bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional and Activation Profiles of Mucosal-Associated Invariant T Cells in Patients With Tuberculosis and HIV in a High Endemic Setting
Authors: Balfour Avuyonke , Schutz Charlotte , Goliath Rene , Wilkinson Katalin A. , Sayed Sumaya , Sossen Bianca , Kanyik Jean-Paul , Ward Amy , Ndzhukule Rhandzu , Gela Anele , Lewinsohn David M. , Lewinsohn Deborah A. , Meintjes Graeme , Shey Muki
Published: March 2021

Background: MAIT cells are non-classically restricted T lymphocytes that recognize and rapidly respond to microbial metabolites or cytokines and have the capacity to kill bacteria-infected cells. Circulating MAIT cell numbers generally decrease in patients with active TB and HIV infection, but findings regarding functional changes differ.

Methods: We conducted a cross-sectional study on the effect of HIV, TB, and HIV-associated TB (HIV-TB) on MAIT cell frequencies, activation and functional profile in a high TB endemic setting in South Africa. Blood was collected from (i) healthy controls (HC, n = 26), 24 of whom had LTBI, (ii) individuals with active TB (aTB, n = 36), (iii) individuals with HIV infection (HIV, n = 50), 37 of whom had LTBI, and (iv) individuals with HIV-associated TB (HIV-TB, n = 26). All TB participants were newly diagnosed and sampled before treatment, additional samples were also collected from 18 participants in the aTB group after 10 weeks of TB treatment. Peripheral blood mononuclear cells (PBMC) stimulated with BCG-expressing GFP (BCG-GFP) and heat-killed (HK) Mycobacterium tuberculosis (M.tb) were analyzed using flow cytometry. MAIT cells were defined as CD3+ CD161+ Vα7.2+ T cells.

Results: Circulating MAIT cell frequencies were depleted in individuals with HIV infection (p = 0.009). MAIT cells showed reduced CD107a expression in aTB (p = 0.006), and reduced IFNγ expression in aTB (p < 0.001) and in HIV-TB (p < 0.001) in response to BCG-GFP stimulation. This functional impairment was coupled with a significant increase in activation (defined by HLA-DR expression) in resting MAIT cells from HIV (p < 0.001), aTB (p = 0.019), and HIV-TB (p = 0.005) patients, and higher HLA-DR expression in MAIT cells expressing IFNγ in aTB (p = 0.009) and HIV-TB (p = 0.002) after stimulation with BCG-GFP and HK-M.tb. After 10 weeks of TB treatment, there was reversion in the observed functional impairment in total MAIT cells, with increases in CD107a (p = 0.020) and IFNγ (p = 0.010) expression.

Conclusions: Frequencies and functional profile of MAIT cells in response to mycobacterial stimulation are significantly decreased in HIV infected persons, active TB and HIV-associated TB, with a concomitant increase in MAIT cell activation. These alterations may reduce the capacity of MAIT cells to play a protective role in the immune response to these two pathogens.
Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome–Results From Open-Label Cyclophosphamide Intervention Study
Authors: Sørland Kari , Sandvik Miriam Kristine , Rekeland Ingrid Gurvin , Ribu Lis , Småstuen Milada Cvancarova , Mella Olav , Fluge Øystein
Published: March 2021

Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide.

Methods: This substudy to the open-label phase II trial “Cyclophosphamide in ME/CFS” included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18–65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30).

Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5–13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7–21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343–4,334) vs. healthy individuals 1,886 p.u. (range 808–8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls.

Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.
Sudden Cardiac Death—A New Insight Into Potentially Fatal Genetic Markers
Authors: Primorac Dragan , Odak Ljubica , Perić Vitorio , Ćatić Jasmina , Šikić Jozica , Radeljić Vjekoslav , Manola Šime , Nussbaum Robert , Vatta Matteo , Aradhya Swaroop , Sofrenović Tanja , Matišić Vid , Molnar Vilim , Skelin Andrea , Mirat Jure , Brachmann Johannes
Published: March 2021

Sudden cardiac death (SCD) is an unexpected and dramatic event. It draws special attention especially in young, seemingly healthy athletes. Our scientific paper is based on the death of a young, 23-year-old professional footballer, who died on the football field after a two-year history of cardiac symptoms. In this study we analyzed clinical, ECG and laboratory data, as well as results of genetic testing analysis in family members. To elucidate potential genetic etiology of SCD in this family, our analysis included 294 genes related to various cardiac conditions.
Livestock Manure Type Affects Microbial Community Composition and Assembly During Composting
Authors: Wan Jinxin , Wang Xiaofang , Yang Tianjie , Wei Zhong , Banerjee Samiran , Friman Ville-Petri , Mei Xinlan , Xu Yangchun , Shen Qirong
Published: March 2021

Composting is an environmentally friendly way to turn plant and animal wastes into organic fertilizers. However, it is unclear to what extent the source of animal waste products (such as manure) affects the physicochemical and microbiological properties of compost. Here, we experimentally tested how the type of livestock manure of herbivores (sheep and cattle) and omnivores (pig and chicken) influences the bacterial and fungal communities and physicochemical properties of compost. Higher pH, NO3-N, Total carbon (TC) content and C/N were found in sheep and cattle manure composts, while higher EC, NH4-N, Total nitrogen (TN) and total phosphorus (TP) content were measured in pig and chicken manure composts. Paired clustering between herbivore and omnivore manure compost metataxonomy composition was also observed at both initial and final phases of composting. Despite this clear clustering, all communities changed drastically during the composting leading to reduced bacterial and fungal diversity and large shifts in community composition and species dominance. While Proteobacteria and Chloroflexi were the major phyla in sheep and cattle manure composts, Firmicutes dominated in pig and chicken manure composts. Together, our results indicate that feeding habits of livestock can determine the biochemical and biological properties of manures, having predictable effects on microbial community composition and assembly during composting. Manure metataxonomy profiles could thus potentially be used to steer and manage composting processes.
Radiomics of Tumor Heterogeneity in Longitudinal Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Predicting Response to Neoadjuvant Chemotherapy in Breast Cancer
Authors: Fan Ming , Chen Hang , You Chao , Liu Li , Gu Yajia , Peng Weijun , Gao Xin , Li Lihua
Published: March 2021

Breast tumor morphological and vascular characteristics can be changed during neoadjuvant chemotherapy (NACT). The early changes in tumor heterogeneity can be quantitatively modeled by longitudinal dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which is useful in predicting responses to NACT in breast cancer. In this retrospective analysis, 114 female patients with unilateral unifocal primary breast cancer who received NACT were included in a development (n = 61) dataset and a testing dataset (n = 53). DCE-MRI was performed for each patient before and after treatment (two cycles of NACT) to generate baseline and early follow-up images, respectively. Feature-level changes (delta) of the entire tumor were evaluated by calculating the relative net feature change (deltaRAD) between baseline and follow-up images. The voxel-level change inside the tumor was evaluated, which yielded a Jacobian map by registering the follow-up image to the baseline image. Clinical information and the radiomic features were fused to enhance the predictive performance. The area under the curve (AUC) values were assessed to evaluate the prediction performance. Predictive models using radiomics based on pre- and post-treatment images, Jacobian maps and deltaRAD showed AUC values of 0.568, 0.767, 0.630 and 0.726, respectively. When features from these images were fused, the predictive model generated an AUC value of 0.771. After adding the molecular subtype information in the fused model, the performance was increased to an AUC of 0.809 (sensitivity of 0.826 and specificity of 0.800), which is significantly higher than that of the baseline imaging- and Jacobian map-based predictive models (p = 0.028 and 0.019, respectively). The level of tumor heterogeneity reduction (evaluated by texture feature) is higher in the NACT responders than in the nonresponders. The results suggested that changes in DCE-MRI features that reflect a reduction in tumor heterogeneity following NACT could provide early prediction of breast tumor response. The prediction was improved when the molecular subtype information was combined into the model.
Neural Correlates of Motor Skill Learning Are Dependent on Both Age and Task Difficulty
Authors: Bootsma Josje M. , Caljouw Simone R. , Veldman Menno P. , Maurits Natasha M. , Rothwell John C. , Hortobágyi Tibor
Published: March 2021

Although a general age-related decline in neural plasticity is evident, the effects of age on neural plasticity after motor practice are inconclusive. Inconsistencies in the literature may be related to between-study differences in task difficulty. Therefore, we aimed to determine the effects of age and task difficulty on motor learning and associated brain activity. We used task-related electroencephalography (EEG) power in the alpha (8–12 Hz) and beta (13–30 Hz) frequency bands to assess neural plasticity before, immediately after, and 24-h after practice of a mirror star tracing task at one of three difficulty levels in healthy younger (19–24 yr) and older (65–86 yr) adults. Results showed an age-related deterioration in motor performance that was more pronounced with increasing task difficulty and was accompanied by a more bilateral activity pattern for older vs. younger adults. Task difficulty affected motor skill retention and neural plasticity specifically in older adults. Older adults that practiced at the low or medium, but not the high, difficulty levels were able to maintain improvements in accuracy at retention and showed modulation of alpha TR-Power after practice. Together, these data indicate that both age and task difficulty affect motor learning, as well as the associated neural plasticity.
Selective Denervation of the Facial Dermato-Muscular Complex in the Rat: Experimental Model and Anatomical Basis
Authors: Tereshenko Vlad , Dotzauer Dominik C. , Maierhofer Udo , Festin Christopher , Luft Matthias , Laengle Gregor , Politikou Olga , Klein Holger J. , Blumer Roland , Aszmann Oskar C. , Bergmeister Konstantin D.
Published: March 2021

The facial dermato-muscular system consists of highly specialized muscles tightly adhering to the overlaying skin and thus form a complex morphological conglomerate. This is the anatomical and functional basis for versatile facial expressions, which are essential for human social interaction. The neural innervation of the facial skin and muscles occurs via branches of the trigeminal and facial nerves. These are also the most commonly pathologically affected cranial nerves, often requiring surgical treatment. Hence, experimental models for researching these nerves and their pathologies are highly relevant to study pathophysiology and nerve regeneration. Experimental models for the distinctive investigation of the complex afferent and efferent interplay within facial structures are scarce. In this study, we established a robust surgical model for distinctive exploration of facial structures after complete elimination of afferent or efferent innervation in the rat. Animals were allocated into two groups according to the surgical procedure. In the first group, the facial nerve and in the second all distal cutaneous branches of the trigeminal nerve were transected unilaterally. All animals survived and no higher burden was caused by the procedures. Whisker pad movements were documented with video recordings 4 weeks after surgery and showed successful denervation. Whole-mount immunofluorescent staining of facial muscles was performed to visualize the innervation pattern of the neuromuscular junctions. Comprehensive quantitative analysis revealed large differences in afferent axon counts in the cutaneous branches of the trigeminal nerve. Axon number was the highest in the infraorbital nerve (28,625 ± 2,519), followed by the supraorbital nerve (2,131 ± 413), the mental nerve (3,062 ± 341), and the cutaneous branch of the mylohyoid nerve (343 ± 78). Overall, this surgical model is robust and reliable for distinctive surgical deafferentation or deefferentation of the face. It may be used for investigating cortical plasticity, the neurobiological mechanisms behind various clinically relevant conditions like facial paralysis or trigeminal neuralgia as well as local anesthesia in the face and oral cavity.
Single Cell Transcriptome Data Analysis Defines the Heterogeneity of Peripheral Nerve Cells in Homeostasis and Regeneration
Authors: Chen Bing , Banton Matthew C. , Singh Lolita , Parkinson David B. , Dun Xin-peng
Published: March 2021

The advances in single-cell RNA sequencing technologies and the development of bioinformatics pipelines enable us to more accurately define the heterogeneity of cell types in a selected tissue. In this report, we re-analyzed recently published single-cell RNA sequencing data sets and provide a rationale to redefine the heterogeneity of cells in both intact and injured mouse peripheral nerves. Our analysis showed that, in both intact and injured peripheral nerves, cells could be functionally classified into four categories: Schwann cells, nerve fibroblasts, immune cells, and cells associated with blood vessels. Nerve fibroblasts could be sub-clustered into epineurial, perineurial, and endoneurial fibroblasts. Identified immune cell clusters include macrophages, mast cells, natural killer cells, T and B lymphocytes as well as an unreported cluster of neutrophils. Cells associated with blood vessels include endothelial cells, vascular smooth muscle cells, and pericytes. We show that endothelial cells in the intact mouse sciatic nerve have three sub-types: epineurial, endoneurial, and lymphatic endothelial cells. Analysis of cell type-specific gene changes revealed that Schwann cells and endoneurial fibroblasts are the two most important cell types promoting peripheral nerve regeneration. Analysis of communication between these cells identified potential signals for early blood vessel regeneration, neutrophil recruitment of macrophages, and macrophages activating Schwann cells. Through this analysis, we also report appropriate marker genes for future single cell transcriptome data analysis to identify cell types in intact and injured peripheral nerves. The findings from our analysis could facilitate a better understanding of cell biology of peripheral nerves in homeostasis, regeneration, and disease.
Transient Astrocytic Gq Signaling Underlies Remote Memory Enhancement
Authors: Iwai Youichi , Ozawa Katsuya , Yahagi Kazuko , Mishima Tsuneko , Akther Sonam , Vo Camilla Trang , Lee Ashley Bomin , Tanaka Mika , Itohara Shigeyoshi , Hirase Hajime
Published: March 2021

Astrocytes elicit transient Ca2+ elevations induced by G protein-coupled receptors (GPCRs), yet their role in vivo remains unknown. To address this, transgenic mice with astrocytic expression of the optogenetic Gq-type GPCR, Optoα1AR, were established, in which transient Ca2+ elevations similar to those in wild type mice were induced by brief blue light illumination. Activation of cortical astrocytes resulted in an adenosine A1 receptor-dependent inhibition of neuronal activity. Moreover, sensory stimulation with astrocytic activation induced long-term depression of sensory evoked response. At the behavioral level, repeated astrocytic activation in the anterior cortex gradually affected novel open field exploratory behavior, and remote memory was enhanced in a novel object recognition task. These effects were blocked by A1 receptor antagonism. Together, we demonstrate that GPCR-triggered Ca2+ elevation in cortical astrocytes has causal impacts on neuronal activity and behavior.
Is Fluoxetine Good for Subacute Stroke? A Meta-Analysis Evidenced From Randomized Controlled Trials
Authors: Liu Guangjie , Yang Xingyu , Xue Tao , Chen Shujun , Wu Xin , Yan Zeya , Wang Zilan , Wu Da , Chen Zhouqing , Wang Zhong
Published: March 2021

Background and Purpose:Fluoxetine is a drug commonly used to treat mental disorders, such as depression and obsessive–compulsive disorder, and some studies have shown that fluoxetine can improve motor and function recovery after stroke. Therefore, we performed a meta-analysis to investigate the efficacy and safety of fluoxetine in the treatment of post-stroke neurological recovery.

Methods:PubMed, Embase, and Cochrane Library were searched for randomized controlled trials (RCTs) that were performed to assess the efficacy and safety of fluoxetine for functional and motor recovery in subacute stroke patients up to October 2020. Review Manager 5.3 software was used to assess the data. The risk ratio (RR) and standardized mean difference (SMD) were analyzed and calculated with a fixed effects model.

Results:We pooled 6,788 patients from nine RCTs. The primary endpoint was modified Rankin Scale (mRS). Fluoxetine did not change the proportion of mRS ≤ 2 (P= 0.47). The secondary endpoints were Fugl-Meyer Motor Scale (FMMS), Barthel Index (BI), and National Institutes of Health Stroke Scale (NIHSS). Fluoxetine improved the FMMS (P< 0.00001) and BI(P< 0.0001) and showed a tendency of improving NIHSS (P= 0.08). In addition, we found that fluoxetine reduced the rate of new-onset depression (P< 0.0001) and new antidepressants (P< 0.0001).

Conclusion:In post-stroke treatment, fluoxetine did not improve participants' mRS and NIHSS but improved FMMS and BI. This difference could result from heterogeneities between the trials: different treatment duration, clinical scales sensitivity, patient age, delay of inclusion, and severity of the deficit.
Clinical and Radiological Characteristics of Acute Cerebrovascular Diseases Among Egyptian Patients With COVID-19 in Upper Egypt
Authors: Khedr Eman M. , Soliman Radwa K. , Abo-Elfetof Noha , Amin Mariam , Mansour Ossama Yassin , Aly Ahmed , Zaki Ahmed F. , Saber Mostafa
Published: March 2021

Background and Purpose: There is little information on the acute cerebrovascular complications of coronavirus disease 2019 (COVID-19) in Egypt. The aim of this study was to estimate the proportion of acute cerebrovascular disease (CVD) among COVID-19 patients and evaluate their clinical and radiological characteristics in comparison with non-COVID-19 CVD.

Materials and Methods: In a retrospective study, COVID-19 patients whom presented with CVD in Assiut and Aswan University Hospitals were compared with non-COVID-19, CVD patients, admitted to Qena University Hospital, prior to the pandemic. The following data were collected: clinical history and presentation, risk factors, comorbidities, brain imaging (MRI or CT), chest CT, and some laboratory investigations.

Results: Fifty-five (12.5%) of the 439 patients with COVID-19 had acute CVD. Of them, 42 (9.6%) had ischemic stroke while 13 patients (2.9%) had hemorrhagic CVD. In the 250 cases of the non-COVID-19 group, 180 had ischemic stroke and 70 had hemorrhagic stroke. A large proportion of patients with COVID-19 who presented with ischemic stroke had large vessel occlusion (LVO), which was significantly higher than in non-COVID-19 patients with CVD (40 vs. 7.2%, P < 0.001). Comorbidities were recorded in 44 (80%) cases. In COVID-19 ischemic stroke patients, risk factors [hypertension and ischemic heart disease (IHD)] and comorbidities (hepatic and renal) were significantly higher than those in non–COVID-19 patients. In addition, 23.5% had hemorrhagic CVD, and six patients with LVO developed hemorrhagic transformation.

Conclusion: Acute CVD among patients with COVID-19 was common in our study. LVO was the commonest. Hypertension, IHD, and anemia are the most common risk factors and could contribute to the worsening of clinical presentation. Comorbidities were common among patients with CVD, although a large number had elevated liver enzymes and creatinine that were partially due to COVID-19 infection itself. The current results begin to characterize the spectrum of CVD associated with COVID-19 in patients in Upper Egypt.

Registration ID: The ID number of this study is IRB no: 17300470.
Critical Dynamics in Spontaneous Resting-State Oscillations Are Associated With the Attention-Related P300 ERP in a Go/Nogo Task
Authors: Herzog Nadine D. , Steinfath Tim P. , Tarrasch Ricardo
Published: March 2021

Sustained attention is the ability to continually concentrate on task-relevant information, even in the presence of distraction. Understanding the neural mechanisms underlying this ability is critical for comprehending attentional processes as well as neuropsychiatric disorders characterized by attentional deficits, such as attention deficit hyperactivity disorder (ADHD). In this study, we aimed to investigate how trait-like critical oscillations during rest relate to the P300 evoked potential—a biomarker commonly used to assess attentional deficits. We measured long−range temporal correlations (LRTC) in resting-state EEG oscillations as index for criticality of the signal. In addition, the attentional performance of the subjects was assessed as reaction time variability (RTV) in a continuous performance task following an oddball paradigm. P300 amplitude and latencies were obtained from EEG recordings during this task. We found that, after controlling for individual variability in task performance, LRTC were positively associated with P300 amplitudes but not latencies. In line with previous findings, good performance in the sustained attention task was related to higher P300 amplitudes and earlier peak latencies. Unexpectedly, we observed a positive relationship between LRTC in ongoing oscillations during rest and RTV, indicating that greater criticality in brain oscillations during rest relates to worse task performance. In summary, our results show that resting-state neuronal activity, which operates near a critical state, relates to the generation of higher P300 amplitudes. Brain dynamics close to criticality potentially foster a computationally advantageous state which promotes the ability to generate higher event-related potential (ERP) amplitudes.
Additive Effects of Environmental Enrichment and Ketamine on Neuropathic Pain Relief by Reducing Glutamatergic Activation in Spinal Cord Injury in Rats
Authors: Tai W. L. , Sun L. , Li H. , Gu P. , Joosten E. A. , Cheung C. W.
Published: March 2021

Spinal cord injury (SCI) impairs mobility and often results in complications like intractable neuropathic pain. A multi-approach management of this chronic pain condition has been encouraged, but little has been explored of the field. Here, we focus on the effect and underlying mechanism of environmental enrichment (EE), which promotes voluntary social and physical activities, combined with a clinical analgesic, ketamine, on SCI-induced neuropathic pain as well as motor dysfunction. We performed T13 spinal hemisection in rats, which induced unilateral motor impairment and neuropathic pain-like behaviors in the hindlimb. Treatment regimen started a week after SCI, which consists of ketamine administration (30 mg kg–1day–1; intramuscular) for 10 days, or EE housing for 20 days, or their combination. Paw withdrawal response to mechanical and thermal stimuli, motor function, burrowing behaviors, and body weight was monitored. Spinal segments at T13 lesion and L4–L6 were collected for histopathological and protein analyses. The joint treatment of EE and ketamine provided greater relief of pain-like behaviors and locomotor recovery than did either paradigm alone. These improvements were associated with reduced cavitation area, astrogliosis, and perilesional phosphorylation of glutamateN-methyl-D-aspartate receptor (NMDAR). Concurrently, lumbar spinal analysis of NMDAR-linked excitatory markers in hypersensitization showed reduced activation of NMDAR, mitogen-activated protein kinase (MAPK) family, nuclear factor (NF)-κB, interleukin (IL)-1β signaling, and restored excitatory amino acid transporter 2 level. Our data support a better therapeutic efficacy of the combination, EE, and ketamine, in the attenuation of neuropathic pain and motor recovery by reducing spinal glutamatergic activation, signifying a potential multifaceted neurorehabilitation strategy to improve SCI patient outcome.
Orexin/Hypocretin and MCH Neurons: Cognitive and Motor Roles Beyond Arousal
Authors: Concetti Cristina , Burdakov Denis
Published: March 2021

The lateral hypothalamus (LH) is classically implicated in sleep-wake control. It is the main source of orexin/hypocretin and melanin-concentrating hormone (MCH) neuropeptides in the brain, which have been both implicated in arousal state switching. These neuropeptides are produced by non-overlapping LH neurons, which both project widely throughout the brain, where release of orexin and MCH activates specific postsynaptic G-protein-coupled receptors. Optogenetic manipulations of orexin and MCH neurons during sleep indicate that they promote awakening and REM sleep, respectively. However, recordings from orexin and MCH neurons in awake, moving animals suggest that they also act outside sleep/wake switching. Here, we review recent studies showing that both orexin and MCH neurons can rapidly (sub-second-timescale) change their firing when awake animals experience external stimuli, or during self-paced exploration of objects and places. However, the sensory-behavioral correlates of orexin and MCH neural activation can be quite different. Orexin neurons are generally more dynamic, with about 2/3rds of them activated before and during self-initiated running, and most activated by sensory stimulation across sensory modalities. MCH neurons are activated in a more select manner, for example upon self-paced investigation of novel objects and by certain other novel stimuli. We discuss optogenetic and chemogenetic manipulations of orexin and MCH neurons, which combined with pharmacological blockade of orexin and MCH receptors, imply that these rapid LH dynamics shape fundamental cognitive and motor processes due to orexin and MCH neuropeptide actions in the awake brain. Finally, we contemplate whether the awake control of psychomotor brain functions by orexin and MCH are distinct from their “arousal” effects.
Nigral Iron Deposition Is Associated With Levodopa-Induced Dyskinesia in Parkinson’s Disease
Authors: Song Tianbin , Li Jiping , Mei Shanshan , Jia Xiaofei , Yang Hongwei , Ye Yongquan , Yuan Jianmin , Zhang Yuqing , Lu Jie
Published: March 2021

Objective

To investigate iron deposition in the substantia nigra (SN) of Parkinson’s disease (PD) patients associated with levodopa-induced dyskinesia (LID).

Methods

Seventeen PD patients with LID, 17 PD patients without LID, and 16 healthy controls were recruited for this study. The mean QSM values of the whole, left, and right SN were compared among the three groups. A multivariate logistic regression model was constructed to determine the factors associated with increased risk of LID. The receiver operating characteristic curve of the QSM value of SN in discriminating PD with and without LID was evaluated.

Results

The mean QSM values of the whole and right SN in the PD with LID were higher than those in the PD without LID (∗P = 0.03, ∗P = 0.03). Multivariate logistic regression analysis revealed that the QSM value of whole, left, or right SN was a predictor of the development of LID (∗P = 0.03, ∗P = 0.04, and ∗P = 0.04). The predictive accuracy of LID in adding the QSM value of the whole, left, and right SN to LID-related clinical risk factors was 70.6, 64.7, and 67.6%, respectively. The QSM cutoff values between PD with and without LID of the whole, left, and right SN were 148.3, 165.4, and 152.7 ppb, respectively.

Conclusion

This study provides the evidence of higher iron deposition in the SN of PD patients with LID than those without LID, suggesting that the QSM value of the SN may be a potential early diagnostic neuroimaging biomarker for LID.
Regional Variations of Insulin Secretion and Insulin Sensitivity in Japanese Participants With Normal Glucose Tolerance
Authors: Watanabe Kiriko , Higa Moritake , Hasegawa Yoshimasa , Kudo Akihiro , Allsopp Richard C. , Willcox Bradley J. , Willcox Donald C. , Sata Masataka , Masuzaki Hiroaki , Shimabukuro Michio
Published: March 2021

Purpose: Regional differences in dietary patterns in Asian countries might affect the balance of insulin response and sensitivity. However, this notion is yet to be validated. To clarify the regional differences in the insulin response and sensitivity and their relationship to nutrients, we compared the insulin secretory response during an oral glucose tolerance test in Japanese participants.

Methods: This observational retrospective cohort study analyzed the data from participants with normal glucose tolerance (NGT) from four distinct areas of Japan with regard to the food environment: Fukushima, Nagano, Tokushima, and Okinawa based on data available in the Japanese National Health Insurance database.

Results: Although the glucose levels were comparable among the four regions, the insulin responses were significantly different among the regions. This difference was observed even within the same BMI category. The plot between the insulin sensitivity index (Matsuda index) and insulinAUC/glucoseAUC or the insulinogenic index showed hyperbolic relationships with variations in regions. The indices of insulin secretion correlated positively with fat intake and negatively with the intake of fish, carbohydrate calories, and dietary fiber.

Conclusions: We found that significant regional differences in insulin response and insulin sensitivity in Japanese participants and that nutritional factors may be linked to these differences independently of body size/adiposity. Insulin response and insulin sensitivity can vary among adult individuals, even within the same race and the same country, and are likely affected by environmental/lifestyle factors as well as genetic traits.
Bronchial Washing Fluid Versus Plasma and Bronchoscopy Biopsy Samples for Detecting Epidermal Growth Factor Receptor Mutation Status in Lung Cancer
Authors: Zhang Xinyu , Li Chun , Ye Maosong , Hu Qin , Hu Jie , Gong Ziying , Li Jieyi , Zhao Xiaokai , Xu Yiqing , Zhang Daoyun , Hou Yingyong , Zhang Xin
Published: March 2021

Background

Bronchial washing fluid (BWF) is a common specimen collected during bronchoscopy and has been suggested to contain both tumor cells and cell-free DNA. However, there is no consensus on the feasibility of BWF in epidermal growth factor receptor (EGFR) genetic analysis because of the limited sample size and varying results in previous studies. This study compared the feasibility, sensitivity, and specificity of detecting EGFR mutation using BWF, bronchoscopy biopsy, and plasma samples in patients with lung cancer (LC).

Materials and Methods

A total of 144 patients (110 with LC and 34 without LC) were enrolled in the study. During diagnostic bronchoscopy for suspected LC lesions, bronchial washing with saline was performed directly or through a guide sheath. BWF was collected as well as paired bronchoscopy biopsy and plasma samples, and EGFR mutation testing was performed via highly sensitive blocker polymerase chain reaction. The EGFR mutation status of histologic samples was set as the standard reference.

Results

Compared with the histologic samples, the sensitivity, specificity, and concordance rate of EGFR mutation detected in BWF samples were 92.5%, 100%, and 97.9%, respectively. Moreover, BWF showed a higher sensitivity in EGFR mutation testing than both plasma (100% [8/8] vs. 62.5% [5/8], p = 0.095) and bronchoscopy biopsy samples (92.5% [37/40] vs. 77.5% [31/40], p = 0.012) and identified EGFR mutations in 6 cases whose biopsy failed to establish an LC diagnosis. The diameter of the target lesion and its contact degree with BWF were positive predictive factors for EGFR testing results.

Conclusions

BWF yields a high sensitivity in EGFR mutation testing, having high concordance with histologic samples, and presenting the benefit of rapid EGFR mutation detection in LC patients.
M2 Macrophage Co-Expression Factors Correlate With Immune Phenotype and Predict Prognosis of Bladder Cancer
Authors: Wang Yutao , Yan Kexin , Wang Jianfeng , Lin Jiaxing , Bi Jianbin
Published: March 2021

Purpose

Therapeutic targets of tumor-associated macrophages have been discovered and used clinically as immunotherapy. M2 macrophages are tumor-associated macrophages that promote cancer progression. This article explores the related factors and the effects of type M2 macrophages.

Method

We obtained bladder cancer (BC) sequencing data from TCGA and GSE31189. We used the CIBERSORT algorithm calculate M2 macrophage proportions among 22 type immune cells. The Estimate package was used to measure BC purity. M2 macrophage-related genes were selected using WGCNA. Receiver operating characteristic curves and Kaplan–Meier analyses were performed to determine the risk score, conducted for M2 macrophage-related factors. The Pearson test was used to determine the correlation among M2 macrophage-related genes, clinical phenotype, immune phenotype and tumor mutation burden (TMB). The TIMER database was used to calculate correlations among M2 macrophages and other cancers.

Results

Expression of four M2 macrophages co-expressed genes (CD163, CD209, CSF1, MMD) positively correlated with infiltration of M2 macrophages, which were enriched in the negative regulation of immune system process and the positive regulation of tumor necrosis factor production. M2 macrophage-related factors are robust biomarkers for predicting the BC and immune phenotypes. The Cox regression model built on these four co-expression factors showed a close correlation with outcome (AUC = 0.64). The four co-expression factors negatively correlated outcome and TMB.

Conclusion

Four co-expressed genes promote high levels of infiltration of type M2 macrophages in the negative regulation of immune system processes and the positive regulation of tumor necrosis factor production processes. These co-expressed genes and the biological process they involve might suggest new strategies for regulation of chemotaxis in M2 macrophages.
Relationship Between Urinary 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol and Lung Cancer Risk in the General Population: A Community-Based Prospective Cohort Study
Authors: Park Eun Young , Lim Min Kyung , Park Eunjung , Oh Jin-Kyoung , Lee Do-Hoon
Published: March 2021

No published studies have prospectively evaluated the association between urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) levels and lung cancer risk in the general population. Here, we conducted a prospective community-based cohort study in the Republic of Korea to evaluate the relationship between urinary NNAL levels and lung cancer risk using prediagnostic urine samples. This prospective cohort study was based on the Korean National Cancer Center Community Cohort. During the follow-up period, 173 primary lung cancer cases were identified. Total urinary NNAL levels were measured by liquid chromatography-tandem mass spectrometry, and data were analyzed using multivariable Cox proportional hazards regression models. The risk of lung cancer was significantly increased per unit of natural log-transformed urinary NNAL (HR, 1.27; 95% CI, 1.09–1.48), after adjusting for age, region, entry year into the cohort, education achievement, alcohol consumption status, BMI, smoking status, and urinary cotinine levels. Cox proportional-hazards models with NNAL quartiles also showed positive dose-response relationships with risk of lung cancer. A significantly increased risk of lung cancer was found in the fourth quartile of urinary NNAL levels (HR, 3.27; 95% CI, 1.37–7.79, P for trend < 0.01). After stratification with sex, the significant association remained in only men. Urinary NNAL levels are associated with the risk of lung cancer in the general population, and this association is independent from the quantification of cigarette smoking and nicotine uptake.
Seizures, Edema, Thrombosis, and Hemorrhages: An Update Review on the Medical Management of Gliomas
Authors: Zoccarato Marco , Nardetto Lucia , Basile Anna Maria , Giometto Bruno , Zagonel Vittorina , Lombardi Giuseppe
Published: March 2021

Patients affected with gliomas develop a complex set of clinical manifestations that deeply impact on quality of life and overall survival. Brain tumor-related epilepsy is frequently the first manifestation of gliomas or may occur during the course of disease; the underlying mechanisms have not been fully explained and depend on both patient and tumor factors. Novel treatment options derive from the growing use of third-generation antiepileptic drugs. Vasogenic edema and elevated intracranial pressure cause a considerable burden of symptoms, especially in high-grade glioma, requiring an adequate use of corticosteroids. Patients with gliomas present with an elevated risk of tumor-associated venous thromboembolism whose prophylaxis and treatment are challenging, considering also the availability of new oral anticoagulant drugs. Moreover, intracerebral hemorrhages can complicate the course of the illness both due to tumor-specific characteristics, patient comorbidities, and side effects of antithrombotic and antitumoral therapies. This paper aims to review recent advances in these clinical issues, discussing the medical management of gliomas through an updated literature review.
Review of MR-Guided Radiotherapy for Esophageal Cancer
Authors: Lee Sangjune Laurence , Bassetti Michael , Meijer Gert J. , Mook Stella
Published: March 2021

In this review, we outline the potential benefits and the future role of MRI and MR-guided radiotherapy (MRgRT) in the management of esophageal cancer. Although not currently used in most clinical practice settings, MRI is a useful non-invasive imaging modality that provides excellent soft tissue contrast and the ability to visualize cancer physiology. Chemoradiation therapy with or without surgery is essential for the management of locally advanced esophageal cancer. MRI can help stage esophageal cancer, delineate the gross tumor volume (GTV), and assess the response to chemoradiotherapy. Integrated MRgRT systems can help overcome the challenge of esophageal motion due to respiratory motion by using real-time imaging and tumor tracking with respiratory gating. With daily on-table MRI, shifts in tumor position and tumor regression can be taken into account for online-adaptation. The combination of accurate GTV visualization, respiratory gating, and online adaptive planning, allows for tighter treatment volumes and improved sparing of the surrounding normal organs. This could lead to a reduction in radiotherapy induced cardiac toxicity, pneumonitis and post-operative complications. Tumor physiology as seen on diffusion weighted imaging or dynamic contrast enhancement can help individualize treatments based on the response to chemoradiotherapy. Patients with a complete response on MRI can be considered for organ preservation while patients with no response can be offered an earlier resection. In patients with a partial response to chemoradiotherapy, areas of residual cancer can be targeted for dose escalation. The tighter and more accurate targeting enabled with MRgRT may enable hypofractionated treatment schedules.
High BLM Expression Predicts Poor Clinical Outcome and Contributes to Malignant Progression in Human Cholangiocarcinoma
Authors: Du Xiaolong , Zhang Chen , Yin Chuanzheng , Wang Wenjie , Yan Xueke , Xie Dawei , Zheng Xichuan , Zheng Qichang , Li Min , Song Zifang
Published: March 2021

Molecular mechanisms underlying the tumorigenesis of a highly malignant cancer, cholangiocarcinoma (CCA), are still obscure. In our study, the CCA expression profile data were acquired from The Cancer Genome Atlas (TCGA) database, and differentially expressed genes (DEGs) in the TCGA-Cholangiocarcinoma (TCGA-CHOL) data set were utilized to construct a co-expression network via weighted gene co-expression network analysis (WGCNA). The blue gene module associated with the histopathologic grade of CCA was screened. Then, five candidate hub genes were screened by combining the co-expression network with protein–protein interaction (PPI) network. After progression and survival analyses, bloom syndrome helicase (BLM) was ultimately identified as a real hub gene. Moreover, the receiver operating characteristic (ROC) curve analysis suggested that BLM had a favorable diagnostic and predictive recurrence value for CCA. The gene set enrichment analysis (GSEA) results for a single hub gene revealed the importance of cell cycle-related pathways in the CCA progression and prognosis. Furthermore, we detected the BLM expression in vitro, and the results demonstrated that the expression level of BLM was much higher in the CCA tissues and cells relative to adjacent non-tumor samples and normal bile duct epithelial cells. Additionally, after further silencing the BLM expression by small interfering RNA (siRNA), the proliferation and migration ability of CCA cells were all inhibited, and the cell cycle was arrested. Altogether, a real hub gene (BLM) and cell cycle-related pathways were identified in the present study, and the gene BLM may be involved in the CCA progression and could act as a reliable biomarker for potential diagnosis and prognostic evaluation.
Restoring Tissue Homeostasis at Metastatic Sites: A Focus on Extracellular Vesicles in Bone Metastasis
Authors: Giannandrea Domenica , Citro Valentina , Lesma Elena , Bignotto Monica , Platonova Natalia , Chiaramonte Raffaella
Published: March 2021

Bone is the most common site of cancer metastasis and the spread of cancer cells to the bone is associated with poor prognosis, pain, increased risk of fractures, and hypercalcemia. The bone marrow microenvironment is an attractive place for tumor dissemination, due to the dynamic network of non-malignant cells. In particular, the alteration of the bone homeostasis favors the tumor homing and the consequent osteolytic or osteoblastic lesions. Extracellular vesicles (EVs) are reported to be involved in the metastatic process, promoting tumor invasion, escape from immune surveillance, extravasation, extracellular matrix remodeling, and metastasis, but the role of EVs in bone metastases is still unclear. Current results suggest the ability of tumor derived EVs in promoting bone localization and metastasis formation, altering the physiological balance between bone destruction and new bone depositions. Moreover, EVs from the bone marrow niche may support the onset of tumor metastasis. This review summarizes recent findings on the role of EVs in the pathological alterations of homeostasis that occur during bone metastasis to show novel potential EV-based therapeutic options to inhibit metastasis formation.
Genetic and Non-genetic Workup for Pediatric Congenital Hearing Loss
Authors: Belcher Ryan , Virgin Frank , Duis Jessica , Wootten Christopher
Published: March 2021

Hearing loss is one of the most common concerns for presentation for a geneticist. Presentation prior to the age of one (congenital hearing loss), profound sensorineural hearing loss (SNHL), and bilateral hearing loss are sensitive and should raise concern for genetic causes of hearing loss and prompt referral for genetic testing. Genetic testing particularly in this instance offers the opportunity for anticipatory guidance including possible course of the hearing loss over time and also connection and evaluation for additional congenital anomalies that may be associated with an underlying syndrome vs. isolated genetic hearing loss.
Feasibility of Doppler Ultrasound for Cortical Cerebral Blood Flow Velocity Monitoring During Major Non-cardiac Surgery of Newborns
Authors: Costerus Sophie A. , Kortenbout Anna J. , Vos Hendrik J. , Govaert Paul , Tibboel Dick , Wijnen René M. H. , de Jong Nico , Bosch Johan G. , de Graaff Jurgen C.
Published: March 2021

Background and Aim: Newborns needing major surgical intervention are at risk of brain injury and impaired neurodevelopment later in life. Disturbance of cerebral perfusion might be an underlying factor. This study investigates the feasibility of serial transfontanellar ultrasound measurements of the pial arteries during neonatal surgery, and whether perioperative changes in cerebral perfusion can be observed and related to changes in the perioperative management.

Methods: In this prospective, observational feasibility study, neonates with congenital diaphragmatic hernia and esophageal atresia scheduled for surgical treatment within the first 28 days of life were eligible for inclusion. We performed transfontanellar directional power Doppler and pulsed wave Doppler ultrasound during major high-risk non-cardiac neonatal surgery. Pial arteries were of interest for the measurements. Extracted Doppler ultrasound parameters were: peak systolic velocity, end diastolic velocity, the resistivity index and pulsatility index.

Results: In 10 out of 14 patients it was possible to perform perioperative measurements; the others failed for logistic and technical reasons. In 6 out of 10 patients, it was feasible to perform serial intraoperative transfontanellar ultrasound measurements with directional power Doppler and pulsed wave Doppler of the same pial artery during neonatal surgery. Median peak systolic velocity was ranging between 5.7 and 7.0 cm s−1 and end diastolic velocity between 1.9 and 3.2 cm s−1. In patients with a vasoactive-inotropic score below 12 the trend of peak systolic velocity and end diastolic velocity corresponded with the mean arterial blood pressure trend.

Conclusion: Perioperative transfontanellar ultrasound Doppler measurements of the pial arteries are feasible and provide new longitudinal data about perioperative cortical cerebral blood flow velocity.

Trial Registration:https://www.trialregister.nl/trial/6972, identifier: NL6972.