bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple Metrics of Temperature, Light, and Water Motion Drive Gradients in Eelgrass Productivity and Resilience
Authors: Krumhansl Kira A. , Dowd Michael , Wong Melisa C.
Published: February 2021

Characterizing the response of ecosystems to global climate change requires that multiple aspects of environmental change be considered simultaneously, however, it can be difficult to describe the relative importance of environmental metrics given their collinearity. Here, we present a novel framework for disentangling the complex ecological effects of environmental variability by documenting the emergent properties of eelgrass (Zostera marina) ecosystems across ∼225 km of the Atlantic Coast of Nova Scotia, Canada, representing gradients in temperature, light, sediment properties, and water motion, and evaluate the relative importance of different metrics characterizing these environmental conditions (e.g., means, extremes, variability on different time scales) for eelgrass bioindicators using lasso regression and commonality analysis. We found that eelgrass beds in areas that were warmer, shallower, and had low water motion had lower productivity and resilience relative to beds in deeper, cooler areas that were well flushed, and that higher temperatures lowered eelgrass tolerance to low-light conditions. There was significant variation in the importance of various metrics of temperature, light, and water motion across biological responses, demonstrating that different aspects of environmental change uniquely impact the cellular, physiological, and ecological processes underlying eelgrass productivity and resilience, and contribute synergistically to the observed ecosystem response. In particular, we identified the magnitude of temperature variability over daily and tidal cycles as an important determinant of eelgrass productivity. These results indicate that ecosystem responses are not fully resolved by analyses that only consider changes in mean conditions, and that the removal of collinear variables prior to analyses relating environmental metrics to biological change reduces the potential to detect important environmental effects. The framework we present can help to identify the conditions that promote high ecosystem function and resilience, which is necessary to inform nearshore conservation and management practices under global climate change.
Out of Sight, Out of Mind: How Conservation Is Failing European Porpoises
Authors: Carlén Ida , Nunny Laetitia , Simmonds Mark P.
Published: February 2021

The conservation of harbor porpoises (Phocoena phocoena) appears to be failing in Europe. There are particular concerns about this species in the Baltic Proper, Black, and Mediterranean Seas, as well as in the Northeast Atlantic, including the Iberian population, off the Spanish and Portuguese coasts. The Baltic Proper porpoise is “critically endangered,” with a population only in the low hundreds, and the Scientific Committee of the International Whaling Commission has repeatedly called for action to ensure its survival. In 2020, the Committee issued a series of recommendations relating to it and the Iberian population. Similarly, the Black Sea harbor porpoise, Phocoena phocoena ssp. relicta, is classified by the IUCN as endangered. Another population which may be genetically distinct is the West Greenland harbor porpoise, which is hunted without quotas or close seasons. European cetaceans and their habitats are covered by a number of international and regional conventions and agreements and, under European Union law, are “highly protected.” In practice, however, these legal protections have failed to generate effective conservation. For example, Special Areas of Conservation (SACs) are required for them and, although sites have been designated in some marine areas/countries, in the absence of appropriate management plans, SACs cannot be expected to help improve the harbor porpoise's conservation status. Compared to many other species, porpoises are relatively long-lived with low reproductive capacity and only poor public recognition. Conservation and management efforts are caught up in a complicated nexus of interactions involving a web of commitments under international conventions and agreements, European environmental laws, and European fisheries policy. However, public disinterest, lack of political will to implement conservation measures, and complicated fishing-related issues hinder any real progress. More positively, recent advice from the International Council for the Exploration of the Seas (ICES) provides a new scientific foundation for conservation action to address fisheries bycatch in the Baltic Proper harbor porpoise population. Populations of other porpoise species (family Phocoenidae) are also threatened, most notably the global population of the critically endangered vaquita, or Gulf of California porpoise (Phocoena sinus). The common threats and factors affecting porpoise populations are discussed and recommendations offered.
Comorbidities in a Cohort of 66 Patients With Psoriatic Arthritis Mutilans—Results From the Nordic PAM Study
Authors: Mistegård Josephine , Gudbjornsson Bjorn , Lindqvist Ulla , Laasonen Leena , Ejstrup Leif , Ståhle Mona , Iversen Lars
Published: February 2021

Objective: Psoriatic arthritis mutilans (PAM) is the most severe phenotype of psoriatic arthritis due to excessive bone erosion causing joint destruction and decreased functional capacity. The aim of this study was to investigate the prevalence of comorbidities among patients with PAM and the association between comorbidities and joint involvement.

Methods: A total of 66 patients aged ≥18 years from the Nordic countries with past or present psoriasis along with at least one mutilated joint were included in the present study.

Results: The median number of comorbid conditions per patient was 1 [interquartile range (IQR) 0–2] and 16.7% reported three or more comorbidities. The most frequent comorbidity was hypertension (36.4%). The median number of mutilated joints per patient was 3 (IQR 1–8.3; range 1–38).

Conclusion: Two thirds of the patients with PAM reported comorbid conditions and the most frequent was hypertension which affected more than a third of the patients. However, this study was unable to detect any association between comorbidities and the severity of PAM.
Evaluation of Host Immune Response in Diabetic Foot Infection Tissues Using an RNA Sequencing-Based Approach
Authors: Heravi Fatemah Sadeghpour , Zakrzewski Martha , Aboulkheyr Estarabadi Hamidreza , Vickery Karen , Hu Honghua
Published: February 2021

The normal continuity of skin tissue can be affected by invading pathogens and lead to a series of complicated physiological events. Using an RNA sequencing-based approach, we have captured a metatranscriptomic landscape from diabetic foot infections (DFIs). The hierarchical clustering of the top 2,000 genes showed the expression of four main clusters in DFIs (A, B, C, and D). Clusters A and D were enriched in genes mainly involved in the recruitment of inflammatory cells and immune responses and clusters B and C were enriched in genes related to skin cell development and wound healing processes such as extracellular structure organization and blood vessel development. Differential expression analysis showed more than 500 differentially expressed genes (DEGs) between samples with a low number of virulence factors and samples with a high number of virulence factors. Up-regulated and down-regulated genes were mainly involved in adaptive/native immune responses and transport of mature mRNAs, respectively. Our results demonstrated the importance of inflammatory cytokines of adaptive/native immunity in the progression of DFIs and provided a useful groundwork for capturing gene snapshots in DFIs. In addition, we have provided a general introduction to the challenges and opportunities of RNA sequencing technology in the evaluation of DFIs. Pathways identified in this study such as immune chemokines, Rho GTPases, and corresponding effectors might be important therapeutic targets in the management of DFIs.
The Vacuole and Mitochondria Patch (vCLAMP) Protein Mcp1 Is Involved in Maintenance of Mitochondrial Function and Mitophagy in Candida albicans
Authors: Mao Xiaolong , Yang Li , Fan Yiming , Wang Jiazhen , Cui Dongkai , Yu Dixiong , Yu Qilin , Li Mingchun
Published: February 2021

The vacuole and mitochondria patches (vCLAMPs) are novel membrane contact sites in yeast. However, their role in autophagy has not been elucidated so far. In this article, the role of Mcp1, one core component of vCLAMP, in mitophagy of Candida albicans was investigated. Deletion of MCP1 led to abnormal accumulation of enlarged mitochondria and attenuated stability of mitochondrial DNA (mtDNA) in C. albicans when cultured in non-fermentable carbon sources. Furthermore, the mcp1Δ/Δ mutant exhibited defective growth and degradation of Csp37-GFP. These results indicate that Mcp1 plays a crucial role in mitophagy and maintenance of mitochondrial functions under the non-fermentable condition. Interestingly, this deletion had no impact on degradation of Atg8 (the macroautophagy reporter) and Lap41 (the cytoplasm-to-vacuole targeting pathway marker) under SD-N medium. Moreover, deletion of MCP1 inhibited filamentous growth and impaired virulence of the pathogen. This study provides an insight to vCLAMPs in cellular functions and pathogenicity in C. albicans.
Autochthonous and Travel Acquired Hepatitis E Virus in Australia
Authors: O’Keefe Jacinta , Tracy Lilly , Yuen Lilly , Bonanzinga Sara , Li Xin , Chong Brian , Nicholson Suellen , Jackson Kathy
Published: February 2021

Background

Hepatitis E virus (HEV) is a common cause of acute viral hepatitis with significant morbidity and mortality, particularly in pregnant women. There are four major genotypes which can cause disease in humans. Genotypes 1 and 2 are usually associated with outbreaks and spread via facal/oral route or contaminated water. Genotypes 3 and 4 are zoonotic and usually associated with handling of pigs or consumption of contaminated pork. The strains circulating in Australia have never been characterized.

Rationale/Aims

The aims for this project are to identify the HEV genotypes found in Australia and link them to possible sources of transmission by phylogenetic analysis.

Materials and Methods

Between 2015 and 2020, 91 HEV isolates were sequenced and genotyped using an in-house PCR. Sixty-six of these were also sequenced by using the international HEVnet primers. Genotypes were determined using the BLASTn program. Relatedness to other strains in Australia was determined by phylogenetic analyses of the HEVnet sequences. Isolates were also stratified by state of origin, gender, age, predisposing factors and travel history (if known).

Results

Of the 91 HEV isolates sequenced, 55 (60.4%) were genotype 1. There were 34 (37.4%) genotype 3 strains and two genotype 4 (2.2%). At least 20 of the genotype 1 strains have been linked to travel in India, and another three with Pakistan. Five of the “Indian” strains were closely related and are suspected to have originated in Gujarat. Phylogenetic analysis also showed that 12 genotype 3 strains were genetically related and potentially acquired in/from New South Wales, Australia. The two genotype 4 strains may have originated in China.

Discussion

This is the first study to describe the HEV isolates identified in Australia. The results infer that HEV may be acquired during overseas travel as well as locally, presumably from consumption of pork or pork-related products. The phylogenetic analyses also reveal clusters of infection originating from India and Pakistan. This study provides some insight into the source and epidemiology of HEV infection in Australia which may be used to guide public health procedure and enable the implementation of measures to deal with potential outbreaks of infection.
Deciphering the Mechanism of Inhibition of SERCA1a by Sarcolipin Using Molecular Simulations
Authors: Barbot Thomas , Beswick Veronica , Montigny Cédric , Quiniou Éric , Jamin Nadège , Mouawad Liliane
Published: February 2021

SERCA1a is an ATPase calcium pump that transports Ca2+ from the cytoplasm to the sarco/endoplasmic reticulum lumen. Sarcolipin (SLN), a transmembrane peptide, regulates the activity of SERCA1a by decreasing its Ca2+ transport rate, but its mechanism of action is still not well-understood. To decipher this mechanism, we have performed normal mode analysis in the all-atom model, with the SERCA1a-SLN complex, or the isolated SERCA1a, embedded in an explicit membrane. The comparison of the results allowed us to provide an explanation at the atomic level for the action of SLN that is in good agreement with experimental observations. In our analyses, the presence of SLN locally perturbs the TM6 transmembrane helix and as a consequence modifies the position of D800, one of the key metal-chelating residues. Additionally, it reduces the flexibility of the gating residues, V304, and E309 in TM4, at the entrance of the Ca2+ binding sites, which would decrease the affinity for Ca2+. Unexpectedly, SLN has also an effect on the ATP binding site more than 35 Å away, due to the straightening of TM5, a long helix considered as the spine of the protein. The straightening of TM5 modifies the structure of the P-N linker that sits above it, and which comprises the 351DKTG354 conserved motif, resulting in an increase of the distance between ATP and the phosphorylation site. As a consequence, the turn-over rate could be affected. All this gives SERCA1a the propensity to go toward a Ca2+ low-affinity E2-like state in the presence of SLN and toward a Ca2+ high-affinity E1-like state in the absence of SLN. In addition to a general mechanism of inhibition of SERCA1a regulatory peptides, this study also provides an insight into the conformational transition between the E2 and E1 states.
Therapeutic Strategies in the Management of COVID-19
Authors: Naik Rajashri R. , Shakya Ashok K.
Published: February 2021

Since December 2019, SARS-CoV-2 (COVID-19), novel corona virus has caused pandemic globally, with rise in the number of cases and death of the patients. Vast majority of the countries that are dealing with rise in the active cases and death of patients suffering from novel corona viruses COVID-19 are trying to content the virus by isolating the patients and treating them with the approved antiviral that have been previously used in treating SARS, MERS, and drugs that are used to treat other viral infections. Some of these are under clinical trials. At present there are no therapeutically effective antiviral present and there are no vaccines or drugs available that are clinically approved for treating the corona virus. The current strategy is to re-purpose the available drugs or antiviral that can minimise or reduce the burden of the health care emergencies. In this article the reuse of antiviral, US-FDA approved drugs, plant based therapeutic, anti-malarial, anti-parasitic, anti–HIV drugs and the traditional medicines that are being currently used in treating the symptoms of COVID–19 patients is discussed emphasis is also given on the treatment using monoclonal antibodies. The present article provides the therapeutic strategies that will qualify as one of the best available treatment for the better management of the COVID–19 patients in order to achieve medical benefits.
Distinctive Oculomotor Behaviors in Alzheimer's Disease and Frontotemporal Dementia
Authors: Lage Carmen , López-García Sara , Bejanin Alexandre , Kazimierczak Martha , Aracil-Bolaños Ignacio , Calvo-Córdoba Alberto , Pozueta Ana , García-Martínez María , Fernández-Rodríguez Andrea , Bravo-González María , Jiménez-Bonilla Julio , Banzo Ignacio , Irure-Ventura Juan , Pegueroles Jordi , Illán-Gala Ignacio , Fortea Juan , Rodríguez-Rodríguez Eloy , Lleó-Bisa Alberto , García-Cena Cecilia E. , Sánchez-Juan Pascual
Published: February 2021

Oculomotor behavior can provide insight into the integrity of widespread cortical networks, which may contribute to the differential diagnosis between Alzheimer's disease and frontotemporal dementia. Three groups of patients with Alzheimer's disease, behavioral variant of frontotemporal dementia (bvFTD) and semantic variant of primary progressive aphasia (svPPA) and a sample of cognitively unimpaired elders underwent an eye-tracking evaluation. All participants in the discovery sample, including controls, had a biomarker-supported diagnosis. Oculomotor correlates of neuropsychology and brain metabolism evaluated with 18F-FDG PET were explored. Machine-learning classification algorithms were trained for the differentiation between Alzheimer's disease, bvFTD and controls. A total of 93 subjects (33 Alzheimer's disease, 24 bvFTD, seven svPPA, and 29 controls) were included in the study. Alzheimer's disease was the most impaired group in all tests and displayed specific abnormalities in some visually-guided saccade parameters, as pursuit error and horizontal prosaccade latency, which are theoretically closely linked to posterior brain regions. BvFTD patients showed deficits especially in the most cognitively demanding tasks, the antisaccade and memory saccade tests, which require a fine control from frontal lobe regions. SvPPA patients performed similarly to controls in most parameters except for a lower number of correct memory saccades. Pursuit error was significantly correlated with cognitive measures of constructional praxis and executive function and metabolism in right posterior middle temporal gyrus. The classification algorithms yielded an area under the curve of 97.5% for the differentiation of Alzheimer's disease vs. controls, 96.7% for bvFTD vs. controls, and 92.5% for Alzheimer's disease vs. bvFTD. In conclusion, patients with Alzheimer's disease, bvFTD and svPPA exhibit differentiating oculomotor patterns which reflect the characteristic neuroanatomical distribution of pathology of each disease, and therefore its assessment can be useful in their diagnostic work-up. Machine learning approaches can facilitate the applicability of eye-tracking in clinical practice.
Reliance on Visual Input for Balance Skill Transfer in Older Adults: EEG Connectome Analysis Using Minimal Spanning Tree
Authors: Chen Yi-Ching , Chou Yu-Chen , Hwang Ing-Shiou
Published: February 2021

Skill transfer from trained balance exercises is critical to reduce the rate of falls in older adults, who rely more on vision to control postural responses due to age-dependent sensory reweighting. With an electroencephalography (EEG) minimum spanning tree (MST) structure, the purpose of this study was to compare the organization of supraspinal neural networks of transfer effect after postural training using full and intermittent visual feedbacks for older adults. Thirty-two older adults were randomly assigned to the stroboscopic vision (SV) (n = 16; age = 64.7 ± 3.0 years) and control (16; 66.3 ± 2.7 years) groups for balance training on a stabilometer (target task) with on-line visual feedback. Center-of-pressure characteristics and an MST-based connectome of the weighted phase-lag index during the bilateral stance on a foam surface (transfer task) were compared before and after stabilometer training. The results showed that both the SV and control groups showed improvements in postural stability in the trained task (p < 0.001). However, unlike the control group (p = 0.030), the SV group who received intermittent visual feedback during the stabilometer training failed to reduce the size of postural sway in the anteroposterior direction of the postural transfer task (unstable stance on the foam surface) in the post-test (p = 0.694). In addition, network integration for the transfer task in the post-test was absent in the SV group (p > 0.05). For the control group in the post-test, it manifested with training-related increases in leaf fraction in beta band (p = 0.015) and maximum betweenness in alpha band (p = 0.018), but a smaller diameter in alpha (p = 0.006)/beta (p = 0.021) bands and average eccentricity in alpha band (p = 0.028). In conclusion, stabilometer training with stroboscopic vision impairs generalization of postural skill to unstable stance for older adults. Adequate visual information is a key mediating factor of supraspinal neural networks to carry over balance skill in older adults.
Risk Factors Influencing Seeking Emergency Medical Service in Urban and Rural China Among Participants With a Previous Transient Ischemic Attack
Authors: Yuan Jing , Shan Guang-Liang , Li Sheng-De , Gao Chun-Peng , Cui Li-Ying , Peng Bin
Published: February 2021

Objective: It is critical to identify factors that significantly impede the correct action of calling emergency medical service (EMS) in the high-risk population with a previous history of transient ischemic attack (TIA) and further explore the urban–rural difference in China.

Methods: Participants with previous TIA from the China National Stroke Screening Survey and its branch study (FAST-RIGHT) were interviewed cross-sectionally (n = 2,036). The associations between the outcome measure of not calling EMS and multiple potential risk factors were examined, including demographic information, live (or not) with families, medical insurance type, urban or rural residence, awareness of stroke symptoms, annual personal income, presence of cardiovascular disease or risk factors, and stroke history in family members or friends. The sample was further stratified to explore the urban–rural difference by their residency.

Results: The proportion of not calling EMS was 36.8% among all participants with previous TIA, and these were 21.7 and 48.4% among urban and rural participants, respectively. Among rural participants, risk factors that were significantly associated with not calling EMS included primary school education [odds ratio (OR) 2.50, 95% confidence interval (CI) 1.89–3.33], living with family (OR 2.09, 95% CI 1.33–3.36), unaware stroke symptoms (OR 2.60, 95% CI 1.81–3.78), and low income (OR 1.57, 95% CI 1.19–2.07). Among urban participants, only low income was significantly associated with an increased risk of not calling EMS (OR 1.74, 95% CI 1.10–2.72).

Conclusions: Rural residents with previous TIA in China had a higher percentage of not calling EMS. Multiple risk factors have been identified that call for targeted intervention strategies.
Dual Energy Computed Tomography of Internal Carotid Artery: A Modified Dual-Energy Algorithm for Calcified Plaque Removal, Compared With Digital Subtraction Angiography
Authors: Qu Hongying , Gao Yongan , Li Meiling , Zhai Shuo , Zhang Miao , Lu Jie
Published: February 2021

Background: Atherosclerotic disease of the internal carotid artery (ICA) is a common reason for ischemic stroke. Computed tomography angiography (CTA) is a common tool for evaluation of internal carotid artery (ICA) stenosis. However, blooming artifacts caused by calcified plaques might lead to overestimation of the stenosis grade. Furthermore, the intracranial ICA is more vulnerable to calcification than other ICA segments. The proposed technique, dual-energy computed tomography (DECT) with a modified three-material decomposition algorithm may facilitate the removal of calcified plaques and thus increase diagnostic accuracy.

Objectives: The objective of the study is to assess the accuracy of the modified three-material decomposition algorithm for grading intracranial ICA stenosis after calcified plaque removal, with digital subtraction angiography (DSA) used as a reference standard.

Materials and Methods: In total, 41 patients underwent DECT angiography and DSA. The three-material decomposition DECT algorithm for calcium removal was applied. We evaluated 64 instances of calcified stenosis using conventional CTA, the previous non-modified calcium removal DECT technique, the modified DECT algorithm, and DSA. The correlation coefficient (r2) between the results generated by the modified algorithm and DSA was also calculated.

Results: The virtual non-calcium images (VNCa) produced by the previous non-modified calcium removal algorithm were named VNCa 1, and those produced by the modified algorithm were named VNCa 2. The assigned degree of stenosis of VNCa 1 (mean stenosis: 39.33 ± 19.76%) differed significantly from that of conventional CTA images (mean stenosis: 59.03 ± 25.96%; P = 0.001), DSA (13.19 ± 17.12%, P < 0.001). VNCa 1 also significantly differed from VNCa 2 (mean stenosis: 15.35 ± 18.70%, P < 0.001). In addition, there was a significant difference between the degree of stenosis of VNCa 2 and conventional CTA images (P < 0.001). No significant differences were observed between VNCa 2 and DSA (P = 0.076). The correlation coefficient (r2) between the stenosis degree of the VNCa 2 and DSA images was 0.991.

Conclusions: The proposed DECT with a modified three-material decomposition algorithm for calcium removal has high sensitivity for the detection of relevant stenoses, and its results were more strongly correlated with DSA than with those of conventional CTA or the previous non-modified algorithm. Further, it overcomes CTA's previous problem of overestimating the degree of stenosis because of blooming artifacts caused by calcified plaques. It is useful to account for calcified plaques while evaluating carotid stenosis.
Extent of FLAIR Hyperintense Vessels May Modify Treatment Effect of Thrombolysis: A Post hoc Analysis of the WAKE-UP Trial
Authors: Grosch Anne Sophie , Kufner Anna , Boutitie Florent , Cheng Bastian , Ebinger Martin , Endres Matthias , Fiebach Jochen B. , Fiehler Jens , Königsberg Alina , Lemmens Robin , Muir Keith W. , Nighoghossian Norbert , Pedraza Salvador , Siemonsen Claus Z. , Thijs Vincent , Wouters Anke , Gerloff Christian , Thomalla Götz , Galinovic Ivana
Published: February 2021

Background and Aims: Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) on MRI are a radiological marker of vessel occlusion and indirect sign of collateral circulation. However, the clinical relevance is uncertain. We explored whether the extent of FHVs is associated with outcome and how FHVs modify treatment effect of thrombolysis in a subgroup of patients with confirmed unilateral vessel occlusion from the randomized controlled WAKE-UP trial.

Methods: One hundred sixty-five patients were analyzed. Two blinded raters independently assessed the presence and extent of FHVs (defined as the number of slices with visible FHV multiplied by FLAIR slice thickness). Patients were then separated into two groups to distinguish between few and extensive FHVs (dichotomization at the median <30 or ≥30).

Results: Here, 85% of all patients (n = 140) and 95% of middle cerebral artery (MCA) occlusion patients (n = 127) showed FHVs at baseline. Between MCA occlusion patients with few and extensive FHVs, no differences were identified in relative lesion growth (p = 0.971) and short-term [follow-up National Institutes of Health Stroke Scale (NIHSS) score; p = 0.342] or long-term functional recovery [modified Rankin Scale (mRS) <2 at 90 days poststroke; p = 0.607]. In linear regression analysis, baseline extent of FHV (defined as a continuous variable) was highly associated with volume of hypoperfused tissue (β = 2.161; 95% CI 0.96–3.36; p = 0.001). In multivariable regression analysis adjusted for treatment group, stroke severity, lesion volume, occlusion site, and recanalization, FHV did not modify functional recovery. However, in patients with few FHVs, the odds for good functional outcome (mRS) were increased in recombinant tissue plasminogen activator (rtPA) patients compared to those who received placebo [odds ratio (OR) = 5.3; 95% CI 1.2–24.0], whereas no apparent benefit was observed in patients with extensive FHVs (OR = 1.1; 95% CI 0.3–3.8), p-value for interaction was 0.11.

Conclusion: While the extent of FHVs on baseline did not alter the evolution of stroke in terms of lesion progression or functional recovery, it may modify treatment effect and should therefore be considered relevant additional information in those patients who are eligible for intravenous thrombolysis.

Clinical Trial Registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered February 2, 2012.
Intracarotid Transplantation of Skin-Derived Precursor Schwann Cells Promotes Functional Recovery After Acute Ischemic Stroke in Rats
Authors: Liang Jingjing , Cui Ronghui , Wang Jinglei , Shen Jiabing , Chen Ying , Cao Maosheng , Ke Kaifu
Published: February 2021

Purpose: Skin-derived Precursor Schwann cells (SKP-SCs) have been reported to provide neuroprotection for the injured and dysmyelinated nervous system. However, little is known about SKP-SCs on acute ischemic stroke (AIS). We aimed to explore the efficacy and the potential mechanism of action of SKP-SCs on AIS in a rat ischemic stroke model.

Methods: Adult male Sprague–Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) for 1.5 h on Day 0 and subsequently received an intracarotid injection of 2 × 106 green fluorescent protein (GFP) -labeled SKP-SCs or phosphate buffered saline (PBS) during reperfusion. Neurological function was assessed by behavioral tests on Days 1, 4, 7, 14, and 28. In a satellite cohort, rat brains were harvested and infarct volume was measured with 2,3,5-triphenyltetrazolium chloride (TTC) staining on Days 1 and 7, and migration and survival of SKP-SCs in the brain were traced by monitoring green fluorescence at 6 and12 h on Day 0, and on Days 1, 4, 7, 14, and 28. Histopathology and immunofluorescence staining were used to analyze the morphology, survival and apoptosis of neurons. Additionally, in an in vitro SKP-SC co-culture model using fetal rat primary cortical neurons underwent oxygen glucose deprivation/reoxygenation (OGD/R), Western blot was used to detect the expression of apoptosis indicators including activated caspase-3, Bax, and Bcl-2. TUNEL staining was used to count apoptotic cells.

Results: Intracarotid transplantation of SKP-SCs effectively migrated to the periinfarct area and survived for at least 4 weeks. Transplanted SKP-SCs inhibited neuronal apoptosis, reduced infarct volume, and improved neurological recovery in the MCAO rats. Moreover, in vitro data showed that SKP-SCs treatment inhibited OGD/R-induced neuronal apoptosis and promoted survival of the cultured primary cortical neurons.

Conclusions: Intracarotid transplantation of SKP-SCs promoted functional recovery in the rat AIS model and possesses the potential to be further developed as a novel therapy to treat ischemic stroke in humans.
Incidence of Electrographic Seizures in Patients With COVID-19
Authors: Waters Brandon L. , Michalak Andrew J. , Brigham Danielle , Thakur Kiran T. , Boehme Amelia , Claassen Jan , Bell Michelle
Published: February 2021

Critical illness and sepsis are commonly associated with subclinical seizures. COVID-19 frequently causes severe critical illness, but the incidence of electrographic seizures in patients with COVID-19 has been reported to be low. This retrospective case series assessed the incidence of and risks for electrographic seizures in patients hospitalized with COVID-19 who underwent continuous video electroencephalography monitoring (cvEEG) between March 1st, 2020 and June 30th, 2020. One hundred and twenty-two patients were initially identified who resulted SARS-CoV-2 nasopharyngeal RT-PCR swab positivity with any electroencephalography order placed in the EMR. Seventy-nine patients met study inclusion criteria: age ≥18 years, >1 h of cvEEG monitoring, and positive SARS-CoV-2 nasopharyngeal swab PCR. Six (8%) of the 79 patients suffered electrographic seizures (ES), three of whom suffered non-convulsive status epilepticus. Acute hyperkinetic movements were the most common reason for cvEEG in patients with ES (84%). None of the patients undergoing cvEEG for persistent coma (29% of all patients) had ES. Focal slowing (67 vs. 10%), sporadic interictal epileptiform discharges (EDs; 33 vs. 6%), and periodic/rhythmic EDs (67 vs. 1%) were proportionally more frequent among patients with electrographic seizures than those without these seizures. While 15% of patients without ES had generalized periodic discharges (GPDs) with triphasic morphology on EEG, none of the patients with ES had this pattern. Further study is required to assess the predictive values of these risk factors on electrographic seizure incidence and subsequent outcomes.
Clinical Presentation and Disease Course of 37 Consecutive Cases of Progressive Multifocal Leukoencephalopathy (PML) at a German Tertiary-Care Hospital: A Retrospective Observational Study
Authors: Graf Lisa M. , Rosenkranz Sina C. , Hölzemer Angelique , Hagel Christian , Goebell Einar , Jordan Sabine , Friese Manuel A. , Addo Marylyn M. , Schulze zur Wiesch Julian , Beisel Claudia
Published: February 2021

Background: Progressive multifocal leukoencephalopathy (PML) caused by JCV is a rare but frequently fatal disease of the central nervous system, usually affecting immunocompromised individuals. Our study aims to expand the data on patient characteristics, diagnosis, clinical course, possible PML-directed treatment, and outcome of patients with PML at a German tertiary-care hospital.

Methods:In this single-center observational cohort study, 37 consecutive patients with a confirmed diagnosis of PML seen at the University Medical Center Hamburg-Eppendorf from 2013 until 2019 were retrospectively analyzed by chart review with a special focus on demographics, risk factors, and clinical aspects as well as PML-directed treatment and survival.

Results:We identified 37 patients with definite, probable, and possible PML diagnosis. 36 patients (97%) had underlying immunosuppressive disorders such as HIV/AIDS (n = 17; 46%), previous treatment with monoclonal antibodies (n = 6; 16%), hematological or oncological malignancies (n = 6; 16%), sarcoidosis (n = 5; 14%), solid organ transplantation (n = 1; 3%), and diagnosis of mixed connective tissue disease (n = 1; 3%). In only one patient no evident immunocompromised condition was detected (n = 1; 3%). Treatment attempts to improve the outcome of PML were reported in 13 patients (n = 13; 35%). Twenty seven percent of patients were lost to follow-up (n = 10). Twenty four-month survival rate after diagnosis of PML was 56% (n = 15).

Conclusion: This interdisciplinary retrospective study describes epidemiology, risk factors, clinical course, and treatment trials in patients with PML at a German tertiary-care hospital. Acquired immunosuppression due to HIV-1 constituted the leading cause of PML in this monocenter cohort.
Revisiting the L-Dopa Response as a Predictor of Motor Outcomes After Deep Brain Stimulation in Parkinson’s Disease
Authors: Lin Zhengyu , Zhang Xiaoxiao , Wang Linbin , Zhang Yingying , Zhou Haiyan , Sun Qingfang , Sun Bomin , Huang Peng , Li Dianyou
Published: February 2021

Objective: To investigate the correlation between preoperative response to the L-dopa challenge test and efficacy of deep brain stimulation (DBS) on motor function in Parkinson’s disease (PD).

Methods: We retrospectively reviewed the data of 38 patients with idiopathic PD who underwent DBS surgery with a median follow-up duration of 7 months. Twenty underwent bilateral globus pallidus interna (GPi) DBS, and 18 underwent bilateral subthalamic nucleus (STN) DBS. The Movement Disorder Society Unified Parkinson Disease Rating Scale-Motor Part (MDS UPDRS-III) was assessed before surgery and at the last follow-up in different medication and stimulation conditions, respectively.

Results: Pearson’s correlation analysis revealed a positive correlation between preoperative L-dopa challenge responsiveness and GPi-DBS responsiveness on the total score (R2 = 0.283, p = 0.016) but not on the non-tremor total score (R2 = 0.158, p = 0.083) of MDS UPDRS-III. Such correlation remained significant (R2′ = 0.332, p = 0.010) after controlling for age at the time of surgery as confounding factor by partial correlation analysis. The preoperative L-dopa challenge responsiveness was significantly correlated with the tremor-controlling outcome of GPi-DBS (R2 = 0.390, p = 0.003). In contrast, we found a positive correlation between preoperative L-dopa challenge responsiveness and STN-DBS responsiveness on the non-tremor total score (R2 = 0.290, p = 0.021), but not on the total score (R2 = 0.130, p = 0.141) of MDS UPDRS-III. The partial correlation analysis further demonstrated that the predictive value of preoperative L-dopa challenge responsiveness on the non-tremor motor outcome of STN-DBS was eliminated (R2′ = 0.120, p = 0.174) after controlling for age at the time of surgery as confounding factor.

Interpretation: The short-term predictive value of preoperative response to the L-dopa challenge test for the motor outcome of GPi-DBS in PD was systematically described. Our findings suggest: (1) a solid therapeutic effect of GPi-DBS in treating L-dopa-responsive tremors; (2) a negative effect of age at the time of surgery on motor outcomes of STN-DBS, (3) a possible preference of STN- to GPi-DBS in L-dopa-resistant tremor control, and (4) a possible preference of GPi- to STN-DBS in elderly PD patients who have a satisfactory dopamine response.
Neurobiological Mechanisms of Transcranial Direct Current Stimulation for Psychiatric Disorders; Neurophysiological, Chemical, and Anatomical Considerations
Authors: Yamada Yuji , Sumiyoshi Tomiki
Published: February 2021

Backgrounds: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique for the treatment of several psychiatric disorders, e.g., mood disorders and schizophrenia. Therapeutic effects of tDCS are suggested to be produced by bi-directional changes in cortical activities, i.e., increased/decreased cortical excitability via anodal/cathodal stimulation. Although tDCS provides a promising approach for the treatment of psychiatric disorders, its neurobiological mechanisms remain to be explored.

Objectives: To review recent findings from neurophysiological, chemical, and brain-network studies, and consider how tDCS ameliorates psychiatric conditions.

Findings: Enhancement of excitatory synaptic transmissions through anodal tDCS stimulation is likely to facilitate glutamate transmission and suppress gamma-aminobutyric acid transmission in the cortex. On the other hand, it positively or negatively modulates the activities of dopamine, serotonin, and acetylcholine transmissions in the central nervous system. These neural events by tDCS may change the balance between excitatory and inhibitory inputs. Specifically, multi-session tDCS is thought to promote/regulate information processing efficiency in the cerebral cortical circuit, which induces long-term potentiation (LTP) by synthesizing various proteins.

Conclusions: This review will help understand putative mechanisms underlying the clinical benefits of tDCS from the perspective of neurotransmitters, network dynamics, intracellular events, and related modalities of the brain function.
Integrative Base Ontology for the Research Analysis of Alzheimer’s Disease-Related Mild Cognitive Impairment
Authors: Gomez-Valades Alba , Martinez-Tomas Rafael , Rincon Mariano
Published: February 2021

Early detection of mild cognitive impairment (MCI) has become a priority in Alzheimer’s disease (AD) research, as it is a transitional phase between normal aging and dementia. However, information on MCI and AD is scattered across different formats and standards generated by different technologies, making it difficult to work with them manually. Ontologies have emerged as a solution to this problem due to their capacity for homogenization and consensus in the representation and reuse of data. In this context, an ontology that integrates the four main domains of neurodegenerative diseases, diagnostic tests, cognitive functions, and brain areas will be of great use in research. Here, we introduce the first approach to this ontology, the Neurocognitive Integrated Ontology (NIO), which integrates the knowledge regarding neuropsychological tests (NT), AD, cognitive functions, and brain areas. This ontology enables interoperability and facilitates access to data by integrating dispersed knowledge across different disciplines, rendering it useful for other research groups. To ensure the stability and reusability of NIO, the ontology was developed following the ontology-building life cycle, integrating and expanding terms from four different reference ontologies. The usefulness of this ontology was validated through use-case scenarios.
Glucose Control Has an Impact on Cerebral Blood Flow Alterations in Chronic Tinnitus Patients
Authors: Xia Wenqing , Cui Jinluan , Luo Yong , Xu Jin-Jing , Chen Huiyou , Yin Xindao , Ma Jianhua , Wu Yuanqing
Published: February 2021

Purpose

Both tinnitus and type 2 diabetes mellitus (T2DM) are linked with cognitive decline and brain dysfunction. This study used arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) to examine the abnormal cerebral blood flow (CBF) patterns existed in tinnitus patients and potential relationships between the abnormal CBF and cognitive performance. The impact of T2DM on CBF alterations in tinnitus patients was further explored.

Methods

Sixty tinnitus patients and 40 non-tinnitus subjects were recruited. CBF images were collected and analyzed using ASL perfusion fMRI. Brain regions with CBF alterations between tinnitus patients and non-tinnitus controls were identified by one-way analysis of variance. Interaction effects between tinnitus and T2DM for CBF changes were also selected. Then, correlation analyses were calculated to specify the link between CBF changes and cognitive performance and between CBF changes and diabetic characteristics.

Results

Tinnitus patients showed decreased CBF, primarily in the auditory area and default mode network (DMN), compared with non-tinnitus controls. Decreased CBF in these regions was correlated with executive function and attention. The interaction effect between tinnitus and T2DM was significant in the right medial prefrontal gyrus. Additionally, CBF in the right medial prefrontal gyrus was correlated with tinnitus distress and cognitive performance. In tinnitus patients, Hemoglobin A1c was associated with CBF in the right medial prefrontal gyrus.

Conclusion

Tinnitus affects brain perfusion in the auditory area and DMN. T2DM and uncontrolled glucose levels may aggravate a CBF decrease in tinnitus patients. These new findings implied that tinnitus patients may benefit from blood glucose control in terms of their cognitive function and tinnitus distress.
Ninjin'yoeito Alleviates Neuropathic Pain Induced by Chronic Constriction Injury in Rats
Authors: Takemoto Risa , Michihara Seiwa , Han Li-Kun , Fujita Nina , Takahashi Ryuji
Published: February 2021

Kampo medicines are frequently used empirically to treat pain in clinical practice. Ninjin'yoeito (NYT), which is associated with few adverse effects, is often used to treat the elderly, but has not yet been examined in detail. We herein investigated the effects of NYT, at 500 and 1,000 mg/kg p.o. (NYT500/NYT1000 group) in single and repeated administrations for 14 days, on pain in rats with peripheral neuropathy induced by loose ligation of the sciatic nerve (chronic constriction injury: CCI). Untreated CCI rats given distilled water were used as a control group. To assess induced pain, the pain threshold was measured using the von Frey test. To evaluate spontaneous pain, the ground-contact area of the paw with neuropathic pain was measured using the Dynamic Weight Bearing test. Serum samples were collected after the test to elucidate the mechanism of action of NYT, and brain-derived neurotrophic factor (BDNF) and corticosterone protein levels, which have been reported to change due to chronic pain, were analyzed. After single administration of NYT, the pain threshold rose in the NYT500 and NYT1000 groups. The pain threshold tended to rise on day 14 of repeated administration in the NYT500 group (p = 0.08) and it significantly rose at NYT1000 group (p < 0.05) compared to Control group. In addition, the foot contact area increased (p = 0.09). Therefore, CCI-induced pain was significantly remitted and spontaneous pain was remitted after repeated administration of NYT. Serum BDNF levels were higher in untreated CCI rats than in normal rats (p = 0.05), but decreased after the repeated administration of NYT (NYT1000, p = 0.15), while serum corticosterone levels were lower (p = 0.12) than those in normal rats and increased after the repeated administration of NYT (NYT1000, p = 0.07). The blood BDNF level has been suggested to influence pain intensity. The findings demonstrated NYT effectively treats neuropathic pain, suggesting that a NYT-induced decrease in blood BDNF contributed to the mechanism of pain relief. In addition, the variation of corticosterone was observed, suggesting that normalization of responsiveness to stress by NYT contributed to the pain relief.
The Roles of circRNAs in Liver Cancer Immunity
Authors: Tang Ying , Jiang Mei , Jiang Hai-Mei , Ye Zeng Jie , Huang Yu-Sheng , Li Xiu-Shen , Qin Bin-Yu , Zhou Rui-Sheng , Pan Hua-Feng , Zheng Da-Yong
Published: February 2021

Circular RNAs (circRNAs) are stable covalently closed non-coding RNAs (ncRNAs). Many studies indicate that circRNAs are involved in the pathological and physiological processes of liver cancer. However, the functions of circRNAs in liver cancer immunity are less known. In this review, we summarized the functions of circRNAs in liver cancer, including proliferative, metastasis and apoptosis, liver cancer stemness, cell cycle, immune evasion, glycolysis, angiogenesis, drug resistance/sensitizer, and senescence. Immune escape is considered to be one of the hallmarks of cancer development, and circRNA participates in the immune escape of liver cancer cells by regulating natural killer (NK) cell function. CircRNAs may provide new ideas for immunotherapy in liver cancer.
Apatinib Plus Temozolomide: An Effective Salvage Treatment for Recurrent Glioblastoma
Authors: Ge Jingjing , Li Cheng , Xue Fengjun , Qi Shaopei , Gao Zhimeng , Yu Chunjiang , Zhang Junping
Published: February 2021

Background

Treatment for recurrent glioblastoma is poor, and there is a need for better therapies. Here we retrospectively assessed the efficacy and toxicity of temozolomide plus apatinib, an oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 in recurrent glioblastoma.

Materials and Methods

A retrospective analysis of patients with recurrent glioblastoma who underwent apatinib plus temozolomide treatment was performed. Apatinib was given at 500 mg once daily. Temozolomide was administered at 200 mg/m2/d on days 1–5 or 50 mg/m2/d continuous daily according to whether they had experienced temozolomide maintenance treatment before. The main clinical data collected included tumor characteristics, status of MGMT promoter, and IDH mutation, number of relapse, response, survival, adverse reactions, and salvage therapies.

Results

From April 2016 to August 2019, thirty-one patients were identified. The objective response rate was 26.3%, and the disease control rate was 84.2%. The progression-free survival (PFS) at 6 months and overall survival (OS) at 12 months were 44.6 and 30.2%. The median PFS and OS were 4.9 and 8.2 months, respectively. Two patients achieved long PFS of 30.9 and 38.7+ months. The median survival time after progression of the patients with or without salvage bevacizumab was 5.1 versus 1.2 months. The most common grade 3 or 4 toxicities were hypertension (5.8%), decreased appetite (5.8%), and thrombocytopenia (4.3%), most of which were resolved after symptomatic treatment or dose reduction.

Conclusion

Apatinib plus temozolomide is an effective salvage regimen with manageable toxicities for recurrent glioblastoma and could not reduce the sensitivity to bevacizumab.