bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between Immunoglobulin G N-glycosylation and Vascular Cognitive Impairment in a Sample With Atherosclerosis: A Case-Control Study
Authors: Wang Meng , Chen Xueyu , Tang Zhaoyang , Zhang Wenran , Hou Haifeng , Sun Xiangfu , Shi Yuqing , Lu Xinxia , Li Peirui , Ji Long , Ding Guoyong , Li Dong
Published: February 2022

Background

Atherosclerosis is considered a crucial component in the pathogenesis of decreased cognitive function, as occurs in vascular cognitive impairment (VCI). Inflammation and the immune response play a significant role in the development of many chronic diseases. Immunoglobulin G (IgG) N-glycosylation has been implicated in the development of a variety of diseases by affecting the anti-inflammatory and proinflammatory responses of IgG. This study aimed to investigate the association between IgG N-glycosylation and VCI in a sample of patients with atherosclerosis through a case-control study.

Method

We recruited a total of 330 patients with atherosclerosis to participate in this case-control study, including 165 VCI patients and 165 sex- and age-matched participants with normal cognitive function. The plasma IgG N-glycans of participants were separated by ultrahigh-performance liquid chromatography. An enzyme-linked immunosorbent assay (ELISA) kit was used to determine the corresponding serum inflammatory factors. Atherosclerosis was diagnosed by carotid ultrasound, and the diagnosis of VCI was based on the “Guidelines for the Diagnosis and Treatment of Vascular Cognitive Impairment in China (2019)”. A multivariate logistic regression model was used to explore the association between IgG N-glycans and VCI. We also analyzed the relationship between IgG N-glycans and the inflammatory state of VCI through canonical correlation analysis (CCA).

Results

Through the multivariate logistic regression analysis, 8 glycans and 13 derived traits reflecting decreased sialylation and galactosylation and increased bisecting GlcNAc significantly differed between the case and control groups after adjusting for confounding factors (P < 0.05, q < 0.05). Similarly, the differences in TNF-α, IL-6, and IL-10 were statistically significant between the case and control groups after adjusting for the effects of confounding factors (P < 0.05, q < 0.05). The CCA results showed that VCI-related initial N-glycans were significantly correlated with VCI-related inflammatory factors (r = 0.272, P = 0.004). The combined AUC value (AUCcombined = 0.885) of 7 initial glycans and inflammatory factors was higher than their respective values (AUCinitial glycans = 0.818, AUCinflammatory factors = 0.773).

Conclusion

The findings indicate that decreased sialylation and galactosylation and increased bisecting GlcNAc reflected by IgG N-glycans might affect the occurrence of VCI in patients with atherosclerosis though promoting the proinflammatory function of IgG. IgG N-glycans may serve as potential biomarkers to distinguish VCI in individuals with atherosclerosis.
Laparotomy-Induced Peripheral Inflammation Activates NR2B Receptors on the Brain Mast Cells and Results in Neuroinflammation in a Vagus Nerve-Dependent Manner
Authors: Yang Jing , Dong Hong-Quan , Liu Yan-Hu , Ji Mu-Huo , Zhang Xun , Dai Hong-Yu , Sun Zhao-Chu , Liu Lu , Zhou Jian , Sha Huan-Huan , Qian Yan-Ning , Li Qing-Guo , Yao Hao , Li Na-Na
Published: February 2022

Background: The pathophysiological mechanisms underlying postoperative cognitive dysfunction (POCD) remain unclear over the years. Neuroinflammation caused by surgery has been recognized as an important element in the development of POCD. Many studies also suggest that the vagus nerve plays an important role in transmitting peripheral injury signals to the central nervous system (CNS) and the resultant neuroinflammation. Previously, we have demonstrated that brain mast cells (BMCs), as the “first responders”, play a vital role in neuroinflammation and POCD. However, how the vagus nerve communicates with BMCs in POCD has not yet been clarified.

Methods: In the current study, we highlighted the role of the vagus nerve as a conduction highway in surgery-induced neuroinflammation for the first time. In our model, we tested if mice underwent unilateral cervical vagotomy (VGX) had less neuroinflammation compared to the shams after laparotomy (LP) at an early stage. To further investigate the roles of mast cells and glutamate in the process, we employed KitW-sh mice and primary bone marrow-derived MCs to verify the glutamate-NR2B axis on MCs once again.

Results: Our results demonstrated that there were higher levels of glutamate and BMCs activation as early as 4 h after LP. Meanwhile, vagotomy could partially block the increases and reduce neuroinflammation caused by peripheral inflammation during the acute phase. Excitingly, inhibition of NR2B receptor and knockout of mast cells can attenuateneuroinflammation induced by glutamate.

Conclusion: Taken together, our findings indicate that the vagus is a high-speed pathway in the transmission of peripheral inflammation to the CNS. Activation of BMCs triggered a neuroinflammatory cascade. Inhibition of NR2B receptor on BMCs can reduce glutamate-induced BMCs activation, neuroinflammation, and memory impairment, suggesting a novel treatment strategy for POCD.
Protein Expression of the Microglial Marker Tmem119 Decreases in Association With Morphological Changes and Location in a Mouse Model of Traumatic Brain Injury
Authors: Mercurio Domenico , Fumagalli Stefano , Schafer Martin K-H , Pedragosa Jordi , Ngassam Lionel Dejeumen Claude , Wilhelmi Verena , Winterberg Sarah , Planas Anna M. , Weihe Eberhard , De Simoni Maria-Grazia
Published: February 2022

The activation of microglia and the infiltration of macrophages are hallmarks of neuroinflammation after acute brain injuries, including traumatic brain injury (TBI). The two myeloid populations share many features in the post-injury inflammatory response, thus, being antigenically indistinguishable. Recently Tmem119, a type I transmembrane protein specifically expressed by microglia under physiological conditions, was proposed as a tool to differentiate resident microglia from blood-borne macrophages, not expressing it. However, the validity of Tmem119 as a specific marker of resident microglia in the context of acute brain injury, where microglia are activated and macrophages are recruited, needs validation. Our purpose was to investigate Tmem119 expression and distribution in relation to the morphology of brain myeloid cells present in the injured area after TBI. Mice underwent sham surgery or TBI by controlled cortical impact (CCI). Brains from sham-operated, or TBI mice, were analyzed by in situ hybridization to identify the cells expressing Tmem119, and by Western blot and quantitative immunofluorescence to measure Tmem119 protein levels in the entire brain regions and single cells. The morphology of Iba1+ myeloid cells was analyzed at different times (4 and 7 days after TBI) and several distances from the contused edge in order to associate Tmem119 expression with morphological evolution of active microglia. In situ hybridization indicated an increased Tmem119 RNA along with increased microglial complement C1q activation in the contused area and surrounding regions. On the contrary, the biochemical evaluation showed a drop in Tmem119 protein levels in the same areas. The Tmem119 immunoreactivity decreased in Iba1+ myeloid cells found in the contused cortex at both time points, with the cells showing the hypertrophic ameboid morphology having no Tmem119 expression. The Tmem119 was present on ramifications of resident microglia and its presence was decreased as a consequence of microglial activation in cortical areas close to contusion. Based on the data, we conclude that the decrease of Tmem119 in reactive microglia may depend on the process of microglial activation, which involves the retracting of their branchings to acquire an ameboid shape. The Tmem119 immunoreactivity decreases in reactive microglia to similar levels than the blood-borne macrophages, thus, failing to discriminate the two myeloid populations after TBI.
Migraine Aura, Transient Ischemic Attacks, Stroke, and Dying of the Brain Share the Same Key Pathophysiological Process in Neurons Driven by Gibbs–Donnan Forces, Namely Spreading Depolarization
Authors: Lemale Coline L. , Lückl Janos , Horst Viktor , Reiffurth Clemens , Major Sebastian , Hecht Nils , Woitzik Johannes , Dreier Jens P.
Published: February 2022

Neuronal cytotoxic edema is the morphological correlate of the near-complete neuronal battery breakdown called spreading depolarization, or conversely, spreading depolarization is the electrophysiological correlate of the initial, still reversible phase of neuronal cytotoxic edema. Cytotoxic edema and spreading depolarization are thus different modalities of the same process, which represents a metastable universal reference state in the gray matter of the brain close to Gibbs–Donnan equilibrium. Different but merging sections of the spreading-depolarization continuum from short duration waves to intermediate duration waves to terminal waves occur in a plethora of clinical conditions, including migraine aura, ischemic stroke, traumatic brain injury, aneurysmal subarachnoid hemorrhage (aSAH) and delayed cerebral ischemia (DCI), spontaneous intracerebral hemorrhage, subdural hematoma, development of brain death, and the dying process during cardio circulatory arrest. Thus, spreading depolarization represents a prime and simultaneously the most neglected pathophysiological process in acute neurology. Aristides Leão postulated as early as the 1940s that the pathophysiological process in neurons underlying migraine aura is of the same nature as the pathophysiological process in neurons that occurs in response to cerebral circulatory arrest, because he assumed that spreading depolarization occurs in both conditions. With this in mind, it is not surprising that patients with migraine with aura have about a twofold increased risk of stroke, as some spreading depolarizations leading to the patient percept of migraine aura could be caused by cerebral ischemia. However, it is in the nature of spreading depolarization that it can have different etiologies and not all spreading depolarizations arise because of ischemia. Spreading depolarization is observed as a negative direct current (DC) shift and associated with different changes in spontaneous brain activity in the alternating current (AC) band of the electrocorticogram. These are non-spreading depression and spreading activity depression and epileptiform activity. The same spreading depolarization wave may be associated with different activity changes in adjacent brain regions. Here, we review the basal mechanism underlying spreading depolarization and the associated activity changes. Using original recordings in animals and patients, we illustrate that the associated changes in spontaneous activity are by no means trivial, but pose unsolved mechanistic puzzles and require proper scientific analysis.
Developing Biomarkers of Mild Traumatic Brain Injury: Promise and Progress of CNS-Derived Exosomes
Authors: Vaughn Melonie N. , Winston Charisse N. , Levin Natalie , Rissman Robert A. , Risbrough Victoria B.
Published: February 2022

Mild traumatic brain injuries (mTBI) are common injuries across civilian and military populations. Although most individuals recover after mTBI, some individuals continue to show long-term symptoms as well as increased risk for neurodegenerative and neuropsychiatric disorders. Currently, diagnosing TBI severity relies primarily on self-report and subjective symptoms, with limited tools for diagnosis or prognosis. Brain-derived exosomes, a form of extracellular vesicle, may offer a solution for interpreting injury states by aiding in diagnosis as well as outcome prediction with relatively low patient burden. Exosomes, which are released into circulation, contain both protein and RNA cargo that can be isolated and quantified, providing a molecular window into molecular status of the exosome source. Here we examined the current literature studying the utility of exosomes, in particular neuronal- and astrocyte-derived exosomes, to identify protein and miRNA biomarkers of injury severity, trajectory, and functional outcome. Current evidence supports the potential for these emerging new tools to capture an accessible molecular window into the brain as it responds to a traumatic injury, however a number of limitations must be addressed in future studies. Most current studies are relatively small and cross sectional; prospective, longitudinal studies across injury severity, and populations are needed to track exosome cargo changes after injury. Standardized exosome isolation as well as advancement in identifying/isolating exosomes from CNS-specific tissue sources will improve mechanistic understanding of cargo changes as well as reliability of findings. Exosomes are also just beginning to be used in model systems to understand functional effects of TBI-associated cargo such as toxicity. Finally linking exosome cargo changes to objective markers of neuronal pathology and cognitive changes will be critical in validating these tools to provide insights into injury and recovery states after TBI.
Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis
Authors: Bahauddin Afrin , Ivannikov Maxim , Wang Zhongying , Jamaluddin Mohammad , Curtis Kyra , Ibtehaj Naazneen , Yeager Linsey , Soong Lynn , Fang Xiang , Huda Ruksana
Published: February 2022

Myasthenia gravis (MG) is an autoimmune disease characterized by chronic muscle fatigue and weakness caused by autoantibodies and complement-mediated damage at neuromuscular junctions. Histone deacetylases (HDACs) are crucial epigenetic regulators of proinflammatory gene expression; however, it is unclear whether HDACs modulate chronic inflammation or autoantibody production associated with MG pathogenesis. We examined expression profiles and serum levels of key inflammatory cytokines (IL-6 and IL-21) and acetylcholine receptor (AChR)-specific autoantibodies following pharmacological inhibition of key HDAC isoforms in a mouse model of MG. We found that HDAC inhibition significantly reduced the production of IL-6, but not IL-21, in AChR-stimulated PBMCs and splenocytes (n = 5 per group). Trichostatin (pan-HDAC inhibitor) treatment of MG-PBMCs (n = 2) also exhibited reduced production of induced IL-6. Although HDAC1 inhibition lowered IL-6 levels the most, HDAC2 inhibition depleted intracellular IL-6 and markedly reduced serum anti-AChR IgG2b in EAMG mice. The transcriptomic profiling and pathway mapping also revealed that autoimmunity-linked, major cell signaling pathways were differentially altered by HDAC1/2 inhibition. HDAC inhibition-mediated reduction in IL-6 and autoantibody levels also correlated with milder disease and preservation of muscle AChR in the treated mice. Overall, our findings revealed isoform-specific functional variance of HDACs in reducing inflammation and identified HDAC-regulated many genes underlying specific inflammatory and autoantibody pathways in EAMG. Thus, the study provides a rationale for further research to evaluate the HDACs or their gene targets as a potential adjunct treatment for MG.
Modified Sensory Testing in Non-verbal Patients Receiving Novel Intrathecal Therapies for Neurological Disorders
Authors: Cornelissen Laura , Donado Carolina , Yu Timothy W. , Berde Charles B.
Published: February 2022

Several neurological disorders may be amenable to treatment with gene-targeting therapies such as antisense oligonucleotides (ASOs) or viral vector-based gene therapy. The US FDA has approved several of these treatments; many others are in clinical trials. Preclinical toxicity studies of ASO candidates have identified dose-dependent neurotoxicity patterns. These include degeneration of dorsal root ganglia, the cell bodies of peripheral sensory neurons. Quantitative sensory testing (QST) refers to a series of standardized mechanical and/or thermal measures that complement clinical neurologic examination in detecting sensory dysfunction. QST primarily relies on patient self-report or task performance (i.e., button-pushing). This brief report illustrates individualized pragmatic approaches to QST in non-verbal subjects receiving early phase investigational intrathecal drug therapies as a component of clinical trial safety protocols. Three children with neurodevelopmental disorders that include Neuronal Ceroid Lipofuscinosis Type 7, Ataxia-Telangiectasia, and Epilepsy of Infancy with Migrating Focal Seizures are presented. These case studies discuss individualized testing protocols, accounting for disease presentation, cognitive and motor function. We outline specific considerations for developing assessments for detecting changes in sensory processing in diverse patient groups and safety monitoring trials of early phase investigational intrathecal drug therapies. QST may complement information obtained from the standard neurologic examination, electrophysiologic studies, skin biopsies, and imaging. QST has limitations and challenges, especially in non-verbal subjects, as shown in the three cases discussed in this report. Future directions call for collaborative efforts to generate sensory datasets and share data registries in the pediatric neurology field.
Combining Literature Review With a Ground Truth Approach for Diagnosing Huntington's Disease Phenocopy
Authors: Nguyen Quang Tuan Rémy , Ortigoza Escobar Juan Dario , Burgunder Jean-Marc , Mariotti Caterina , Saft Carsten , Hjermind Lena Elisabeth , Youssov Katia , Landwehrmeyer G. Bernhard , Bachoud-Lévi Anne-Catherine
Published: February 2022

One percent of patients with a Huntington's disease (HD) phenotype do not have the Huntington (HTT) gene mutation. These are known as HD phenocopies. Their diagnosis is still a challenge. Our objective is to provide a diagnostic approach to HD phenocopies based on medical expertise and a review of the literature. We employed two complementary approaches sequentially: a review of the literature and two surveys analyzing the daily clinical practice of physicians who are experts in movement disorders. The review of the literature was conducted from 1993 to 2020, by extracting articles about chorea or HD-like disorders from the database Pubmed, yielding 51 articles, and analyzing 20 articles in depth to establish the surveys. Twenty-eight physicians responded to the first survey exploring the red flags suggestive of specific disease entities. Thirty-three physicians completed the second survey which asked for the classification of paraclinical tests according to their diagnostic significance. The analysis of the results of the second survey used four different clustering algorithms and the density-based clustering algorithm DBSCAN to classify the paraclinical tests into 1st, 2nd, and 3rd-line recommendations. In addition, we included suggestions from members of the European Reference Network-Rare Neurological Diseases (ERN-RND Chorea & Huntington disease group). Finally, we propose guidance that integrate the detection of clinical red flags with a classification of paraclinical testing options to improve the diagnosis of HD phenocopies.
Diagnostic Delay and Its Predictors in Cluster Headache
Authors: Kim Byung-Su , Chung Pil-Wook , Kim Byung-Kun , Lee Mi Ji , Chu Min Kyung , Ahn Jin-Young , Bae Dae Woong , Song Tae-Jin , Sohn Jong-Hee , Oh Kyungmi , Kim Daeyoung , Kim Jae-Moon , Park Jeong Wook , Chung Jae Myun , Moon Heui-Soo , Cho Soohyun , Seo Jong-Geun , Kim Soo-Kyoung , Choi Yun-Ju , Park Kwang-Yeol , Chung Chin-Sang , Cho Soo-Jin
Published: February 2022

Objective

Cluster headache (CH) is a rare, primary headache disorder, characterized of excruciating, strictly one-sided pain attacks and ipsilateral cranial autonomic symptoms. Given the debilitating nature of CH, delayed diagnosis can increase the disease burden. Thus, we aimed to investigate the diagnostic delay, its predictors, and clinical influence among patients with CH.

Methods

Data from a prospective multicenter CH registry over a 4-year period were analyzed. CH was diagnosed according to the International Classification of Headache Disorders (ICHD)-3 criteria, and diagnostic delay of CH was assessed as the time interval between the year of the first onset and the year of CH diagnosis. Patients were classified into three groups according to the tertiles of diagnostic delay (1st tertile, <1 year; 2nd tertile, 1–6 years; and 3rd tertile, ≥7 years).

Results

Overall, 445 patients were evaluated. The mean duration of diagnosis delay was 5.7 ± 6.7 years, (range, 0–36 years). Regarding the age of onset, majority of young patients (age <20 years) belonged to the third tertile (60%), whereas minority of old patients (>40 years) belonged to the third tertile (9.0%). For year of onset, the proportion of patients in the 3rd tertile was the highest for the groups before the publication year of the ICHD-2 (74.7%) and the lowest for the groups after the publication year of the ICHD-3 beta version (0.5%). Compared with the first CH, episodic CH [multivariable-adjusted odds ratio (aOR) = 5.91, 95% CI = 2.42–14.48], chronic CH (aOR = 8.87, 95% CI = 2.66–29.51), and probable CH (aOR = 4.12, 95% CI = 1.48–11.43) were associated with the tertiles of diagnostic delay. Age of onset (aOR = 0.97, 95% CI = 0.95–0.99) and PHQ-9 score (aOR = 0.96, 95% CI = 0.93–0.99) were inversely associated with the tertile of diagnostic delay. The prevalence of suicidal ideation was highest in the patients of the third tertile. The mean HIT-6 score increased significantly with the diagnostic delay (p = 0.041).

Conclusions

Patients with a younger onset of CH have a higher risk of diagnostic delay. Nevertheless, the rate of delayed diagnosis gradually improved over time and with the publication of the ICHD criteria, supporting the clinical significance of diagnostic clinical criteria and headache education to reduce the disease burden of CH.
Right-Lateralized Enhancement of the Auditory Cortical Network During Imagined Music Performance
Authors: Tanaka Shoji , Kirino Eiji
Published: February 2022

Although the primary role of the auditory cortical areas is to process actual sounds, these areas are also activated by tasks that process imagined music, suggesting that the auditory cortical areas are involved in the processes underlying musical imagery. However, the mechanism by which these areas are involved in such processes is unknown. To elucidate this feature of the auditory cortical areas, we analyzed their functional networks during imagined music performance in comparison with those in the resting condition. While imagined music performance does not produce any musical sounds, the participants heard the same actual sounds from the MRI equipment in both experimental conditions. Therefore, if the functional connectivity between these conditions differs significantly, one can infer that the auditory cortical areas are actively involved in imagined music performance. Our functional connectivity analysis revealed a significant enhancement in the auditory network during imagined music performance relative to the resting condition. The reconfiguration profile of the auditory network showed a clear right-lateralized increase in the connectivity of the auditory cortical areas with brain regions associated with cognitive, memory, and emotional information processing. On the basis of these results, we hypothesize that auditory cortical areas and their networks are actively involved in imagined music performance through the integration of auditory imagery into mental imagery associated with music performance.
Automated Segmentation of Midbrain Structures in High-Resolution Susceptibility Maps Based on Convolutional Neural Network and Transfer Learning
Authors: Zhao Weiwei , Wang Yida , Zhou Fangfang , Li Gaiying , Wang Zhichao , Zhong Haodong , Song Yang , Gillen Kelly M. , Wang Yi , Yang Guang , Li Jianqi
Published: February 2022

Background

Accurate delineation of the midbrain nuclei, the red nucleus (RN), substantia nigra (SN) and subthalamic nucleus (STN), is important in neuroimaging studies of neurodegenerative and other diseases. This study aims to segment midbrain structures in high-resolution susceptibility maps using a method based on a convolutional neural network (CNN).

Methods

The susceptibility maps of 75 subjects were acquired with a voxel size of 0.83 × 0.83 × 0.80 mm3 on a 3T MRI system to distinguish the RN, SN, and STN. A deeply supervised attention U-net was pre-trained with a dataset of 100 subjects containing susceptibility maps with a voxel size of 0.63 × 0.63 × 2.00 mm3 to provide initial weights for the target network. Five-fold cross-validation over the training cohort was used for all the models’ training and selection. The same test cohort was used for the final evaluation of all the models. Dice coefficients were used to assess spatial overlap agreement between manual delineations (ground truth) and automated segmentation. Volume and magnetic susceptibility values in the nuclei extracted with automated CNN delineation were compared to those extracted by manual tracing. Consistencies of volume and magnetic susceptibility values by different extraction strategies were assessed by Pearson correlation coefficients and Bland-Altman analyses.

Results

The automated CNN segmentation method achieved mean Dice scores of 0.903, 0.864, and 0.777 for the RN, SN, and STN, respectively. There were no significant differences between the achieved Dice scores and the inter-rater Dice scores (p > 0.05 for each nucleus). The overall volume and magnetic susceptibility values of the nuclei extracted by the automatic CNN method were significantly correlated with those by manual delineation (p < 0.01).

Conclusion

Midbrain structures can be precisely segmented in high-resolution susceptibility maps using a CNN-based method.
Individual Sensory Modality Dominance as an Influential Factor in the Prefrontal Neurofeedback Training for Spatial Processing: A Functional Near-Infrared Spectroscopy Study
Authors: Sakurada Takeshi , Matsumoto Mayuko , Yamamoto Shin-ichiroh
Published: February 2022

Neurofeedback is a neuromodulation technique used to improve brain function by self-regulating brain activity. However, the efficacy of neurofeedback training varies widely between individuals, and some participants fail to self-regulate brain activity. To overcome intersubject variation in neurofeedback training efficacy, it is critical to identify the factors that influence this type of neuromodulation. In this study, we considered that individual differences in cognitive ability may influence neurofeedback training efficacy and aimed to clarify the effect of individual working memory (WM) abilities, as characterized by sensory modality dominance, on neurofeedback training efficacy in healthy young adults. In particular, we focused on the abilities of individuals to retain internal (tactile or somatosensory) or external (visual) body information in their WM. Forty participants performed functional near-infrared spectroscopy-based neurofeedback training aimed at producing efficient and lower-level activity in the bilateral dorsolateral prefrontal cortex and frontopolar cortex. We carried out a randomized, sham-controlled, double-blind study that compared WM ability before and after neurofeedback training. Individual WM ability was quantified using a target searching task that required the participants to retain spatial information presented as vibrotactile or visual stimuli. Participants who received feedback information based on their own prefrontal activity showed gradually decreasing activity in the right prefrontal area during the neurofeedback training and demonstrated superior WM ability during the target searching task with vibrotactile stimuli compared with the participants who performed dummy neurofeedback training. In comparison, left prefrontal activity was not influenced by the neurofeedback training. Furthermore, the efficacy of neurofeedback training (i.e., lower right prefrontal activity and better searching task performance) was higher in participants who exhibited tactile dominance rather than visual dominance in their WM. These findings indicate that sensory modality dominance in WM may be an influential neurophysiological factor in determining the efficacy of neurofeedback training. These results may be useful in the development of neurofeedback training protocols tailored to individual needs.
A Nutrient Formulation Affects Developmental Myelination in Term Infants: A Randomized Clinical Trial
Authors: Schneider Nora , Bruchhage Muriel M. K. , O'Neill Barry V. , Hartweg Mickaël , Tanguy Jérôme , Steiner Pascal , Mutungi Gisella , O'Regan Jonathan , Mcsweeney Séamus , D'Sa Viren , Deoni Sean C. L.
Published: February 2022

Background and Objectives

Observational studies suggest differences between breast-fed and formula-fed infants in developmental myelination, a key brain process for learning. The study aims to investigate the efficacy of a blend of docosahexaenoic acid (DHA), arachidonic acid (ARA), iron, vitamin B12, folic acid, and sphingomyelin (SM) from a uniquely processed whey protein concentrate enriched in alpha-lactalbumin and phospholipids compared with a control formulation on myelination, cognitive, and behavioral development in the first 6 months of life.

Methods

These are 6-month results from an ongoing two-center, randomized controlled trial with a 12-month intervention period (completed for all participants). In this study, full term, neurotypical infants of both sexes (N = 81) were randomized into investigational (N = 42) or control groups (N = 39). In addition, non-randomized breast-fed children (N = 108) serve as a natural reference group. Main outcomes are myelination (MRI), cognitive (Bayley Scales of Infant and Toddler Development, 3rd edition [Bayley-III]), social-emotional development (Ages and Stages Questionnaires: Social-Emotional, 2nd edition [ASQ:SE-2]), sleep (Brief Infant Sleep Questionnaire [BISQ]), and safety (growth and adverse events [AEs]).

Results

The full analyses set comprises N = 66 infants. Significant differences in myelin structure, volume, and rate of myelination were observed in favor of the investigational myelin blend at 3 and 6 months of life. Effects were demonstrated for whole brain myelin and for cerebellar, parietal, occipital, and temporal regions, known to be functionally involved in sensory, motor, and language skills. No statistically significant differences were found for early behavior and cognition scores.

Conclusions

This is the first study demonstrating the efficacy of a myelin nutrient blend in well-nourished, term infants on developmental myelination, which may be foundational for later cognitive and learning outcomes.

Clinical Trial Registration

ClinicalTrials.gov, identifier: NCT03111927.
Chemical Composition and Potential Biological Activity of Melanoidins From Instant Soluble Coffee and Instant Soluble Barley: A Comparative Study
Authors: Antonietti Sofia , Silva Amélia M. , Simões Cristiana , Almeida Diana , Félix Luis M. , Papetti Adele , Nunes Fernando M.
Published: February 2022

In this work a comparative study of the chemical composition and potential biological activity of high molecular weight (HMW) melanoidins isolated from instant soluble coffee (ISC) and instant soluble barley (ISB) was performed. ISB HMW melanoidins were almost exclusively composed by an ethanol soluble (EtSn) melanoidin fraction composed by glucose (76% w/w) partially susceptible to in vitro digestion, whereas ISC was composed mainly by arabinogalactans (~41% w/w) and lower amounts of galactomannans (~14% w/w) presenting a range of ethanol solubilities and resistant to in vitro digestion. Melanoidins from ISC presented a significantly higher content of condensed phenolic compounds (17/100 g) when compared to ISB (8/100 g) showing also a higher in vitro scavenging of ABTS•+ (329 mmol Trolox/100 g vs. 124 mmol Trolox/100 g) and NO radicals (inhibition percentage of 57 and 26%, respectively). Nevertheless, ISB EtSn melanoidins presented, on average a higher inhibitory effect on NO production from LPS-stimulated macrophages. ISB melanoidins, up to 1 mg/mL, did not induce toxicity in Caco-2, HepG2 and RAW 264.7 cell lines while at the highest concentration ISC slightly reduced cell viability. Thus, consumption of a diet rich in ISC and ISB melanoidins may reduce the oxidative stress, the inflammatory levels and increase the protective effects against chronic inflammatory diseases.
Unraveling Muscle Impairment Associated With COVID-19 and the Role of 3D Culture in Its Investigation
Authors: Seixas Maria Luiza G. A. , Mitre Lucas Pari , Shams Shahin , Lanzuolo Gabriel Barbugian , Bartolomeo Cynthia Silva , Silva Eduardo A. , Prado Carla Maximo , Ureshino Rodrigo , Stilhano Roberta Sessa
Published: February 2022

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been considered a public health emergency, extensively investigated by researchers. Accordingly, the respiratory tract has been the main research focus, with some other studies outlining the effects on the neurological, cardiovascular, and renal systems. However, concerning SARS-CoV-2 outcomes on skeletal muscle, scientific evidence is still not sufficiently strong to trace, treat and prevent possible muscle impairment due to the COVID-19. Simultaneously, there has been a considerable amount of studies reporting skeletal muscle damage in the context of COVID-19. Among the detrimental musculoskeletal conditions associated with the viral infection, the most commonly described are sarcopenia, cachexia, myalgia, myositis, rhabdomyolysis, atrophy, peripheral neuropathy, and Guillain-Barré Syndrome. Of note, the risk of developing sarcopenia during or after COVID-19 is relatively high, which poses special importance to the condition amid the SARS-CoV-2 infection. The yet uncovered mechanisms by which musculoskeletal injury takes place in COVID-19 and the lack of published methods tailored to study the correlation between COVID-19 and skeletal muscle hinder the ability of healthcare professionals to provide SARS-CoV-2 infected patients with an adequate treatment plan. The present review aims to minimize this burden by both thoroughly exploring the interaction between COVID-19 and the musculoskeletal system and examining the cutting-edge 3D cell culture techniques capable of revolutionizing the study of muscle dynamics.
Risk-Benefit Assessment of Feed Additives in the One Health Perspective
Authors: Mantovani Alberto , Aquilina Gabriele , Cubadda Francesco , Marcon Francesca
Published: February 2022

Safety and sustainability of animal feeds is a pillar of the safety of the entire food chain. Feed additive assessment incorporates consumer safety as well as animal health and welfare, which, in turn, can affect productivity and hence food security. The safety of feed users and the environment are other important components of the assessment process which, therefore, builds on a One Health perspective. In several instances the assessment entails a balanced assessment of benefits and risks for humans, animals and/or the environment. Three case studies are selected to discuss issues for a consistent framework on Risk-Benefit Assessment (RBA) of feed additives, based on EFSA opinions and literature: (a) Supplementation of feeds with trace elements with recognized human toxicity (cobalt, iodine) - RBA question: can use levels, hence human exposure, be reduced without increasing the risk of deficiency in animals?; (b) Aflatoxin binders in dairy animals - RBA question: can the use reduce the risk for human health due to aflatoxin M1, without unexpected adverse effects for animals or humans?; (c) Use of formaldehyde as preservative in feedstuffs to prevent microbial contamination - RBA question: is the reduction of microbiological risks outweighed by risks for the consumers, farmed animals or the workers? The case studies indicate that the safety of use of feed additives can involve RBA considerations which fit into a One Health perspective. As in other RBA circumstances, the main issues are defining the question and finding “metrics” that allow a R/B comparison; in the case of feed additives, R and B may concern different species (farm animals and humans). A robust assessment of animal requirements, together with sustainability considerations, might be a significant driving force for a RBA leading to a safe and effective use.
The Prognostic Role of Glycemia in Patients With Pancreatic Carcinoma: A Systematic Review and Meta-Analysis
Authors: Wang Xiaofang , Xu Wanfeng , Hu Xiaoru , Yang Xianghong , Zhang Mingming
Published: February 2022

Background

Fasting blood glucose and glycated hemoglobin (HbA1c) levels are associated with the risk of pancreatic cancer.

Aim

To examine the relationship between perioperative glucose and HbA1c levels and prognosis in patients with pancreatic cancer.

Methods

PubMed, Embase, and the Cochrane Library were queried for potentially eligible studies published up to May 2021. The exposures were perioperative fasting glucose and HbA1c levels. The primary outcome was survival. The secondary outcome was complications. All analyses were performed using the random-effects model.

Results

Ten studies (48,424 patients) were included. The pre-operative (HR=1.10, 95%CI: 0.89-1.35; I2 = 45.1%, Pheterogeneity=0.078) and postoperative (HR=1.19, 95%CI: 0.92-1.54; I2 = 67.9%, Pheterogeneity=0.001) blood glucose levels were not associated with the survival to pancreatic cancer. Similar results were observed for HbA1c (HR=1.09, 95%CI: 0.75-1.58; I2 = 64.2%, Pheterogeneity=0.039), fasting blood glucose (FBG)/HbA1c (HR=1.16, 95%CI: 0.67-1.68; I2 = 0.0%, Pheterogeneity=0.928), and FBG (HR=1.75, 95%CI: 0.81-3.75; I2 = 79.4%, Pheterogeneity=0.008). Pre-operative blood glucose levels were not associated with postoperative complications (OR=0.90, 95%CI: 0.52-1.56), but postoperative glucose levels were associated with postoperative complications (OR=3.06, 95%CI: 1.88-4.97; I2 = 0.0%, Pheterogeneity=0.619).

Conclusion

Blood glucose, FBG, and HbA1c levels are not associated with the survival of patients with pancreatic cancer. Postoperative blood glucose levels could predict postoperative complications.
In-Vivo Induced CAR-T Cell for the Potential Breakthrough to Overcome the Barriers of Current CAR-T Cell Therapy
Authors: Xin Tianqing , Cheng Li , Zhou Chuchao , Zhao Yimeng , Hu Zhenhua , Wu Xiaoyan
Published: February 2022

Chimeric antigen receptor T cell (CAR-T cell) therapy has shown impressive success in the treatment of hematological malignancies, but the systemic toxicity and complex manufacturing process of current autologous CAR-T cell therapy hinder its broader applications. Universal CAR-T cells have been developed to simplify the production process through isolation and editing of allogeneic T cells from healthy persons, but the allogeneic CAR-T cells have recently encountered safety concerns, and clinical trials have been halted by the FDA. Thus, there is an urgent need to seek new ways to overcome the barriers of current CAR-T cell therapy. In-vivo CAR-T cells induced by nanocarriers loaded with CAR-genes and gene-editing tools have shown efficiency for regressing leukemia and reducing systemic toxicity in a mouse model. The in-situ programming of autologous T-cells avoids the safety concerns of allogeneic T cells, and the manufacture of nanocarriers can be easily standardized. Therefore, the in-vivo induced CAR-T cells can potentially overcome the abovementioned limitations of current CAR-T cell therapy. Here, we provide a review on CAR structures, gene-editing tools, and gene delivery techniques applied in immunotherapy to help design and develop new in-vivo induced CAR-T cells.
Methylation of Immune-Related Genes in Peripheral Blood Leukocytes and Breast Cancer
Authors: Tian Tian , Fu JinMing , Li DaPeng , Liu YuPeng , Sun HongRu , Wang Xuan , Zhang XianYu , Zhang Ding , Zheng Ting , Zhao Yashuang , Pang Da
Published: February 2022

Abnormal DNA methylation contributes to breast cancer (BC). Immune-related genes play crucial roles in BC development and progression. This study aims to investigate the effect of methylation of immune-related genes in peripheral blood leukocytes (PBLs) on BC risk. GSE51032 and GSE104942 datasets were used to identify significantly differentially methylated CpG sites (DMCs) of immune-related genes. A case-control study was conducted using MethylTarget sequencing to validate the relationship between the methylation levels of the screened genes and BC risk. We also evaluated the association between methylation haplotypes of screened genes and BC risk. Moreover, we sorted the blood leukocytes into T cells, B cells, and monocytes to detect the difference of DNA methylation in different cell subtypes. A total of five DMCs were screened from GEO datasets, including cg01760846 (PSMC1), cg07141527 (SPPL3), cg15658543 (CARD11), cg21568368 (PSMB8), and cg24045276 (NCF2). In the case-control study, there were significant associations between methylation of the CpG sites in the five genes and BC risk. Methylation haplotype burdens ofPSMC1,CARD11, andPSMB8were associated with reduced BC risk. Moreover, there were heterogeneities in the methylation levels of the genes in different cell subtypes. In conclusion, methylation ofPSMC1,SPPL3,CARD11,PSMB8, andNCF2in PBLs were associated with BC risk. The five-gene methylation could be the potential biomarkers for predicting BC risk.
Trends in Surgical Morbidity and Survival Outcomes for Radical Hysterectomy in West China: An 11-Year Retrospective Cohort Study
Authors: Jing Huining , Yang Ying , Liu Yinxia , Zou Peijun , Li Zhengyu
Published: February 2022

Objectives

To vertically analyze the trend of surgical approaches, demographics, surgical morbidity, and long-term survival outcomes of early-stage cervical cancer over the past 11 years and to determine whether there have been any significant changes.

Methods

A total of 851 patients with consecutive International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IA–IIA cervical cancer diagnosed between January 2008 and June 2018 at a single center in China were included in this retrospective study. Trends in the rate of minimally invasive surgery (MIS), demographics, surgical morbidities, and long-term survival outcomes were determined. We categorized patients into two groups according to their year of operation. The demographics, pathological factors, surgical morbidity, and long-term survival outcomes were compared between these two groups.

Results

Regarding the surgical approach, there was a significant increase in the rate of laparoscopic radical hysterectomy (LRH) performed over the study period, from 7.8% in 2008 to 72.5% in 2018 (p < 0.0001). The mean age of patients who underwent abdominal radical hysterectomy (ARH) has increased slightly from 2008 to 2018, and those who underwent ARH in the second half of the study period (2014–2018) were significantly older (45.01 vs. 47.50 years; p = 0.001). The most impressive changes over the past 11 years have occurred in the surgical morbidity in both the ARH and LRH groups. The overall surgical morbidity decreased from 29.2% in 2008 to 11.9% in 2018, with an annual rate of 1.57%. The median estimated blood loss volume of the ARH group was 500 ml (range 50–2,000) in the first few years compared to 400 ml (30–2500) in the last few years of the study period (p < 0.0001), which in the LRH group was 350 ml (range 150–800) and 150 ml (range 5–1,000), respectively (p < 0.0001). Similarly, allogeneic blood transfusions and hospital stay have all decreased dramatically over time in both approaches. On the other hand, our study did not reveal any significant statistical changes in long-term survival outcomes over the follow-up period in either group.

Conclusions

The findings of our study demonstrate that great progress in surgically managed cervical cancer has been made over the last decade in West China. Our retrospective study demonstrated that the year of operation does not appear to influence the long-term survival, but the surgical morbidity impressively decreased over the study period in both the ARH and LRH groups, which reflects that the higher hospital surgical volume for radical hysterectomy (RH) was not associated with lower survival outcomes but related to the reduction of surgical morbidity.
Potential Influence of Anesthetic Interventions on Breast Cancer Early Recurrence According to Estrogen Receptor Expression: A Sub-Study of a Randomized Trial
Authors: Li Mohan , Zhang Yuelun , Pei Lijian , Zhang Zhiyong , Tan Gang , Huang Yuguang
Published: February 2022

Background

Effects of anesthetic interventions on cancer prognosis remain controversial. There is evidence that estrogen receptor (ER)-negative breast cancer patients have an early recurrence peak. We aimed to assess the potential benefit of regional anesthesia-analgesia versus general anesthesia regarding early recurrence in breast cancer according to ER expression.

Methods

Based on a multicenter randomized controlled trial (clinicaltrials.gov, NCT00418457), we included all the patients from Peking Union Medical College Hospital research center in this study. The primary outcome was breast cancer recurrence after surgery. The Cox proportional hazard model was used to compare recurrence between groups.

Results

In total, 1,253 breast cancer patients were included in this sub-study, among whom the median follow-up time was 53 months. In this sub-study, 320 patients were ER-negative, and 933 were ER-positive. As for ER-negative patients, the recurrence risk in the PPA (paravertebral blocks and propofol general anesthesia) group showed no statistical difference compared with the GA (sevoflurane and opioids general anesthesia) group (19.1% versus 23.4%; adjusted HR: 0.80, 95% CI: 0.50–1.30; P = 0.377). In the first 18 months after breast cancer surgery, which is considered as the classical early peak of recurrence, after adjustment for menstruation and the pathological stage of tumor, the decrease of early recurrence observed in the PPA group was not significant compared with the GA group (adjusted HR: 0.63, 95% CI: 0.34–1.14; P = 0.127).

Conclusions

In our study, the effects of early recurrence after breast cancer surgery in both ER-negative and ER-positive patients were similar between regional anesthesia-analgesia and general anesthesia. Large samples of ER-negative patients will be needed to clarify the effects of anesthetic interventions.
Use of Pralsetinib as Neoadjuvant Therapy for Non-Small Cell Lung Cancer Patient With RET Rearrangement
Authors: Zhou Ning , Li Tong , Liang Maoli , Ren Fan , Ni Hong , Liu Wei , Shi Tao , Xu Dongbo , Chen Qiusong , Yu Haonan , Song Zuoqing , Zu Lingling , Li Shuo , Xu Song
Published: February 2022

RET rearrangements are rare, and occur in 1%-2% of all non-small cell lung cancer (NSCLC) patients. Pralsetinib has a significant anti-tumor effect in patients with advanced NSCLC and a RET rearrangement. Previous studies have confirmed the efficiency of neoadjuvant target therapy for NSCLC. Herein we present a case involving a female patient who was diagnosed with stage IIIA lung adenocarcinoma and harbored a KIF5B-RET rearrangement based on next-generation sequencing. Radiologic downstaging was indicated after pralsetinib treatment. Therefore, a right lower lobectomy and systemic lymphadenectomy were successfully performed. The postoperative pathologic results revealed a response rate of 74% for primary tumor and no residual viable tumor cells were observed in lymph nodes. The tumor, nodes, and metastases (TNM) stage was ypT1cN1M0. The tumor micro-environment (TME) of the primary tumor was also assessed.