bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative 7-Tesla Imaging of Cortical Myelin Changes in Early Multiple Sclerosis
Authors: Barletta Valeria , Herranz Elena , Treaba Constantina A. , Mehndiratta Ambica , Ouellette Russell , Mangeat Gabriel , Granberg Tobias , Sloane Jacob A. , Klawiter Eric C. , Cohen-Adad Julien , Mainero Caterina
Published: September 2021

Cortical demyelination occurs early in multiple sclerosis (MS) and relates to disease outcome. The brain cortex has endogenous propensity for remyelination as proven from histopathology study. In this study, we aimed at characterizing cortical microstructural abnormalities related to myelin content by applying a novel quantitative MRI technique in early MS. A combined myelin estimation (CME) cortical map was obtained from quantitative 7-Tesla (7T) T2* and T1 acquisitions in 25 patients with early MS and 19 healthy volunteers. Cortical lesions in MS patients were classified based on their myelin content by comparison with CME values in healthy controls as demyelinated, partially demyelinated, or non-demyelinated. At follow-up, we registered changes in cortical lesions as increased, decreased, or stable CME. Vertex-wise analysis compared cortical CME in the normal-appearing cortex in 25 MS patients vs. 19 healthy controls at baseline and investigated longitudinal changes at 1 year in 10 MS patients. Measurements from the neurite orientation dispersion and density imaging (NODDI) diffusion model were obtained to account for cortical neurite/dendrite loss at baseline and follow-up. Finally, CME maps were correlated with clinical metrics. CME was overall low in cortical lesions (p = 0.03) and several normal-appearing cortical areas (p < 0.05) in the absence of NODDI abnormalities. Individual cortical lesion analysis revealed, however, heterogeneous CME patterns from extensive to partial or absent demyelination. At follow-up, CME overall decreased in cortical lesions and non-lesioned cortex, with few areas showing an increase (p < 0.05). Cortical CME maps correlated with processing speed in several areas across the cortex. In conclusion, CME allows detection of cortical microstructural changes related to coexisting demyelination and remyelination since the early phases of MS, and shows to be more sensitive than NODDI and relates to cognitive performance.
Case Report: Plasma Biomarkers Reflect Immune Mechanisms of Guillain–Barré Syndrome
Authors: Wu Chia-Lun , Chao Chung-Hao , Lin Shun-Wen , Chien Yu-Yi , Huang Wen-Yi , Weng Wei-Chieh , Su Feng-Chieh , Wei Yi-Chia
Published: September 2021

This case series reported a group of patients with Guillain–Barré syndrome (GBS) and their plasma cytokine changes before and after immunotherapy. We aimed to understand GBS's pathogenesis and pathophysiology through observing the interval differences of the representative cytokines, which were the thymus and activation regulated chemokine (TARC) for T-cell chemotaxis, CD40 ligand (CD40L) for cosimulation of B and T cells, activated complement component C5/C5a, and brain-derived neurotrophic factor (BDNF) for survival and regenerative responses to nerve injuries. The fluorescence magnetic bead-based multiplexing immunoassay simultaneously quantified the five cytokines in a single sample. From June 2018 to December 2019, we enrolled five GBS patients who had completed before–after blood cytokine measurements. One patient was diagnosed with paraneoplastic GBS and excluded from the following cytokine analysis. The BDNF level decreased consistently in all the patients and made it a potential biomarker for the acute stage of GBS. Interval changes of the other four cytokines were relatively inconsistent and possibly related to interindividual differences in the immune response to GBS triggers, types of GBS variants, and classes of antiganglioside antibodies. In summary, utilizing the multiplexing immunoassay helps in understanding the complex immune mechanisms of GBS and the variation of immune responses in GBS subtypes; this method is feasible for identifying potential biomarkers of GBS.
Blood Pressure Management After Endovascular Thrombectomy
Authors: Peng Teng J. , Ortega-Gutiérrez Santiago , de Havenon Adam , Petersen Nils H.
Published: September 2021

Endovascular thrombectomy (EVT) has changed the landscape of acute stroke therapy and has become the standard of care for selected patients presenting with anterior circulation large-vessel occlusion (LVO) stroke. Despite successful reperfusion, many patients with LVO stroke do not regain functional independence. Particularly, patients presenting with extremes of blood pressure (BP) or hemodynamic variability are found to have a worse clinical recovery, suggesting blood pressure optimization as a potential neuroprotective strategy. Current guidelines acknowledge the lack of randomized trials to evaluate the optimal hemodynamic management during the immediate post-stroke period. Following reperfusion, lower blood pressure targets may be warranted to prevent reperfusion injury and promote penumbral recovery, but adequate BP targets adjusted to individual patient factors such as degree of reperfusion, infarct size, and overall hemodynamic status remain undefined. This narrative review outlines the physiological mechanisms of BP control after EVT and summarizes key observational studies and clinical trials evaluating post-EVT BP targets. It also discusses novel treatment strategies and areas of future research that could aid in the determination of the optimal post-EVT blood pressure.
A Prospective Multicenter Registry on Feasibility, Safety, and Outcome of Endovascular Recanalization in Childhood Stroke (Save ChildS Pro)
Authors: Sporns Peter B. , Kemmling André , Lee Sarah , Fullerton Heather , Kunz Wolfgang G. , Wilson Jenny L. , Mackay Mark T. , Steinlin Maja , Fiehler Jens , Psychogios Marios , Wildgruber Moritz
Published: September 2021

Rationale: Early evidence for the benefit of mechanical thrombectomy (MT) in pediatric patients with intracranial large vessel occlusion has been shown in previous retrospective cohorts. Higher-level evidence is needed to overcome the limitations of these studies such as the lack of a control group and the retrospective design. Randomized trials will very likely not be feasible, and several open questions remain, for example, the impact of arteriopathic etiologies or a possible lower age limit for MT. Save ChildS Pro therefore aims to demonstrate the safety and effectiveness of MT in pediatric patients compared to the best medical management and intravenous thrombolysis.

Design: Save ChildS Pro is designed as a worldwide multicenter prospective registry comparing the safety and effectiveness of MT to the best medical care alone in the treatment of pediatric arterial ischemic stroke (AIS). It will include pediatric patients (<18 years) with symptomatic acute intracranial arterial occlusion who underwent either MT or best medical treatment including intravenous thrombolysis.

Outcomes: The primary endpoint of Save ChildS Pro is the modified Rankin Scale score at 90 days post-stroke. Secondary endpoints will comprise the decrease of the Pediatric National Institutes of Health Stroke Scale score from admission to discharge and rate of complications.

Discussion: Save ChildS Pro aims to provide high-level evidence for MT for pediatric patients with AIS, thereby improving functional outcome and quality of life and reducing the individual, societal, and economic burden of death and disability resulting from pediatric stroke.

Clinical Trial Registration: Save ChildS Pro is registered at the German Clinical Trials Registry (DRKS; identifier: DRKS00018960).
Distinguishing Self, Other, and Autonomy From Visual Feedback: A Combined Correlation and Acceleration Transfer Analysis
Authors: Demirel Berkay , Moulin-Frier Clément , Arsiwalla Xerxes D. , Verschure Paul F. M. J. , Sánchez-Fibla Martí
Published: September 2021

In cognitive science, Theory of Mind (ToM) is the mental faculty of assessing intentions and beliefs of others and requires, in part, to distinguish incoming sensorimotor (SM) signals and, accordingly, attribute these to either the self-model, the model of the other, or one pertaining to the external world, including inanimate objects. To gain an understanding of this mechanism, we perform a computational analysis of SM interactions in a dual-arm robotic setup. Our main contribution is that, under the common fate principle, a correlation analysis of the velocities of visual pivots is shown to be sufficient to characterize "the self" (including proximo-distal arm-joint dependencies) and to assess motor to sensory influences, and "the other" by computing clusters in the correlation dependency graph. A correlational analysis, however, is not sufficient to assess the non-symmetric/directed dependencies required to infer autonomy, the ability of entities to move by themselves. We subsequently validate 3 measures that can potentially quantify a metric for autonomy: Granger causality (GC), transfer entropy (TE), as well as a novel “Acceleration Transfer” (AT) measure, which is an instantaneous measure that computes the estimated instantaneous transfer of acceleration between visual features, from which one can compute a directed SM graph. Subsequently, autonomy is characterized by the sink nodes in this directed graph. This study results show that although TE can capture the directional dependencies, a rectified subtraction operation denoted, in this study, as AT is both sufficient and computationally cheaper.
The Application of ASSRs, P50, and MMN in the Exploration of Cognitive Dysfunction Involving Inputs and Processing in Insomnia Patients
Authors: Zhao Hongwei , Liu Chang , Wang Changming , Zheng Xiangyu , Peng Yanhui , Lv Yudan
Published: September 2021

Objective cognitive dysfunction has been commonly found in patients with insomnia, such as attention, memory, speed of information processing, and executive functions. Auditory steady-state responses (ASSRs), P50, mismatch negativity (MMN) can meet varied need and estimate such different cognitive dysfunction. Thus, we can examine whether insomnia is associated with different cognitive dysfunction by such multiple event-related potential (ERP) tasks. Methods we used polysomnography (PSG) to record such objective PSG parameters. ASSR, P50, and MMN were performed in sequence, different ERP components have been analyzed such as latency or amplitude between insomnia group and control group. And we chosed person correlation to make correlation analysis between different ERP components and gender, education, and sleep characteristics. Results there is a significant gender difference of ASSR latency found in insomnia group, and the similar result has been found in suppression ratio of amplitudes (S2:S1) for P50. Additionally, a significant correlation between sleep characteristics and ASSR, P50 has been found. Furthermore, there was a significant difference of MMN latency between insomnia and control group, and between sleep characteristics and varied MMN parameters as latency and amplitude. Discussion our results suggested robust electrophysiological abnormalities as ASSR, P50, and MMN in insomnia patients. Such abnormalities included gender difference, education difference, difference in depressive tendency, and difference in sleep parameters. That results revealed varied cognitive dysfunction involving inputs and processing in insomnia patients. And at the same time, we have also explored the neuropsychological mechanisms underlying the cognitive dysfunction with such different ERP tasks.
Why Firing Rate Distributions Are Important for Understanding Spinal Central Pattern Generators
Authors: Lindén Henrik , Berg Rune W.
Published: September 2021

Networks in the spinal cord, which are responsible for the generation of rhythmic movements, commonly known as central pattern generators (CPGs), have remained elusive for decades. Although it is well-known that many spinal neurons are rhythmically active, little attention has been given to the distribution of firing rates across the population. Here, we argue that firing rate distributions can provide an important clue to the organization of the CPGs. The data that can be gleaned from the sparse literature indicate a firing rate distribution, which is skewed toward zero with a long tail, akin to a normal distribution on a log-scale, i.e., a “log-normal” distribution. Importantly, such a shape is difficult to unite with the widespread assumption of modules composed of recurrently connected excitatory neurons. Spinal modules with recurrent excitation has the propensity to quickly escalate their firing rate and reach the maximum, hence equalizing the spiking activity across the population. The population distribution of firing rates hence would consist of a narrow peak near the maximum. This is incompatible with experiments, that show wide distributions and a peak close to zero. A way to resolve this puzzle is to include recurrent inhibition internally in each CPG modules. Hence, we investigate the impact of recurrent inhibition in a model and find that the firing rate distributions are closer to the experimentally observed. We therefore propose that recurrent inhibition is a crucial element in motor circuits, and suggest that future models of motor circuits should include recurrent inhibition as a mandatory element.
Mapping Verb Retrieval With nTMS: The Role of Transitivity
Authors: Ntemou Effrosyni , Ohlerth Ann-Katrin , Ille Sebastian , Krieg Sandro M. , Bastiaanse Roelien , Rofes Adrià
Published: September 2021

Navigated Transcranial Magnetic Stimulation (nTMS) is used to understand the cortical organization of language in preparation for the surgical removal of a brain tumor. Action naming with finite verbs can be employed for that purpose, providing additional information to object naming. However, little research has focused on the properties of the verbs that are used in action naming tasks, such as their status as transitive (taking an object; e.g., to read) or intransitive (not taking an object; e.g., to wink). Previous neuroimaging data show higher activation for transitive compared to intransitive verbs in posterior perisylvian regions bilaterally. In the present study, we employed nTMS and production of finite verbs to investigate the cortical underpinnings of transitivity. Twenty neurologically healthy native speakers of German participated in the study. They underwent language mapping in both hemispheres with nTMS. The action naming task with finite verbs consisted of transitive (e.g., The man reads the book) and intransitive verbs (e.g., The woman winks) and was controlled for relevant psycholinguistic variables. Errors were classified in four different error categories (i.e., non-linguistic errors, grammatical errors, lexico-semantic errors and, errors at the sound level) and were analyzed quantitatively. We found more nTMS-positive points in the left hemisphere, particularly in the left parietal lobe for the production of transitive compared to intransitive verbs. These positive points most commonly corresponded to lexico-semantic errors. Our findings are in line with previous aphasia and neuroimaging studies, suggesting that a more widespread network is used for the production of verbs with a larger number of arguments (i.e., transitives). The higher number of lexico-semantic errors with transitive compared to intransitive verbs in the left parietal lobe supports previous claims for the role of left posterior areas in the retrieval of argument structure information.
Estimation of Emotional Arousal Changes of a Group of Individuals During Movie Screening Using Steady-State Visual-Evoked Potential
Authors: Park Seonghun , Kim Do-Won , Han Chang-Hee , Im Chang-Hwan
Published: September 2021

Neurocinematics is an emerging discipline in neuroscience, which aims to provide new filmmaking techniques by analyzing the brain activities of a group of audiences. Several neurocinematics studies attempted to track temporal changes in mental states during movie screening; however, it is still needed to develop efficient and robust electroencephalography (EEG) features for tracking brain states precisely over a long period. This study proposes a novel method for estimating emotional arousal changes in a group of individuals during movie screening by employing steady-state visual evoked potential (SSVEP), which is a widely used EEG response elicited by the presentation of periodic visual stimuli. Previous studies have reported that the emotional arousal of each individual modulates the strength of SSVEP responses. Based on this phenomenon, movie clips were superimposed on a background, eliciting an SSVEP response with a specific frequency. Two emotionally arousing movie clips were presented to six healthy male participants, while EEG signals were recorded from the occipital channels. We then investigated whether the movie scenes that elicited higher SSVEP responses coincided well with those rated as the most impressive scenes by 37 viewers in a separate experimental session. Our results showed that the SSVEP response averaged across six participants could accurately predict the overall impressiveness of each movie, evaluated with a much larger group of individuals.
Manual Gestures Modulate Early Neural Responses in Loudness Perception
Authors: Sun Jiaqiu , Wang Ziqing , Tian Xing
Published: September 2021

How different sensory modalities interact to shape perception is a fundamental question in cognitive neuroscience. Previous studies in audiovisual interaction have focused on abstract levels such as categorical representation (e.g., McGurk effect). It is unclear whether the cross-modal modulation can extend to low-level perceptual attributes. This study used motional manual gestures to test whether and how the loudness perception can be modulated by visual-motion information. Specifically, we implemented a novel paradigm in which participants compared the loudness of two consecutive sounds whose intensity changes around the just noticeable difference (JND), with manual gestures concurrently presented with the second sound. In two behavioral experiments and two EEG experiments, we investigated our hypothesis that the visual-motor information in gestures would modulate loudness perception. Behavioral results showed that the gestural information biased the judgment of loudness. More importantly, the EEG results demonstrated that early auditory responses around 100 ms after sound onset (N100) were modulated by the gestures. These consistent results in four behavioral and EEG experiments suggest that visual-motor processing can integrate with auditory processing at an early perceptual stage to shape the perception of a low-level perceptual attribute such as loudness, at least under challenging listening conditions.
Investigating Managers’ Fine-Grained Evaluation Processes in Organizations: Exploring Two Dual-Process Perspectives
Authors: Sun Haoye , Verbeke Willem J. M. I. , Belschak Frank , van Strien Jan , Wang Lei
Published: September 2021

The dual-process theory is a significant theory in both organizational theory and social psychology and two conjectures about this theory are considered in this manuscript; the default-interventionist vs. parallel-competitive account. Our research goal is to empirically investigate these two views. In concrete terms, by using event-related potentials (ERPs), we seek to study the fine-grained brain processes and self-reported feelings involved in managers’ evaluations of target employees within an economic context (firing employees) vs. a social network context (excluding employees). Using the stereotype content model categories, each target employee has high (or low) warmth and high (or low) levels of competence. In the fine-grained ERP analysis of the brain process, we focus on three time windows of interest: novelty detection (N2) and goal violation detection (N400) at the unconscious level, and we then evaluate conscious emotional arousal (late positive potential, LPP). Finally, we focus on the self-reported feelings when having to fire or exclude target employees. As goal pursuit theory predicts, the brain dynamics and self-reported measures differ widely across the two organizational contexts; in concrete terms, processes at a later stage overrule early stages depending on the context. This implies that the data bespeaks more for the parallel-competitive account than the default-interventionist account. We discuss the implications of these findings for research in management and management practice.
A Novel Two-Stage Refine Filtering Method for EEG-Based Motor Imagery Classification
Authors: Yan Yuxin , Zhou Haifeng , Huang Lixin , Cheng Xiao , Kuang Shaolong
Published: September 2021

Cerebral stroke is a common disease across the world, and it is a promising method to recognize the intention of stroke patients with the help of brain–computer interface (BCI). In the field of motor imagery (MI) classification, appropriate filtering is vital for feature extracting of electroencephalogram (EEG) signals and consequently influences the accuracy of MI classification. In this case, a novel two-stage refine filtering method was proposed, inspired by Gradient-weighted Class Activation Mapping (Grad-CAM), which uses the gradients of any target concept flowing into the final convolutional layer to highlight the important part of training data for predicting the concept. In the first stage, MI classification was carried out and then the frequency band to be filtered was calculated according to the Grad-CAM of the MI classification results. In the second stage, EEG was filtered and classified for a higher classification accuracy. To evaluate the filtering effect, this method was applied to the multi-branch neural network proposed in our previous work. Experiment results revealed that the proposed method reached state-of-the-art classification kappa value levels and acquired at least 3% higher kappa values than other methods This study also proposed some promising application scenarios with this filtering method.
Identification of Phonology-Related Genes and Functional Characterization of Broca’s and Wernicke’s Regions in Language and Learning Disorders
Authors: Unger Nina , Heim Stefan , Hilger Dominique I. , Bludau Sebastian , Pieperhoff Peter , Cichon Sven , Amunts Katrin , Mühleisen Thomas W.
Published: September 2021

Impaired phonological processing is a leading symptom of multifactorial language and learning disorders suggesting a common biological basis. Here we evaluated studies of dyslexia, dyscalculia, specific language impairment (SLI), and the logopenic variant of primary progressive aphasia (lvPPA) seeking for shared risk genes in Broca’s and Wernicke’s regions, being key for phonological processing within the complex language network. The identified “phonology-related genes” from literature were functionally characterized using Atlas-based expression mapping (JuGEx) and gene set enrichment. Out of 643 publications from the last decade until now, we extracted 21 candidate genes of which 13 overlapped with dyslexia and SLI, six with dyslexia and dyscalculia, and two with dyslexia, dyscalculia, and SLI. No overlap was observed between the childhood disorders and the late-onset lvPPA often showing symptoms of learning disorders earlier in life. Multiple genes were enriched in Gene Ontology terms of the topics learning (CNTNAP2, CYFIP1, DCDC2, DNAAF4, FOXP2) and neuronal development (CCDC136, CNTNAP2, CYFIP1, DCDC2, KIAA0319, RBFOX2, ROBO1). Twelve genes showed above-average expression across both regions indicating moderate-to-high gene activity in the investigated cortical part of the language network. Of these, three genes were differentially expressed suggesting potential regional specializations: ATP2C2 was upregulated in Broca’s region, while DNAAF4 and FOXP2 were upregulated in Wernicke’s region. ATP2C2 encodes a magnesium-dependent calcium transporter which fits with reports about disturbed calcium and magnesium levels for dyslexia and other communication disorders. DNAAF4 (formerly known as DYX1C1) is involved in neuronal migration supporting the hypothesis of disturbed migration in dyslexia. FOXP2 is a transcription factor that regulates a number of genes involved in development of speech and language. Overall, our interdisciplinary and multi-tiered approach provided evidence that genetic and transcriptional variation of ATP2C2, DNAAF4, and FOXP2 may play a role in physiological and pathological aspects of phonological processing.
Repeated Parental Singing During Kangaroo Care Improved Neural Processing of Speech Sound Changes in Preterm Infants at Term Age
Authors: Kostilainen Kaisamari , Partanen Eino , Mikkola Kaija , Wikström Valtteri , Pakarinen Satu , Fellman Vineta , Huotilainen Minna
Published: September 2021

Preterm birth carries a risk for adverse neurodevelopment. Cognitive dysfunctions, such as language disorders may manifest as atypical sound discrimination already in early infancy. As infant-directed singing has been shown to enhance language acquisition in infants, we examined whether parental singing during skin-to-skin care (kangaroo care) improves speech sound discrimination in preterm infants. Forty-five preterm infants born between 26 and 33 gestational weeks (GW) and their parents participated in this cluster-randomized controlled trial (ClinicalTrials ID IRB00003181SK). In both groups, parents conducted kangaroo care during 33–40 GW. In the singing intervention group (n = 24), a certified music therapist guided parents to sing or hum during daily kangaroo care. In the control group (n = 21), parents conducted standard kangaroo care and were not instructed to use their voices. Parents in both groups reported the duration of daily intervention. Auditory event-related potentials were recorded with electroencephalogram at term age using a multi-feature paradigm consisting of phonetic and emotional speech sound changes and a one-deviant oddball paradigm with pure tones. In the multi-feature paradigm, prominent mismatch responses (MMR) were elicited to the emotional sounds and many of the phonetic deviants in the singing intervention group and in the control group to some of the emotional and phonetic deviants. A group difference was found as the MMRs were larger in the singing intervention group, mainly due to larger MMRs being elicited to the emotional sounds, especially in females. The overall duration of the singing intervention (range 15–63 days) was positively associated with the MMR amplitudes for both phonetic and emotional stimuli in both sexes, unlike the daily singing time (range 8–120 min/day). In the oddball paradigm, MMRs for the non-speech sounds were elicited in both groups and no group differences nor connections between the singing time and the response amplitudes were found. These results imply that repeated parental singing during kangaroo care improved auditory discrimination of phonetic and emotional speech sounds in preterm infants at term age. Regular singing routines can be recommended for parents to promote the development of the auditory system and auditory processing of speech sounds in preterm infants.
The Relationships Among Transverse Sinus Stenosis Measured by CT Venography, Venous Trans-stenotic Pressure Gradient and Intracranial Pressure in Patients With Unilateral Venous Pulsatile Tinnitus
Authors: Qiu Xiaoyu , Zhao Pengfei , Li Xiaoshuai , Ding Heyu , Lv Han , Zeng Rong , Wang Guopeng , Jin Long , Yang Zhenghan , Gong Shusheng , Wang Zhenchang
Published: September 2021

Objectives

To assess a non-invasive means of predicting a venous trans-stenotic pressure gradient (TPG) and intracranial pressure (ICP) as opposed to invasive examinations in unilateral venous pulsatile tinnitus (PT) patients.

Methods

Thirty patients with unilateral venous PT who presented symptomatic-sided transverse sinus stenosis (TSS) on computed tomography venography (CTV), ipsilateral TPG measured by digital subtraction angiography (DSA) and cerebrospinal fluid (CSF) pressure measured by lumbar puncture were included. The ratio of TSS was calculated by dividing the cross-sectional areas of the maximal stenosed transverse sinus by that of the adjacent normal transverse sinus on CTV. The correlations among and predictive values of TSS, TPG, and ICP were analyzed.

Results

In patients with unilateral venous PT, the symptomatic-sided and average bilateral TSS values were 78 ± 11 and 77 ± 9%; ICP, 230.50 ± 55.75 mmH2O; and the TPG, 9.51 ± 5.76 mmHg. The symptomatic-sided TSS was linearly and positively correlated with TPG (R2 = 0.400), and the symptomatic-sided and bilateral average TSS both showed weak correlations with ICP (R2 = 0.288, R′2 = 0.156). When the degree of TSS increased by 10%, the TPG and ICP increased by approximately 3.3 mmHg and 25.8 mmH2O, respectively. The receiver operating characteristic curve showed the optimal threshold of ipsilateral TSS for a positive TPG was 0.75, while TSS had no significant predictive value for ICP (p > 0.05). TPG and ICP also exhibited a linear positive correlation (R2 = 0.552). When ICP increased by 10 mmH2O, the TPG increased by approximately 0.77 mmHg, and the optimal threshold of ICP for a positive TPG was 227.5.

Conclusion

TSS, TPG, and ICP are interrelated. TSS measured by CTV can predict TPG in patients with unilateral venous PT.
Antitumoral Action of Resveratrol Through Adenosinergic Signaling in C6 Glioma Cells
Authors: Sánchez-Melgar Alejandro , Muñoz-López Sonia , Albasanz José Luis , Martín Mairena
Published: September 2021

Gliomas are the most common and aggressive primary tumors in the central nervous system. The nucleoside adenosine is considered to be one major constituent within the tumor microenvironment. The adenosine level mainly depends on two enzymatic activities: 5′-nucleotidase (5′NT or CD73) that synthesizes adenosine from AMP, and adenosine deaminase (ADA) that converts adenosine into inosine. Adenosine activates specific G-protein coupled receptors named A1, A2A, A2B, and A3 receptors. Resveratrol, a natural polyphenol present in grapes, peanuts, and berries, shows several healthy effects, including protection against cardiovascular, endocrine, and neurodegenerative diseases and cancer. However, the molecular mechanisms of resveratrol actions are not well known. Recently, we demonstrated that resveratrol acts as an agonist for adenosine receptors in rat C6 glioma cells. The present work aimed to investigate the involvement of adenosine metabolism and adenosine receptors in the molecular mechanisms underlying the antitumoral action of resveratrol. Results presented herein show that resveratrol was able to decrease cell numbers and viability and to reduce CD73 and ADA activities, leading to the increase of extracellular adenosine levels. Some resveratrol effects were reduced by the blockade of A1 or A3 receptors by DPCPX or MRS1220, respectively. These results suggest that reduced CD73 activity located in the plasma membrane in addition to a fine-tuned modulatory role of adenosine receptors could be involved, at least in part, in the antiproliferative action of resveratrol in C6 glioma cells.
Olivocochlear Changes Associated With Aging Predominantly Affect the Medial Olivocochlear System
Authors: Vicencio-Jimenez Sergio , Weinberg Madison M. , Bucci-Mansilla Giuliana , Lauer Amanda M.
Published: September 2021

Age-related hearing loss (ARHL) is a public health problem that has been associated with negative health outcomes ranging from increased frailty to an elevated risk of developing dementia. Significant gaps remain in our knowledge of the underlying central neural mechanisms, especially those related to the efferent auditory pathways. Thus, the aim of this study was to quantify and compare age-related alterations in the cholinergic olivocochlear efferent auditory neurons. We assessed, in young-adult and aged CBA mice, the number of cholinergic olivocochlear neurons, auditory brainstem response (ABR) thresholds in silence and in presence of background noise, and the expression of excitatory and inhibitory proteins in the ventral nucleus of the trapezoid body (VNTB) and in the lateral superior olive (LSO). In association with aging, we found a significant decrease in the number of medial olivocochlear (MOC) cholinergic neurons together with changes in the ratio of excitatory and inhibitory proteins in the VNTB. Furthermore, in old mice we identified a correlation between the number of MOC neurons and ABR thresholds in the presence of background noise. In contrast, the alterations observed in the lateral olivocochlear (LOC) system were less significant. The decrease in the number of LOC cells associated with aging was 2.7-fold lower than in MOC and in the absence of changes in the expression of excitatory and inhibitory proteins in the LSO. These differences suggest that aging alters the medial and lateral olivocochlear efferent pathways in a differential manner and that the changes observed may account for some of the symptoms seen in ARHL.
Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis
Authors: Barton Samantha K. , Gregory Jenna M. , Selvaraj Bhuvaneish T. , McDade Karina , Henstridge Christopher M. , Spires-Jones Tara L. , James Owen G. , Mehta Arpan R. , Story David , Burr Karen , Magnani Dario , Isaacs Adrian M. , Smith Colin , Chandran Siddharthan
Published: September 2021

Pathological hallmarks of amyotrophic lateral sclerosis (ALS), including protein misfolding, are well established in oligodendrocytes. More recently, an RNA trafficking deficit of key myelin proteins has been suggested in oligodendrocytes in ALS but the extent to which this affects myelination and the relative contribution of this to disease pathogenesis is unclear. ALS autopsy research findings showing demyelination contrasts with the routine clinical-pathological workup of ALS cases where it is rare to see white matter abnormalities other than simple Wallerian degeneration secondary to widespread neuronal loss. To begin to address this apparent variance, we undertook a comprehensive evaluation of myelination at an RNA, protein and structural level using human pathological material from sporadic ALS patients, genetic ALS patients (harboring C9orf72 mutation) and age- and sex-matched non-neurological controls. We performed (i) quantitative spatial profiling of the mRNA transcript encoding myelin basic protein (MBP), (ii) quantification of MBP protein and (iii) the first quantitative structural assessment of myelination in ALS post-mortem specimens by electron microscopy. We show no differences in MBP protein levels or ultrastructural myelination, despite a significant dysregulation in the subcellular trafficking of MBP mRNA in ALS patients compared to controls. We therefore confirm that whilst there are cell autonomous mRNA trafficking deficits affecting oligodendrocytes in ALS, this has no effect on myelin structure.
Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity
Authors: Longenecker Ryan J. , Gu Rende , Homan Jennifer , Kil Jonathan
Published: September 2021

Aminoglycosides (AG) antibiotics are a common treatment for recurrent infections in cystic fibrosis (CF) patients. AGs are highly ototoxic, resulting in a range of auditory dysfunctions. It was recently shown that the acoustic startle reflex (ASR) can assess behavioral evidence of hyperacusis and tinnitus in an amikacin cochleotoxicity mouse model. The goal of this study was to establish if tobramycin treatment led to similar changes in ASR behavior and to establish whether ebselen can prevent the development of these maladaptive neuroplastic symptoms. CBA/Ca mice were divided into three groups: Group 1 served as a control and did not receive tobramycin or ebselen, Group 2 received tobramycin (200 mg/kg/s.c.) and the vehicle (DMSO/saline/i.p.) daily for 14 continuous days, and Group 3 received the same dose/schedule of tobramycin as Group 2 and ebselen at (20 mg/kg/i.p.). Auditory brainstem response (ABR) and ASR hearing assessments were collected at baseline and 2, 6, 10, 14, and 18 weeks from the start of treatment. ASR tests included input/output (I/O) functions which assess general hearing and hyperacusis, and Gap-induced prepulse inhibition of the acoustic startle (GPIAS) to assess tinnitus. At 18 weeks, histologic analysis showed predominantly normal appearing hair cells and spiral ganglion neuron (SGN) synapses. Following 14 days of tobramycin injections, 16 kHz thresholds increased from baseline and fluctuated over the 18-week recovery period. I/O functions revealed exaggerated startle response magnitudes in 50% of mice over the same period. Gap detection deficits, representing behavioral evidence of tinnitus, were observed in a smaller subset (36%) of animals. Interestingly, increases in ABR wave III/wave I amplitude ratios were observed. These tobramycin data corroborate previous findings that AGs can result in hearing dysfunctions. We show that a 14-day course of tobramycin treatment can cause similar levels of hearing loss and tinnitus, when compared to a 14-day course of amikacin, but less hyperacusis. Evidence suggests that tinnitus and hyperacusis might be common side effects of AG antibiotics.
Glucagon-Like Peptide-2 Modulates Enteric Paneth Cells Immune Response and Alleviates Gut Inflammation During Intravenous Fluid Infusion in Mice With a Central Catheter
Authors: Deng Guifang , Lei Qiucheng , Gao Xuejin , Zhang Yupeng , Zheng Huazhen , Bi Jingcheng , Wang Xinying
Published: September 2021

Background: Glucagon-like peptide-2 (GLP-2) has protective effects on gastrointestinal functions. Our previous study found that GLP-2 could significantly reduce intestinal permeability and bacterial translocation in total parenteral nutrition (TPN) animal model. However, the effects of GLP-2 on the impairment of the intestinal Paneth cells immune function and gut inflammation during intravenous fluid infusion mainly consisted of nutritional materials is currently scattered.

Objective: The current study was aimed to investigate the efficacy of the GLP-2 in alleviating gut inflammation and modulating enteric Paneth cells immune response in parenterally fed mice and its underlying mechanisms.

Methods: Thirty-six male ICR mice underwent venous catheterization were divided into 3 groups: Chow, TPN, and TPN+GLP-2 groups. GLP-2 was administered intravenously at 60 μg/day for 5 days. The small intestine tissue and serum samples were collected on the 7th day.

Results: Compared with the TPN group, the expression of tight junction proteins occludin and claudin-1 were significantly increased in the TPN+GLP-2 group. In addition, the expression of lysozyme, sPLA2, insulin-like growth factor-1, and epithelial protection and repair genes were improved in the TPN+GLP-2 group. The levels of IL-6 and TNF-α proteins and mRNAs in the ileum tissues were remarkably reduced in the TPN+GLP-2 group, while IL-10 protein and mRNA level were elevated in the TPN+GLP-2 group (all p < 0.05). Moreover, the TPN+GLP-2 group has higher levels of serum endotoxin, D-lactic acid, and MPO than those of the TPN group.

Conclusions: GLP-2 alleviated gut inflammation and improved enteric Paneth cells immune responses through intravenous fluid infusion, possibly by improving the functioning of epithelial protection and repair, and reducing mucosal inflammatory responses.
Exploring Innovations in Human Milk Analysis in the Neonatal Intensive Care Unit: A Survey of the United States
Authors: Ramey Stacey R. , Merlino Barr Stephanie , Moore Katie A. , Groh-Wargo Sharon
Published: September 2021

Introduction: Human milk (HM) is the ideal enteral feeding for nearly all infants and offers unique benefits to the very low birthweight (VLBW) infant population. It is a challenge to meet the high nutrient requirements of VLBW infants due to the known variability of HM composition. Human milk analysis (HMA) assesses the composition of HM and allows for individualized fortification. Due to recent U.S. Food and Drug Administration (FDA) approval, it has relatively recent availability for clinical use in the US.

Aim: To identify current practices of HMA and individualized fortification in neonatal intensive care units (NICUs) across the United States (US) and to inform future translational research efforts implementing this nutrition management method.

Methods: An institutional review board (IRB) approved survey was created and collected data on the following subjects such as NICU demographics, feeding practices, HM usage, HM fortification practices, and HMA practices. It was distributed from 10/30–12/21/2020 via online pediatric nutrition groups and listservs selected to reach the intended audience of NICU dietitians and other clinical staff. Each response was assessed prior to inclusion, and descriptive analysis was performed.

Results: About 225 survey responses were recorded during the survey period with 119 entries included in the analysis. This represented 36 states and Washington D.C., primarily from level III and IV NICUs. HMA was reported in 11.8% of responding NICUs. The most commonly owned technology for HMA is the Creamatocrit Plus TM (EKF Diagnostics), followed by the HM Analyzer by Miris (Uppsala, Sweden). In NICUs practicing HMA, 84.6% are doing so clinically.

Discussion: Feeding guidelines and fortification of HM remain standard of care, and interest in HMA was common in this survey. Despite the interest, very few NICUs are performing HMA and individualized fortification. Barriers identified include determining who should receive individualized fortification and how often, collecting a representative sample, and the cost and personnel required.

Conclusions: Human milk analysis and individualized fortification are emerging practices within NICUs in the US. Few are using it in the clinical setting with large variation in execution among respondents and many logistical concerns regarding implementation. Future research may be beneficial to evaluate how practices change as HMA and individualized fortification gain popularity and become more commonly used in the clinical setting.
Adjuvant Treatment Recommendations in Early-Stage Endometrial Cancer: What Changes With the Introduction of The Integrated Molecular-Based Risk Assessment
Authors: Nero Camilla , Ciccarone Francesca , Pietragalla Antonella , Duranti Simona , Daniele Gennaro , Scambia Giovanni , Lorusso Domenica
Published: September 2021

Adjuvant therapy recommendations for endometrial cancer were historically based on the individual patient’s risk of disease recurrence using clinicopathologic factors such as age, stage, histologic subtype, tumor grade, and lymphovascular space invasion. Despite the excellent prognosis for early stages, considerable under- and overtreatment remains. Integrated genomic characterization by the Cancer Genome Atlas (TCGA) in 2013 defined four distinct endometrial cancer subgroups (POLE mutated, microsatellite instability, low copy number, and high copy number) with possible prognostic value. The validation of surrogate markers (p53, Mismatch repair deficiency, and POLE) to determine these subgroups and the addition of other molecular prognosticators (CTNNB1, L1CAM) resulted in a practical and clinically useful molecular classification tool. The incorporation of such molecular alterations into established clinicopathologic risk factors resulted in a refined, improved risk assessment. Thus, the ESGO/ESTRO/ESP consensus in 2020 defined for the first time different prognostic risk groups integrating molecular markers. Finally, the feasibility and clinical utility of molecular profiling for tailoring adjuvant therapy in the high-intermediate-risk group is currently under investigation (NCT03469674).
Rictor Activates Cav 1 Through the Akt Signaling Pathway to Inhibit the Apoptosis of Gastric Cancer Cells
Authors: Cao Rui-zhen , Min Li , Liu Si , Tian Ru-yue , Jiang Hai-yan , Liu Juan , Shao Lin-lin , Cheng Rui , Zhu Sheng-tao , Guo Shui-long , Li Peng
Published: September 2021

Background

Rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) protein is a core subunit of mammalian target of rapamycin complex 2, and is associated with cancer progression. However, the biological function of Rictor in cancer, particularly its clinical relevance in gastric cancer (GC) remains largely unknown.

Methods

Rictor expression and its association with clinicopathologic characteristics in GC were analyzed by immunohistochemistry. Effect of Rictor and Caveolin-1 (Cav 1) on GC cells apoptosis was evaluated via overexpression experiment in vitro. Mechanisms of Rictor and Cav 1 in GC were explored through overexpression and knockdown, by immunofluorescence and western blot analyses.

Results

Rictor was upregulated in GC, and mainly located in the cytoplasm of cancer cells. Moreover, higher Rictor levels were associated with worse prognosis. Rictor could inhibit GC cell apoptosis and promote cell growth in vitro. The results of immunofluorescence revealed that Cav 1 localized in GC cell membrane but did not co-localize with Rictor. Further, Rictor regulated apoptosis-related proteins, long non-coding RNAs and also activated cellular signaling, thereby positively regulating Cav 1 expression. This effect was attenuated by the Akt inhibitor ly294002. Cav 1 did not significantly affect the ability of Rictor to inhibit tumor cell apoptosis.

Conclusions

Rictor is upregulated in GC and associated with worse prognosis. It inhibits tumor apoptosis and activates Cav 1 through the Akt signaling pathway to inhibit the apoptosis of GC cells. Rictor is, therefore, a promising prognostic biomarker and possible therapeutic target in GC patients.
The Clinical Significance and Prognostic Value of HER2 Expression in Bladder Cancer: A Meta-Analysis and a Bioinformatic Analysis
Authors: Gan Kai , Gao Yue , Liu Kuangzheng , Xu Bin , Qin Weijun
Published: September 2021

Objective

Human Epidermal Growth Factor Receptor 2 (HER2) is highly expressed in multiple malignancies and associated with patients’ prognosis, but its role in bladder cancer (BCa) remains elusive. We conducted this meta-analysis to explore the clinical significance and prognostic value of HER2 in BCa.

Methods

PubMed was searched for studies published between January 1, 2000 and January 1, 2020. The odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95%CIs) were used to investigate the relationship between HER2 and BCa pathological features. TCGA was mined for the information regarding as well.

Results

Our study included 14 articles enrolling 1398 people. Expression of HER2 is higher in bladder cancer than in normal tissues. HER2 over-expression is associated with CIS, multifocal tumor, large tumor size, high tumor stage and grade, lymph node metastasis, progression, recurrence and papillary tumor. We could not find a significant association between HER2 expression and survival time in BCa patients.

Conclusions

Our meta and bioinformatic analysis indicated that HER2 expression was related to pathological malignancy and poor prognosis in BCa.