bluuebunny/crossref_metadata_2025 huggingface dataset:
Microglial Hyperreactivity Evolved to Immunosuppression in the Hippocampus of a Mouse Model of Accelerated Aging and Alzheimer’s Disease Traits
Authors: Molina-Martínez Patricia , Corpas Rubén , García-Lara Elisa , Cosín-Tomás Marta , Cristòfol Rosa , Kaliman Perla , Solà Carme , Molinuevo José Luis , Sánchez-Valle Raquel , Antonell Anna , Lladó Albert , Sanfeliu Coral
Published: January 2021

Neuroinflammation is a risk factor for Alzheimer’s disease (AD). We sought to study the glial derangement in AD using diverse experimental models and human brain tissue. Besides classical pro-inflammatory cytokines, we analyzed chitinase 3 like 1 (CHI3L1 or YKL40) and triggering receptor expressed on myeloid cells 2 (TREM2) that are increasingly being associated with astrogliosis and microgliosis in AD, respectively. The SAMP8 mouse model of accelerated aging and AD traits showed elevated pro-inflammatory cytokines and activated microglia phenotype. Furthermore, 6-month-old SAMP8 showed an exacerbated inflammatory response to peripheral lipopolysaccharide in the hippocampus and null responsiveness at the advanced age (for this strain) of 12 months. Gene expression of TREM2 was increased in the hippocampus of transgenic 5XFAD mice and in the cingulate cortex of autosomal dominant AD patients, and to a lesser extent in aged SAMP8 mice and sporadic early-onset AD patients. However, gene expression of CHI3L1 was increased in mice but not in human AD brain samples. The results support the relevance of microglia activation in the pathways leading to neurodegeneration and suggest diverse neuroinflammatory responses according to the AD process. Therefore, the SAMP8 mouse model with marked alterations in the dynamics of microglia activation and senescence may provide a complementary approach to transgenic mouse models for the study of the neuroinflammatory mechanisms underlying AD risk and progression.
Motor Dyscoordination and Alteration of Functional Correlation Between DGKγ and PKCγ in Senescence-Accelerated Mouse Prone 8 (SAMP8)
Authors: Tsumagari Ryosuke , Maruo Kenta , Nakao Takaaki , Ueda Shuji , Yamanoue Minoru , Shirai Yasuhito
Published: January 2021

Senescence-accelerated mouse prone 8 (SAMP8) is an animal model of age-related central nervous system (CNS) disorders. Although SAMP8 shows deficits in learning, memory, and emotion, its motor coordination has not been clarified. We have recently reported that DGKγ-regulated PKCγ activity is important for cerebellar motor coordination. However, involvement of the functional correlation between the kinases in age-related motor dyscoordination still remains unknown. Therefore, we have investigated the motor coordination in SAMP8 and involvement of the functional correlation between DGKγ and PKCγ in the age-related motor dyscoordination. Although 6 weeks old SAMP8 showed equivalent motor coordination with control mice (SAMR1) in the rotarod test, 24 weeks old SAMP8 exhibited significantly less latency in the rotarod test and more frequent slips in the beam test compared to the age-matched SAMR1. Furthermore, 24 weeks old SAMP8 showed the higher locomotor activity in open field test and Y-maze test. Western blotting revealed that DGKγ expression decreased in the cerebellum of 24 weeks old SAMP8, while PKCγ was upregulated. These results suggest that SAMP8 is a useful model of age-related motor dysfunction and that the DGKγ-regulated PKCγ activity is involved in the age-related motor dyscoordination.
New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases
Authors: Boltze Johannes , Aronowski Jaroslaw A. , Badaut Jerome , Buckwalter Marion S. , Caleo Mateo , Chopp Michael , Dave Kunjan R. , Didwischus Nadine , Dijkhuizen Rick M. , Doeppner Thorsten R. , Dreier Jens P. , Fouad Karim , Gelderblom Mathias , Gertz Karen , Golubczyk Dominika , Gregson Barbara A. , Hamel Edith , Hanley Daniel F. , Härtig Wolfgang , Hummel Friedhelm C. , Ikhsan Maulana , Janowski Miroslaw , Jolkkonen Jukka , Karuppagounder Saravanan S. , Keep Richard F. , Koerte Inga K. , Kokaia Zaal , Li Peiying , Liu Fudong , Lizasoain Ignacio , Ludewig Peter , Metz Gerlinde A. S. , Montagne Axel , Obenaus Andre , Palumbo Alex , Pearl Monica , Perez-Pinzon Miguel , Planas Anna M. , Plesnila Nikolaus , Raval Ami P. , Rueger Maria A. , Sansing Lauren H. , Sohrabji Farida , Stagg Charlotte J. , Stetler R. Anne , Stowe Ann M. , Sun Dandan , Taguchi Akihiko , Tanter Mickael , Vay Sabine U. , Vemuganti Raghu , Vivien Denis , Walczak Piotr , Wang Jian , Xiong Ye , Zille Marietta
Published: January 2021

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.
From Hyposociability to Hypersociability—The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior
Authors: Gao Wen-Jun , Mack Nancy R.
Published: January 2021

Abnormal social behavior, including both hypo- and hypersociability, is often observed in neurodevelopmental disorders such as autism spectrum disorders. However, the mechanisms associated with these two distinct social behavior abnormalities remain unknown. Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein in the excitatory synapses and an essential regulator of synaptic maturation by binding to NMDA and AMPA receptors. TheDLG4gene encodes PSD-95, and it is a risk gene for hypersocial behavior. Interestingly, PSD-95 knockout mice exhibit hyposociability during adolescence but hypersociability in adulthood. The adolescent hyposociability is accompanied with an NMDAR hyperfunction in the medial prefrontal cortex (mPFC), an essential part of the social brain for control of sociability. The maturation of mPFC development is delayed until young adults. However, how PSD-95 deficiency affects the functional maturation of mPFC and its connection with other social brain regions remains uncharacterized. It is especially unknown how PSD-95 knockout drives the switch of social behavior from hypo- to hyper-sociability during adolescent-to-adult development. We propose an NMDAR-dependent developmental switch of hypo- to hyper-sociability. PSD-95 deficiency disrupts NMDAR-mediated synaptic connectivity of mPFC and social brain during development in an age- and pathway-specific manner. By utilizing the PSD-95 deficiency mouse, the mechanisms contributing to both hypo- and hyper-sociability can be studied in the same model. This will allow us to assess both local and long-range connectivity of mPFC and examine how they are involved in the distinct impairments in social behavior and how changes in these connections may mature over time.
A Challenging Diagnosis of Atypical Glut1-DS: A Case Report and Literature Review
Authors: Yu Miaomiao , Miao Jing , Lv Yudan , Wang Xue , Zhang Wuqiong , Shao Na , Meng Hongmei
Published: January 2021

Glucose transporter type 1 deficiency syndrome (Glut1-DS) is a rare neurometabolic disorder caused by mutations of the SLC2A1 gene. Paroxysmal exercise-induced dyskinesia is regarded as a representative symptom of Glut1-DS. Paroxysmal non-kinesigenic dyskinesia is usually caused by aberrations of the MR1 and KCNMA1 genes, but it also appears in Glut1-DS. We herein document a patient with Glut1-DS who suffered first from paroxysmal exercise-induced dyskinesia and subsequently paroxysmal non-kinesigenic dyskinesia and experienced a recent worsening of symptoms accompanied with a low fever. The lumbar puncture result showed a decreased glucose concentration and increased white blood cell (WBC) count in cerebrospinal fluid (CSF). The exacerbated symptoms were initially suspected to be caused by intracranial infection due to a mild fever of <38.0°C, decreased CSF glucose, and increased CSF WBC count. However, the second lumbar puncture result indicated a decreased glucose concentration and normal WBC count in CSF with no anti-infective agents, and the patient's symptoms were not relieved apparently. The continuous low glucose concentration attracted our attention, and gene analysis was performed. According to the gene analysis result, the patient was diagnosed with Glut1-DS finally. This case indicates that the complex paroxysmal dyskinesia in Glut1-DS may be confusing and pose challenges for accurate diagnosis. Except intracranial infection, Glut1-DS should be considered as a differential diagnosis upon detection of a low CSF glucose concentration and dyskinesia. The case presented here may encourage clinicians to be mindful of this atypical manifestation of Glut1-DS in order to avoid misdiagnosis.
Hyperventilation in Adult TBI Patients: How to Approach It?
Authors: Gouvea Bogossian Elisa , Peluso Lorenzo , Creteur Jacques , Taccone Fabio Silvio
Published: January 2021

Hyperventilation is a commonly used therapy to treat intracranial hypertension (ICTH) in traumatic brain injury patients (TBI). Hyperventilation promotes hypocapnia, which causes vasoconstriction in the cerebral arterioles and thus reduces cerebral blood flow and, to a lesser extent, cerebral blood volume effectively, decreasing temporarily intracranial pressure. However, hyperventilation can have serious systemic and cerebral deleterious effects, such as ventilator-induced lung injury or cerebral ischemia. The routine use of this therapy is therefore not recommended. Conversely, in specific conditions, such as refractory ICHT and imminent brain herniation, it can be an effective life-saving rescue therapy. The aim of this review is to describe the impact of hyperventilation on extra-cerebral organs and cerebral hemodynamics or metabolism, as well as to discuss the side effects and how to implement it to manage TBI patients.
Endovascular Treatment of Ruptured Middle Cerebral Artery Aneurysms With a Low-Profile Visualized Intraluminal Support Device
Authors: Xue Gaici , Zhou Yu , Liu Peng , Zuo Qiao , Yang Pengfei , Fang Yibin , Li Qiang , Zhao Rui , Xu Yi , Hong Bo , Huang Qinghai , Liu Jianmin
Published: January 2021

Objective: Stenting in ruptured middle cerebral artery (MCA) aneurysms was reported with a high perioperative complication rate. However, the treatment devices and physician's experience have continued to evolve. We performed this retrospective study to evaluate the safety and efficacy of LVIS stent-assisted coiling for ruptured MCA aneurysms.

Methods: Patients with acutely ruptured MCA aneurysms treated between November 2014 and October 2019 were retrospectively reviewed. Clinical and angiographic data of those treated with LVIS stents were collected from a prospectively maintained database.

Results: A total of 40 patients with 40 ruptured MCA aneurysms were enrolled, which comprised 26.3% (40/152) of all the ruptured MCA aneurysms at the same time. All stents were successfully deployed except for one (2.5%), which had a poor stent opening. Ischemic procedure-related complications were encountered in three patients (7.5%). One patient died of complications related to high-grade SAH on admission. Follow-up (mean 15.9 months) angiography was performed for 36 patients, which showed 33 (91.7%) aneurysms were completely occluded, 1 (2.8%) was improved, 1 (2.8%) was stable, and 1 (2.8%) was recanalized. Clinical follow-up (mean 29.6 months) was available for all survived patients, which showed 38 (95.0%) patients had favorable neurologic outcomes (mRS score 0–2), and 2 (5.0%) patients had poor neurologic outcomes.

Conclusion: The use of LVIS stents is feasible, safe, and effective with glycoprotein IIb/IIIa inhibitor for the treatment of ruptured MCA aneurysms in the acute setting. Prospective, multicenter studies with larger sample sizes are still required to further evaluate the safety and long-term efficacy.
Enhanced Hemodynamic and Clinical Response to αCGRP in Migraine Patients—A TCD Study
Authors: Visočnik Darja , Zaletel Marjan , Žvan Bojana , Zupan Matija
Published: January 2021

Introduction: Sensitisation of the nervous system in a patient with migraine is supposed to be associated with calcitonin gene-related peptide (CGRP) activity. Therefore, the vascular response to human αCGRP (hαCGRP) could be a surrogate marker for the sensitization. We hypothesize that vascular response to hαCGRP is augmented in a patient with migraine.

Methods: Twenty healthy subjects and 20 patients with migraine participated in our study. TCD was used to monitor mean arterial velocity in the middle cerebral artery (vm MCA). Simultaneously, end-tidal CO2 (Et-CO2), mean arterial pressure (MAP), and heart rate (HR) were measured. The reconstruction of the signals was made for basal conditions, during and after CGRP infusion which were compared using statistics.

Results: In both groups, we found significant decrease between measurement points of vm MCA and Et-CO2 during and after hαCGRP infusion. MAP did not show significant trends during the infusion, but it was significantly increased after the infusion in migraine patients only. Responses to hαCGRP, defined as differences between two measurement points, were significantly higher for vm MCA and Et-CO2 in patients with migraine. A significant difference between groups was found in MAP response. Significant relationships were found between migraine and vm MCA, Et-CO2, and MAP.

Conclusion: In patients with migraine, vm MCA responses to hαCGRP are significantly higher and are associated with CGRP-induced headache which indicates that patients with migraine are more prone to sensitization.
The Importance of Childhood for Adult Health and Development—Study Protocol of the Zurich Longitudinal Studies
Authors: Wehrle Flavia M. , Caflisch Jon , Eichelberger Dominique A. , Haller Giulia , Latal Beatrice , Largo Remo H. , Kakebeeke Tanja H. , Jenni Oskar G.
Published: January 2021

Evidence is accumulating that individual and environmental factors in childhood and adolescence should be considered when investigating adult health and aging-related processes. The data required for this is gathered by comprehensive long-term longitudinal studies. This article describes the protocol of the Zurich Longitudinal Studies (ZLS), a set of three comprehensive cohort studies on child growth, health, and development that are currently expanding into adulthood. Between 1954 and 1961, 445 healthy infants were enrolled in the first ZLS cohort. Their physical, motor, cognitive, and social development and their environment were assessed comprehensively across childhood, adolescence, and into young adulthood. In the 1970s, two further cohorts were added to the ZLS and assessed with largely matched study protocols: Between 1974 and 1979, the second ZLS cohort included 265 infants (103 term-born and 162 preterm infants), and between 1970 and 2002, the third ZLS cohort included 327 children of participants of the first ZLS cohort. Since 2019, the participants of the three ZLS cohorts have been traced and invited to participate in a first wave of assessments in adulthood to investigate their current health and development. This article describes the ZLS study protocol and discusses opportunities, methodological and conceptual challenges, and limitations arising from a long-term longitudinal cohort recruited from a study about development in early life. In the future, the ZLS will provide data to investigate childhood antecedents of adult health outcomes and, ultimately, will help respond to the frequent call of scientists to shift the focus of aging research into the first decades of life and, thus, to take a lifespan perspective on aging.
Viability of Preictal High-Frequency Oscillation Rates as a Biomarker for Seizure Prediction
Authors: Scott Jared M. , Gliske Stephen V. , Kuhlmann Levin , Stacey William C.
Published: January 2021

Motivation: There is an ongoing search for definitive and reliable biomarkers to forecast or predict imminent seizure onset, but to date most research has been limited to EEG with sampling rates <1,000 Hz. High-frequency oscillations (HFOs) have gained acceptance as an indicator of epileptic tissue, but few have investigated the temporal properties of HFOs or their potential role as a predictor in seizure prediction. Here we evaluate time-varying trends in preictal HFO rates as a potential biomarker of seizure prediction.

Methods: HFOs were identified for all interictal and preictal periods with a validated automated detector in 27 patients who underwent intracranial EEG monitoring. We used LASSO logistic regression with several features of the HFO rate to distinguish preictal from interictal periods in each individual. We then tested these models with held-out data and evaluated their performance with the area-under-the-curve (AUC) of their receiver-operating curve (ROC). Finally, we assessed the significance of these results using non-parametric statistical tests.

Results: There was variability in the ability of HFOs to discern preictal from interictal states across our cohort. We identified a subset of 10 patients in whom the presence of the preictal state could be successfully predicted better than chance. For some of these individuals, average AUC in the held-out data reached higher than 0.80, which suggests that HFO rates can significantly differentiate preictal and interictal periods for certain patients.

Significance: These findings show that temporal trends in HFO rate can predict the preictal state better than random chance in some individuals. Such promising results indicate that future prediction efforts would benefit from the inclusion of high-frequency information in their predictive models and technological architecture.
Pathophysiological Changes and the Role of Notch-1 Activation After Decompression in a Compressive Spinal Cord Injury Rat Model
Authors: Cheng Xing , Yu Zhengran , Xu Jinghui , Quan Daping , Long Houqing
Published: January 2021

Surgical decompression is the primary treatment for cervical spondylotic myelopathy (CSM) patients with compressive spinal cord injury (CSCI). However, the prognosis of patients with CSCI varies, and the pathophysiological changes following decompression remain poor. This study aimed to investigate the pathophysiological changes and the role of Notch-1 activation after decompression in a rat CSCI model. Surgical decompression was conducted at 1 week post-injury (wpi). DAPT was intraperitoneally injected to down-regulate Notch-1 expression. Basso, Beattie, and Bresnahan scores and an inclined plane test were used to evaluate the motor function recovery. Hematoxylin and eosin staining was performed to assess pathophysiological changes, while hypoxia-inducible factor 1 alpha, vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), matrix metalloproteinase (MMP)-9, MMP-2, Notch-1, and Hes-1 expression in the spinal cord were examined by immunohistochemical analysis or quantitative PCR. The results show that early decompression can partially promote motor function recovery. Improvements in structural and cellular damage and hypoxic levels were also observed in the decompressed spinal cord. Moreover, decompression resulted in increased VEGF and vWF expression, but decreased MMP-9 and MMP-2 expression at 3 wpi. Expression levels of Notch-1 and its downstream gene Hes-1 were increased after decompression, and the inhibition of Notch-1 significantly reduced the decompression-induced motor function recovery. This exploratory study revealed preliminary pathophysiological changes in the compressed and decompressed rat spinal cord. Furthermore, we confirmed that early surgical decompression partially promotes motor function recovery may via activation of the Notch-1 signaling pathway after CSCI. These results could provide new insights for the development of drug therapy to enhance recovery following surgery.
Survival Predictors of Heart Rate Variability After Myocardial Infarction With and Without Low Left Ventricular Ejection Fraction
Authors: Hayano Junichiro , Ueda Norihiro , Kisohara Masaya , Yuda Emi , Carney Robert M. , Blumenthal James A.
Published: January 2021

Background

Heart rate variability (HRV) and heart rate (HR) dynamics are used to predict the survival probability of patients after acute myocardial infarction (AMI), but the association has been established in patients with mixed levels of left ventricular ejection fraction (LVEF).

Objective

We investigated whether the survival predictors of HRV and HR dynamics depend on LVEF after AMI.

Methods

We studied 687 post-AMI patients including 147 with LVEF ≤35% and 540 with LVEF >35%, of which 23 (16%) and 22 (4%) died during the 25 month follow-up period, respectively. None had an implanted cardioverter-defibrillator. From baseline 24 h ECG, the standard deviation (SDNN), root mean square of successive difference (rMSSD), percentage of successive difference >50 ms (pNN50) of normal-to-normal R-R interval, ultra-low (ULF), very-low (VLF), low (LF), and high (HF) frequency power, deceleration capacity (DC), short-term scaling exponent (α1), non-Gaussianity index (λ25s), and the amplitude of cyclic variation of HR (Acv) were calculated.

Results

The predictors were categorized into three clusters; DC, SDNN, α1, ULF, VLF, LF, and Acv as Cluster 1, λ25s independently as Cluster 2, and rMSSD, pNN50, and HF as Cluster 3. In univariate analyses, mortality was best predicted by indices belonging to Cluster 1 regardless of LVEF. In multivariate analyses, however, mortality in patients with low LVEF was best predicted by the combinations of Cluster 1 predictors or Cluster 1 and 3 predictors, whereas in patients without low LVEF, it was best predicted by the combinations of Cluster 1 and 2 predictors.

Conclusion

The mortality risk in post-AMI patients with low LVEF is predicted by indices reflecting decreased HRV or HR responsiveness and cardiac parasympathetic dysfunction, whereas in patients without low LVEF, the risk is predicted by a combination of indices that reflect decreased HRV or HR responsiveness and indicator that reflects abrupt large HR changes suggesting sympathetic involvement.
Reduction in Nesfatin-1 Levels in the Cerebrospinal Fluid and Increased Nigrostriatal Degeneration Following Ventricular Administration of Anti-nesfatin-1 Antibody in Mice
Authors: Chen Huanhuan , Li Xuelian , Ma Hui , Zheng Wei , Shen Xiaoli
Published: January 2021

Nesfatin-1 is one of several brain-gut peptides that have a close relationship with the central dopaminergic system. Our previous studies have shown that nesfatin-1 is capable of protecting nigral dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. A recent study also revealed a reduced blood level of nesfatin-1 in patients with Parkinson’s disease (PD). The current study was designed to investigate whether reduced nesfatin-1 in cerebrospinal fluid (CSF) induces nigrostriatal system degeneration. An intra-cerebroventricular (ICV) injection technique was used to administer anti-nesfatin-1 antibody directly into the lateral ventricle of the brain. Enzyme-linked immunosorbent assay (ELISA) results showed that ICV injection of anti-nesfatin-1 antibody into the lateral ventricle of the brain once daily for 2 weeks caused a significant reduction in nesfatin-1 levels in the CSF (93.1%). Treatment with anti-nesfatin-1 antibody resulted in a substantial loss (23%) of TH-positive (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc), as shown by immunofluorescence staining, a depletion in dopamine and its metabolites in the striatum detected by high-performance liquid chromatography (HPLC), and obvious nuclear shrinkage and mitochondrial lesions in dopaminergic neurons in the SNpc detected by transmission electron microscopy (TEM). Furthermore, the results from our Western blot and ELISA experiments demonstrated that anti-nesfatin-1 antibody injection induced an upregulation of caspase-3 activation, increased the expression of p-ERK, and elevated brain-derived neurotrophic factor (BDNF) levels in the SNpc. Taken together, these observations suggest that reduced nesfatin-1 in the brain may induce nigrostriatal dopaminergic system degeneration; this effect may be mediated via mitochondrial dysfunction-related apoptosis. Our data support a role of nesfatin-1 in maintaining the normal physiological function of the nigrostriatal dopaminergic system.
Using Muse: Rapid Mobile Assessment of Brain Performance
Authors: Krigolson Olave E. , Hammerstrom Mathew R. , Abimbola Wande , Trska Robert , Wright Bruce W. , Hecker Kent G. , Binsted Gordon
Published: January 2021

The advent of mobile electroencephalography (mEEG) has created a means for large scale collection of neural data thus affording a deeper insight into cognitive phenomena such as cognitive fatigue. Cognitive fatigue – a neural state that is associated with an increased incidence of errorful performance – is responsible for accidents on a daily basis which at times can cost human lives. To gain better insight into the neural signature of cognitive fatigue in the present study we used mEEG to examine the relationship between perceived cognitive fatigue and human-event related brain potentials (ERPs) and electroencephalographic (EEG) oscillations in a sample of 1,000 people. As a secondary goal, we wanted to further demonstrate the capability of mEEG to accurately measure ERP and EEG data. To accomplish these goals, participants performed a standard visual oddball task on an Apple iPad while EEG data were recorded from a Muse EEG headband. Counter to traditional EEG studies, experimental setup and data collection was completed in less than seven minutes on average. An analysis of our EEG data revealed robust N200 and P300 ERP components and neural oscillations in the delta, theta, alpha, and beta bands. In line with previous findings we observed correlations between ERP components and EEG power and perceived cognitive fatigue. Further, we demonstrate here that a linear combination of ERP and EEG features is a significantly better predictor of perceived cognitive fatigue than any ERP or EEG feature on its own. In sum, our results provide validation of mEEG as a viable tool for research and provide further insight into the impact of cognitive fatigue on the human brain.
Neuregulin1-ErbB4 Signaling in Spinal Cord Participates in Electroacupuncture Analgesia in Inflammatory Pain
Authors: Wan Chaofan , Xu Yunlong , Cen Baoyan , Xia Yucen , Yao Lin , Zheng Yuanjia , Zhao Jiaying , He Su , Chen Yongjun
Published: January 2021

Chronic inflammatory pain is a severe clinical symptom that aggravates the life quality of patients and places a huge economic burden on individuals and society. As one complementary and alternative therapy, electroacupuncture (EA) is widely used in clinical practice to treat chronic inflammatory pain based on its safety and efficacy. Previous studies have revealed the potential role of adenosine, neuropeptides, and inflammatory factors in EA analgesia in various pain models, but the identity of some of the signaling pathways involved remain unknown. In the present study, we explored whether neuregulin1 (NRG1)-ErbB4 signaling is involved in EA analgesia in inflammatory pain. Repeated EA treatment at the acupoints Zusanli (ST36) and Sanyinjiao (SP6) for 3 consecutive days remarkably attenuated mechanical allodynia and thermal hyperalgesia in complete Freund’s adjuvant (CFA)-treated mice, with an increased expression of NRG1 in spinal cord (SC). We found that ErbB4 kinase participated in both the EA and NRG1 mediated analgesic effects on inflammatory pain by pharmacological inhibition or genetic ablation ErbB4 in vivo. Intriguingly, the mice with conditional knockout of ErbB4 from PV+ interneurons in SC showed abnormal basal mechanical threshold. Meanwhile, NRG1 treatment could not relieve tactile allodynia in PV-Erbb4–/– mice or AAV-PV-Erbb4–/– mice after CFA injection. These experimental results suggest that regulating NRG1-ErbB4 signaling in SC could reduce pain hypersensitivity and contribute to EA analgesia in inflammatory pain.
Sex Differences in Autism Spectrum Disorder: An Investigation on Core Symptoms and Psychiatric Comorbidity in Preschoolers
Authors: Prosperi Margherita , Turi Marco , Guerrera Silvia , Napoli Eleonora , Tancredi Raffaella , Igliozzi Roberta , Apicella Fabio , Valeri Giovanni , Lattarulo Caterina , Gemma Andrea , Santocchi Elisa , Calderoni Sara , Muratori Filippo , Vicari Stefano
Published: January 2021

Findings regarding sex differences in autism spectrum disorder (ASD), as far as core symptoms and psychiatric comorbidities (PC) are concerned, are inconsistent, inconclusive, or conflicting among studies. The lower prevalence of ASD in females than in males and the age and intelligence quotient (IQ) heterogeneity among samples made it difficult to investigate these differences. This case–control study tries to deepen the impact of sex differences on core symptoms of autism and PC in 214 preschoolers with ASD (mean age, 45.26) without impairment in non-verbal IQ (nvIQ ≥70). A total of 107 ASD females (mean age, 44.51 ± 13.79 months) were matched one by one with 107 males (mean age, 46.01 ± 13.42 months) for chronological age (±6 months) and nvIQ (±6 points). We used the Autism Diagnostic Observation Schedule 2 (ADOS-2) and the Child Behavior Checklist (CBCL) 1.5–5 to explore autism severity and PC. The results highlight that ASD females did not significantly differ from ASD males regarding the severity of autism. Statistically significant lower levels of emotionally reactive (p = 0.005, η2 = 0.04), anxious-depressed (p = 0.001, η2 = 0.05), internalizing problems (p = 0.04, η2 = 0.02), and DSM-Oriented Scales anxiety problems (p = 0.02, η2 = 0.04) in ASD females than in ASD males were also detected. Our findings of no difference in the autism severity and lower internalizing problems in females than males with ASD extend the knowledge of autism in females during preschool years. Compared to other similar studies on this topic, we can state that these results are not supported by differences in nvIQ between sexes nor by the presence of cognitive impairment. It confirms the need for clinicians to consider sex differences when describing autism psychopathology.
The Interplay Between Diet and the Epigenome in the Pathogenesis of Type-1 Diabetes
Authors: Kohil Amira , Al-Asmakh Maha , Al-Shafai Mashael , Terranegra Annalisa
Published: January 2021

The autoimmune disease, Type 1 Diabetes Mellitus (T1DM), results in the destruction of pancreatic β-cells, and the International Diabetes Federation reports that its incidence is increasing worldwide. T1DM is a complex disease due to the interaction between genetic and environmental factors. Certain dietary patterns and nutrients are known to cause epigenetic modifications in physiological conditions and diseases. However, the interplay between diet and epigenetics is not yet well-understood in the context of T1DM. Several studies have described epigenetic mechanisms involved in the autoimmune reactions that destroy the β-cells, but few explored diet components as potential triggers for epigenetic modifications. Clarifying the link between diet and epigenome can provide new insights into the pathogenesis of T1DM, potentially leading to new diagnostic and therapeutic approaches. In this mini review, we shed light on the influence of the diet-epigenome axis on the pathophysiology of T1DM.
Hypercholesterolemia Is an Associated Factor for Risk of Differentiated Thyroid Cancer in Chinese Population
Authors: Zhao Junyu , Tian Yutian , Yao Jinming , Gu He , Zhang Rui , Wang Huanjun , Liao Lin , Dong Jianjun
Published: January 2021

Background

Hyperlipidemia has been hypothesized as a risk factor for thyroid cancer. However, the association between hypercholesterolemia and thyroid cancer is unclear, especially in Chinese population without available published data. We conducted this study to investigate the relationship between hypercholesterolemia and differentiated thyroid cancer (DTC) in Chinese population.

Methods

Three thousand seven hundred forty-eight patients were enrolled in the study, including 2,021 DTC patients and 1,727 benign subjects with benign thyroid nodules. Demographic characteristics, medical history, and clinical hematological examination were collected. Stratified analyses of association between hypercholesterolemia and risk of DTC were done. Multivariable logistic regression models were used to estimate the association between hypercholesterolemia and the risk of thyroid nodules being malignant. This study protocol was approved by the ethics committee of Shandong Provincial Qianfoshan Hospital and assigned in ClinicalTrials.gov protocol registration and results system (NCT03006289, https://clinicaltrials.gov/ct2/show/NCT03006289).

Results

The level of serum total cholesterol in patients with DTC is higher than that in benign subjects (P < 0.001). After adjusting hypercholesterolemia, age (P < 0.001), triglyceride (P = 0.003), and thyroid stimulating hormone (TSH) (P < 0.001) are found to be confounding factors. The risk of DTC in patients younger than 45 years old is 2.08 times than that of patients older than 45 years old (odds ratio = 0.48, 95% CI (0.38, 0.61), P < 0.001). A high TSH level is highly associated with the increased risk of DTC (P < 0.001). The multivariable logistic regression analysis revealed that the absence of hypercholesterolemia could reduce the risk of thyroid nodules being malignant (odds ratio = −0.75, 95% CI (−1.39, −0.12), P = 0.02). Comparing to the higher level of serum total cholesterol (>5.7 mmol/L), the closer the serum total cholesterol level is to normal (3.17–5.7 mmol/L), the less the risk of thyroid nodules being malignant is, and this difference is statistically significant (odds ratio = −0.67, 95% CI (−1.31, −0.03), P = 0.040). However, this difference is not found in the group of patients with lower level of total cholesterol (<3.17 mmol/L, odds ratio = 0.43, 95% CI (−1.22, 2.09), P = 0.068), suggesting that hypocholesterolemia is not a protective factor in the risk of thyroid nodules being malignant.

Conclusions

Hypercholesterolemia is an associated factor for risk of DTC in Chinese population.
Development of an Oncogenic Driver Alteration Associated Immune-Related Prognostic Model for Stage I-II Lung Adenocarcinoma
Authors: Xu Jian-Zhao , Gong Chen , Xie Zheng-Fu , Zhao Hua
Published: January 2021

Lung adenocarcinoma (LUAD) needs to be stratified for its heterogeneity. Oncogenic driver alterations such asEGFRmutation,ALKtranslocation,ROS1translocation, andBRAFmutation predict response to treatment for LUAD. Since oncogenic driver alterations may modulate immune response in tumor microenvironment that may influence prognosis in LUAD, the effects ofEGFR,ALK,ROS1, andBRAFalterations on tumor microenvironment remain unclear. Immune-related prognostic model associated with oncogenic driver alterations is needed. In this study, we performed the Cox-proportional Hazards Analysis based on the L1-penalized (LASSO) Analysis to establish an immune-related prognostic model (IPM) in stage I-II LUAD patients, which was based on 3 immune-related genes (PDE4B,RIPK2, andIFITM1) significantly enriched in patients withoutEGFR,ALK,ROS1, andBRAFalterations in The Cancer Genome Atlas (TCGA) database. Then, patients were categorized into high-risk and low-risk groups individually according to the IPM defined risk score. The predicting ability of the IPM was validated in GSE31210 and GSE26939 downloaded from the Gene Expression Omnibus (GEO) database. High-risk was significantly associated with lower overall survival (OS) rates in 3 independent stage I-II LUAD cohorts (allP< 0.05). Moreover, the IPM defined risk independently predicted OS for patients in TCGA stage I-II LUAD cohort (P= 0.011). High-risk group had significantly higher proportions of macrophages M1 and activated mast cells but lower proportions of memory B cells, resting CD4 memory T cells and resting mast cells than low-risk group (allP< 0.05). In addition, the high-risk group had a significantly lower expression ofCTLA-4,PDCD1,HAVCR2, andTIGITthan the low-risk group (allP< 0.05). In summary, we established a novel IPM that could provide new biomarkers for risk stratification of stage I-II LUAD patients.
Trace Elements Status and Metallothioneins DNA Methylation Influence Human Hepatocellular Carcinoma Survival Rate
Authors: Udali Silvia , De Santis Domenica , Mazzi Filippo , Moruzzi Sara , Ruzzenente Andrea , Castagna Annalisa , Pattini Patrizia , Beschin Greta , Franceschi Antonia , Guglielmi Alfredo , Martinelli Nicola , Pizzolo Francesca , Ambrosani Francesca , Olivieri Oliviero , Choi Sang-Woon , Friso Simonetta
Published: January 2021

Background

Mechanisms underlying hepatocellular carcinoma (HCC) development are largely unknown. The role of trace elements and proteins regulating metal ions homeostasis, i.e. metallothioneins (MTs), recently gained an increased interest. Object of the study was to investigate the role of promoter DNA methylation in MTs transcriptional regulation and the possible prognostic significance of serum trace elements in HCC.

Methods

Forty-nine HCC patients were enrolled and clinically characterized. Cu, Se, and Zn contents were measured by Inductively Coupled Plasma Mass Spectrometry in the serum and, for a subset of 27 patients, in HCC and homologous non-neoplastic liver (N) tissues. MT1G and MT1H gene expression in hepatic tissues was assessed by Real-Time RT-PCR and the specific promoter DNA methylation by Bisulfite-Amplicon Sequencing.

Results

Patients with Cu serum concentration above the 80th percentile had a significantly decreased survival rate (P < 0.001) with a marked increased hazard ratio for mortality (HR 6.88 with 95% CI 2.60–18.23, P < 0.001). Se and Zn levels were significantly lower in HCC as compared to N tissues (P < 0.0001). MT1G and MT1H gene expression was significantly down-regulated in HCC as compared to N tissues (P < 0.05). MTs promoter was hypermethylated in 9 out of the 19 HCC tissues showing MTs down-regulation and methylation levels of three specific CpGs paralleled to an increased mortality rate among the 23 patients analyzed (P = 0.015).

Conclusions

MT1G and MT1H act as potential tumor suppressor genes regulated through promoter DNA methylation and, together with serum Cu concentrations, be related to survival rate in HCC.
Sodium Fluorescein for Spinal Intradural Tumors
Authors: Olguner Semih Kivanc , Arslan Ali , Açık Vedat , İstemen İsmail , Can Mehmet , Gezercan Yurdal , Ökten Ali İhsan
Published: January 2021

Technological innovations in spinal intradural tumor surgery simplify treatment. Surgical treatment of cranial benign and malignant pathologies under microscope with sodium (Na)-fluorescein guidance has often been reported, but few studies have focused on spinal intradural tumors. We aimed to investigate the usefulness of Na-fluorescein under yellow filter in intradural spinal tumor surgery by retrospectively reviewing cases involving intramedullary and extramedullary tumors operated under the guidance of Na-fluorescein. Forty-nine adult patients with a diagnosis of spinal intradural tumor operated under a yellow filter (560 nm) microscope using Na-fluorescein dye were included in the study. Demographic data, such as age and sex, neurological status, extent of tumor resection, histopathological diagnosis, Na-fluorescein staining pattern, and its usefulness during surgery were noted and statistically analyzed. Of all recruited patients, 26 women (53.1%) and 23 men (46.9%), were included for analysis. The age range of the patients was 18–64 years, with a mean age of 41.6 ± 13.9. An intradural intramedullary mass was found in 30.6% (n = 15) of the patients, and an intradural extramedullary mass in 69.4% (n: 34). While Na-fluorescein staining was homogeneous in all intradural extramedullary tumors, 73.3% (n: 11) of intradural intramedullary tumors were homogeneous, and 13.3% (n: 2) moderately heterogeneous. In the whole study group, the Na-fluorescein staining pattern was helpful in surgical resection in 47 cases (95.9%). While 34/34 (100%) found it helpful for extramedullary tumors, 13/15 (86.7%) did in intramedullary tumors, and for 2/15 (13.3%) it was not. In conclusion, Na-fluorescein helps in distinguishing tumor from healthy tissue in intradural extramedullary and intramedullary tumor surgery under a yellow filter microscope in most cases, thus providing convenient assistance to surgeons.
Accelerometric Gait Analysis Devices in Children—Will They Accept Them? Results From the AVAPed Study
Authors: Wiedmann Isabella , Grassi Marcello , Duran Ibrahim , Lavrador Ricardo , Alberg Evelyn , Daumer Martin , Schoenau Eckhard , Rittweger Jörn
Published: January 2021

Aims: To assess children's acceptance to wear a 3D-accelerometer which is attached to the waist under real-world conditions, and also to compare gait speed during supervised testing with the non-supervised gait speed in every-day life.

Methods: In a controlled observational, cross sectional study thirty subjects with cerebral palsy (CP), with level I&II of the Gross Motor Function Classification System (GMFCS) and 30 healthy control children (Ctrl), aged 3–12 years, were asked to perform a 1-min-walking test (1 mwt) under laboratory conditions, and to wear an accelerometric device for a 1-week wearing home measurement (1 WHM). Acceptance was measured via wearing time, and by a questionnaire in which subjects rated restrictions in their daily living and wearing comfort. In addition, validity of 3D-accelerometric gait speed was checked through gold standard assessment of gait speed with a mobile perambulator.

Results: Wearing time amounted to 10.3 (SD 3.4) hours per day, which was comparable between groups (T = 1.10, P = 0.3). Mode for wearing comfort [CP 1, Range (1,4), Ctrl 1, Range (1,6)] and restriction of daily living [CP 1, Range (1,3), Ctrl 1, Range (1,4)] was comparable between groups. Under laboratory conditions, Ctrl walked faster in the 1 mwt than CP (Ctrl 1.72 ± 0.29 m/s, CP 1.48 ± 0.41 m/s, P = 0.018). Similarly, a statistically significant difference was found when comparing real-world walking speed and laboratory walking speed (CP: 1 mwt 1.48 ± 0.41 m/s, 1 WHM 0.89 ± 0.09 m/s, P = 0.012; Ctrl: 1mwt 1.72 ± 0.29, 1 WHM 0.97 ± 0.06, P < 0.001).

Conclusion: 3D-accelerometry is well-enough accepted in a pediatric population of patients with CP and a Ctrl group to allow valid assessments. Assessment outside the laboratory environment yields information about real world activity that was not captured by routine clinical tests. This suggests that assessment of habitual activities by wearable devices reflects the functioning of children in their home environment. This novel information constitutes an important goal for rehabilitation medicine. The study is registered at the German Register of Clinical Trials with the title “Acceptance and Validity of 3D Accelerometric Gait Analysis in Pediatric Patients” (AVAPed; DRKS00011919).
Selective Treatment of PDA in High-Risk VLBW Infants With Birth Weight ≤800 g or <27 Weeks and Short-Term Outcome: A Cohort Study
Authors: Ibrahim Thowfique , Abdul Haium Abdul Alim , Tapawan Sarah Jane , Dela Puerta Rowena , Allen John C. , Chandran Suresh , Chua Mei Chien , Rajadurai Victor Samuel
Published: January 2021

Background:Patent ductus arteriosus (PDA) causing significant left to right shunt can increase key morbidities in preterm infants. Yet, treatment does not improve outcomes and spontaneous closure is the natural course of PDA. The Impact of PDA on 23–26-week gestation infants is uncertain. Selective treatment of such infants would likely balance outcomes.

Objective:To test the hypothesis that treatment of PDA in high-risk VLBW infants [birth weight ≤800 g or gestation <27 weeks, hemodynamically significant, ductal diameter (DD, ≥1.6 mm), and mechanical ventilation] and expectant management in low-risk infants will reduce the need for treatment and surgical ligation, without altering short term morbidities.

Methods:This prospective observational study was initiated subsequent to the introduction of a new treatment protocol in 2016. The 12-months before and after protocol introduction were, respectively, defined as standard and early selective treatment periods. In the early selective treatment cohort, PDA was treated with indomethacin, maximum of two courses, 1 week apart. Surgical ligation was considered after 30 days of age if indicated (DD ≥2 mm, mechanical ventilation). Primary outcomes were need for treatment and rate of ligation. Protocol compliance and secondary outcomes were documented.

Results:415 infants were studied, 202 and 213 in the standard treatment and early selective treatment cohorts, respectively. Numbers treated (per protocol) in the standard treatment and early selective treatment cohorts were 27.7 and 19.3% (56/202 and 41/213) (p= 0.049), and the respective ligation rates were 7.54 and 2.96% (P= 0.045). Secondary outcomes were comparable.

Conclusion:The early selective treatment protocol reduced the rates of treatment and surgical ligation of PDA, without altering key morbidities. Further studies under a randomized control trial setting is warranted.