decreased mitochondrial membrane potential. These phenomena were in agreement with increased generation of reactive oxygen species, which was evidenced by a decreased reduced/oxidised glutathione ratio and an increased level of dichlorofluorescein (DCF) oxidation. Activation of cyclin-dependent kinase 5, and phosphorylation of glycogen synthase kinase 3β on Ser9 occurred, leading to its inhibition and, accordingly, to hypophosphorylation of microtubule associated protein tau (MAPT). Abnormal phosphorylation and dysfunction of MAPT, the manager of the neuronal cytoskeleton, harmonised with changes in synaptic proteins. In conclusion, this is the first study demonstrating widespread synaptic changes in hippocampi of adolescent offspring prenatally exposed to MIA.
A THP-1 Cell Line-Based Exploration of Immune Responses Toward Heat-Treated BLG
Authors: Deng Ying , Govers Coen , Beest Ellen ter , van Dijk Aalt-Jan , Hettinga Kasper , Wichers Harry J.
Published: January 2021

Allergen recognition and processing by antigen presenting cells is essential for the sensitization step of food allergy. Macrophages and dendritic cells are both phagocytic antigen presenting cells and play important roles in innate immune responses and signaling between the innate and adaptive immune system. To obtain a model system with a homogeneous genetic background, we derived macrophages and dendritic cells from THP-1 monocytes. The difference between macrophages and dendritic cells was clearly shown by differences in their transcription response (microarray) and protein expression levels. Their resemblance to primary cells was analyzed by comparison to properties as described in literature. The uptake of β-lactoglobulin after wet-heating (60°C in solution) by THP-1 derived macrophages was earlier reported to be significantly increased. To analyse the subsequent immune response, we incubated THP-1 derived macrophages and dendritic cells with native and differently processed β-lactoglobulin and determined the transcription and cytokine expression levels of the cells. A stronger transcriptional response was found in macrophages than in dendritic cells, while severely structurally modified β-lactoglobulin induced a more limited transcriptional response, especially when compared to native and limitedly modified β-lactoglobulin. These results show that processing is relevant for the transcriptional response toward β-lactoglobulin of innate immune cells.