Publications by authors named "Ge Tan"

80 Publications

Reduced CXCL4/PF4 expression as a driver of increased human hematopoietic stem and progenitor cell proliferation in polycythemia vera.

Blood Cancer J 2021 Feb 11;11(2):31. Epub 2021 Feb 11.

Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1038/s41408-021-00423-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878875PMC
February 2021

Inhibition of CpG methylation improves the barrier integrity of bronchial epithelial cells in asthma.

Allergy 2020 Nov 19. Epub 2020 Nov 19.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.

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http://dx.doi.org/10.1111/all.14667DOI Listing
November 2020

Microstructural features of the cerebral cortex: Implications for predicting epilepsy relapse after drug withdrawal.

Brain Res 2021 Jan 6;1751:147200. Epub 2020 Nov 6.

From the Epilepsy Center, Department of Neurology, West China Hospital, Sichuan University, No. 37, Guoxue Road, Chengdu 610041, Sichuan Province, China. Electronic address:

A considerable portion of patients with well-controlled seizures and visually normal brain structures experience seizure recurrence after anti-seizure medication is withdrawn. Microstructural abnormalities of the cortex may play an essential role in epilepsy relapse. Patients with idiopathic/cryptogenic epilepsy were registered. At the follow-up endpoint, 18 patients with relapse (PR+ group), 20 patients without relapse (PR- group), and 30 healthy controls were included. High-resolution T1-weighted images were obtained at the time of drug withdrawal. Microstructural features including cortical thickness, surface area, cortical volume and mean curvature in 68 cortical areas were calculated. A general linear model was applied to investigate intergroup differences, and then post hoc analysis was performed. Additionally, factor analysis was conducted to extract components from imaging measures showing a difference between PR- and PR+ groups, and independent associations between components and epilepsy relapse were assessed using a logistic regression model. Cortical thickness of the left paracentral lobule, left temporal pole and right superior frontal gyrus; surface area of the bilateral lingual gyrus and bilateral pericalcarine cortex; and cortical volume of the bilateral pericalcarine cortex had significant intergroup differences (false discovery rate correction, P < 0.05). All measures, except for cortical thickness of the left temporal pole, showed differences between PR- and PR+ groups. Two dominant components were extracted from these measures, and both were independently associated with epilepsy relapse. In conclusion, epilepsy patients with relapse presented distinct microstructural features of cortex at the time of drug withdrawal, which may serve as a potential biomarker for predicting seizure recurrence.
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http://dx.doi.org/10.1016/j.brainres.2020.147200DOI Listing
January 2021

Hemolysis transforms liver macrophages into antiinflammatory erythrophagocytes.

J Clin Invest 2020 10;130(10):5576-5590

Division of Internal Medicine and.

During hemolysis, macrophages in the liver phagocytose damaged erythrocytes to prevent the toxic effects of cell-free hemoglobin and heme. It remains unclear how this homeostatic process modulates phagocyte functions in inflammatory diseases. Using a genetic mouse model of spherocytosis and single-cell RNA sequencing, we found that erythrophagocytosis skewed liver macrophages into an antiinflammatory phenotype that we defined as MarcohiHmoxhiMHC class IIlo erythrophagocytes. This phenotype transformation profoundly mitigated disease expression in a model of an anti-CD40-induced hyperinflammatory syndrome with necrotic hepatitis and in a nonalcoholic steatohepatitis model, representing 2 macrophage-driven sterile inflammatory diseases. We reproduced the antiinflammatory erythrophagocyte transformation in vitro by heme exposure of mouse and human macrophages, yielding a distinctive transcriptional signature that segregated heme-polarized from M1- and M2-polarized cells. Mapping transposase-accessible chromatin in single cells by sequencing defined the transcription factor NFE2L2/NRF2 as a critical driver of erythrophagocytes, and Nfe2l2/Nrf2 deficiency restored heme-suppressed inflammation. Our findings point to a pathway that regulates macrophage functions to link erythrocyte homeostasis with innate immunity.
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http://dx.doi.org/10.1172/JCI137282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524492PMC
October 2020

Clinical, radiological, and laboratory characteristics and risk factors for severity and mortality of 289 hospitalized COVID-19 patients.

Allergy 2021 02 24;76(2):533-550. Epub 2020 Aug 24.

Department of Allergology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Background: The coronavirus disease 2019 (COVID-19) has become a global pandemic, with 10%-20% of severe cases and over 508 000 deaths worldwide.

Objective: This study aims to address the risk factors associated with the severity of COVID-19 patients and the mortality of severe patients.

Methods: 289 hospitalized laboratory-confirmed COVID-19 patients were included in this study. Electronic medical records, including patient demographics, clinical manifestation, comorbidities, laboratory tests results, and radiological materials, were collected and analyzed. According to the severity and outcomes of the patients, they were divided into three groups: nonsurvived (n = 49), survived severe (n = 78), and nonsevere (n = 162) groups. Clinical, laboratory, and radiological data were compared among these groups. Principal component analysis (PCA) was applied to reduce the dimensionality and visualize the patients on a low-dimensional space. Correlations between clinical, radiological, and laboratory parameters were investigated. Univariate and multivariate logistic regression methods were used to determine the risk factors associated with mortality in severe patients. Longitudinal changes of laboratory findings of survived severe cases and nonsurvived cases during hospital stay were also collected.

Results: Of the 289 patients, the median age was 57 years (range, 22-88) and 155 (53.4%) patients were male. As of the final follow-up date of this study, 240 (83.0%) patients were discharged from the hospital and 49 (17.0%) patients died. Elder age, underlying comorbidities, and increased laboratory variables, such as leukocyte count, neutrophil count, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), procalcitonin (PCT), D-dimer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood urea nitrogen (BUN) on admission, were found in survived severe cases compared to nonsevere cases. According to the multivariate logistic regression analysis, elder age, a higher number of affected lobes, elevated CRP levels on admission, increased prevalence of chest tightness/dyspnea, and smoking history were independent risk factors for death of severe patients. A trajectory in PCA was observed from "nonsevere" toward "nonsurvived" via "severe and survived" patients. Strong correlations between the age of patients, the affected lobe numbers, and laboratory variables were identified. Dynamic changes of laboratory findings of survived severe cases and nonsurvived cases during hospital stay showed that continuing increase of leukocytes and neutrophil count, sustained lymphopenia and eosinopenia, progressing decrease in platelet count, as well as high levels of NLR, CRP, PCT, AST, BUN, and serum creatinine were associated with in-hospital death.

Conclusions: Survived severe and nonsurvived COVID-19 patients had distinct clinical and laboratory characteristics, which were separated by principle component analysis. Elder age, increased number of affected lobes, higher levels of serum CRP, chest tightness/dyspnea, and smoking history were risk factors for mortality of severe COVID-19 patients. Longitudinal changes of laboratory findings may be helpful in predicting disease progression and clinical outcome of severe patients.
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http://dx.doi.org/10.1111/all.14496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404752PMC
February 2021

Clinical and electroencephalographic features of benign childhood epilepsy with centrotemporal spikes comorbidity with attention-deficit hyperactivity disorder in Southwest China.

Epilepsy Behav 2020 10 27;111:107240. Epub 2020 Jun 27.

Department of Neurology, West China Hospital, Sichuan University, Wai Nan Guo Xue Lane 37#, Chengdu, Sichuan 610041, China. Electronic address:

Purpose: This study was conducted to analyze the clinical and electroencephalographic (EEG) features of attention-deficit hyperactivity disorder (ADHD) in children with benign partial epilepsy with centrotemporal spikes (BECTS) in Southwest China, to address the question of what the risk factors are for patients with BECTS who suffer from ADHD.

Methods: Overall 118 right-handed children with BECTS were included from two medical centers. Of them, 29 patients were with diagnosed ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) at baseline, and the remaining were considered as typical BECTS. Clinical and EEG characteristics were collected at baseline and follow-up endpoint of one year. All the patients completed an eight-hour video-electroencephalogram (VEEG) without sedation at those two time points using a digital system with international 10-20 array electrode placement. At the follow-up endpoint, we also evaluated the intelligence level of all patients using the Wechsler Intelligence Scale for Children-IV (WISC-IV). Multivariate logistical regression model was performed to assess the risk factors of ADHD in BECTS patients.

Results: Compared with typical BECTS, patients with BECTS-ADHD had an earlier age of onset, a longer disease course and tended to have lower intelligence quotient (IQ) scores. Their epileptiform discharges were more likely to diffuse to one or both hemispheres, and a higher percentage of patients with BECTS-ADHD patients needed multitherapy to control seizures. Multivariate analysis showed that age of onset, disease course, intelligence score, number of antiepileptic drugs (AEDs), and bilateral or diffusing discharges were independently associated with the occurrence of ADHD in patients with BECTS (p < .05). Additionally, we found that delayed diagnosis (37.3%) and nonadherence to treatment (16.1%) were the main reasons of a long disease course.

Conclusion: Benign partial epilepsy with centrotemporal spikes with ADHD has the characteristics of early age of onset, long course of disease and low intelligence score. In addition, the epileptiform discharges of BECTS-ADHD were prone to be bilateral or diffuse, and polypharmacological treatment is also common in this group.
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http://dx.doi.org/10.1016/j.yebeh.2020.107240DOI Listing
October 2020

Effect of Vestibular Rehabilitation on Spontaneous Brain Activity in Patients With Vestibular Migraine: A Resting-State Functional Magnetic Resonance Imaging Study.

Front Hum Neurosci 2020 12;14:227. Epub 2020 Jun 12.

Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Previous studies have shown that vestibular migraine (VM) is a cerebral disease with recurrent vertigo. Vestibular rehabilitation (VR) is an effective type of physical therapy for minimizing vestibular symptoms, as it improves vestibular compensation in patients with VM. Currently, the cerebral regions that are associated with the pathogenesis of VM are largely unknown. To further understand the underlying mechanisms of VM, we performed resting-state functional magnetic resonance imaging (fMRI) before and after 1 month of VR in 14 patients with VM. The Dizziness Handicap Inventory (DHI), the 36-Item Short-Form Health Survey (SF-36), the Hamilton Depression Scale (HAMD) and the Hamilton Anxiety Scale (HAMA) scores were included as clinical outcomes. The amplitude of low-frequency fluctuation (ALFF) was assessed to characterize spontaneous brain activity. The correlations between the clinical characteristics and ALFF values were assessed. After 1 month of VR training, the DHI scores in patients with VM were significantly lower than those at baseline ( = 0.03), as were the HAMA scores ( = 0.02). We also found that the ALFF values in the left posterior cerebellum of VM patients increased significantly after 1 month of VR training. Moreover, the ALFF values in the left cerebellum were inversely correlated with the patients' DHI scores. Overall, this study showed that VR exercise for 1 month has a positive effect on vestibular symptoms in patients with VM. Asymmetric cerebellar hyperactivity might be a functional compensation for vestibular dysfunction in patients with VM.
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http://dx.doi.org/10.3389/fnhum.2020.00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303278PMC
June 2020

Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors.

Allergy 2020 11 24;75(11):2829-2845. Epub 2020 Aug 24.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

Background: Morbidity and mortality from COVID-19 caused by novel coronavirus SARS-CoV-2 is accelerating worldwide, and novel clinical presentations of COVID-19 are often reported. The range of human cells and tissues targeted by SARS-CoV-2, its potential receptors and associated regulating factors are still largely unknown. The aim of our study was to analyze the expression of known and potential SARS-CoV-2 receptors and related molecules in the extensive collection of primary human cells and tissues from healthy subjects of different age and from patients with risk factors and known comorbidities of COVID-19.

Methods: We performed RNA sequencing and explored available RNA-Seq databases to study gene expression and co-expression of ACE2, CD147 (BSG), and CD26 (DPP4) and their direct and indirect molecular partners in primary human bronchial epithelial cells, bronchial and skin biopsies, bronchoalveolar lavage fluid, whole blood, peripheral blood mononuclear cells (PBMCs), monocytes, neutrophils, DCs, NK cells, ILC1, ILC2, ILC3, CD4 and CD8 T cells, B cells, and plasmablasts. We analyzed the material from healthy children and adults, and from adults in relation to their disease or COVID-19 risk factor status.

Results: ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA andPPIB), CD26 (DPP4), and related molecules were expressed in both epithelium and in immune cells. We also observed a distinct age-related expression profile of these genes in the PBMCs and T cells from healthy children and adults. Asthma, COPD, hypertension, smoking, obesity, and male gender status generally led to the higher expression of ACE2- and CD147-related genes in the bronchial biopsy, BAL, or blood. Additionally, CD147-related genes correlated positively with age and BMI. Interestingly, we also observed higher expression of CD147-related genes in the lesional skin of patients with atopic dermatitis.

Conclusions: Our data suggest different receptor repertoire potentially involved in the SARS-CoV-2 infection at the epithelial barriers and in the immune cells. Altered expression of these receptors related to age, gender, obesity and smoking, as well as with the disease status, might contribute to COVID-19 morbidity and severity patterns.
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http://dx.doi.org/10.1111/all.14429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300910PMC
November 2020

Validation of the predictive model for seizure recurrence after withdrawal of antiepileptic drugs.

Epilepsy Behav 2021 Jan 19;114(Pt A):106987. Epub 2020 May 19.

Department of Neurology, West China Hospital, Sichuan University, Wai Nan Guo Xue Lane 37#, Chengdu 610041, China. Electronic address:

Purpose: The purpose of this study was to validate the practicability of Lamberink's prediction model in risk assessment of antiepileptic drug (AED) withdrawal in a real, seizure-free population and to find a practical cutoff value to guide clinical withdrawal.

Methods: A group of seizure-free patients from West China Hospital was recruited. Each patient had been seizure-free for at least two years. The seizure recurrence risk among the patients was calculated by an online AED withdrawal risk calculator. The predictive ability of Lamberink's model was assessed by analyzing discrimination and calibration with receiver operating characteristic (ROC) curves and calibration plots, respectively.

Results: A total of 184 seizure-free patients received risk evaluation, all of whom were followed up for at least two years or had an earlier report of seizure relapse. Of these patients, 128 patients were followed up for at least five years or had an earlier report of relapse within five years. Sixty-two of 184 (33.7%) patients relapsed within two years, while 81 of 184 (44.0%) patients relapsed within five years after the start of AEDs' withdrawal. Cox regression analyses showed that seizure duration before remission and the age of seizure onset were independent predictors of relapse at two years. For predictors of recurrence at five years, seizure duration before remission, age at onset, and withdrawal were significant. For discrimination, ROC curve analysis showed that the area under the curve (AUC) for the seizure recurrence within two and five years was 0.605 (95% confidence interval [CI]: 0.518-0.692, p = 0.02) and 0.656 (95% CI: 0.563-0.749, p = 0.003), respectively. For calibration, it was poor in two-year prediction; the observed number was considerably lower than the predicted number. However, the calibration plot showed good calibration with the five-year prediction except for the second, fourth, and eighth deciles. With a cutoff two-year recurrence risk of 47%, the model had a sensitivity of 0.758 and a specificity of 0.410; the largest Youden index was 1.168. With a cutoff five-year recurrence risk of 77%, the model had a sensitivity of 0.358 and a specificity of 0.979; the largest Youden index was 1.337.

Conclusions: Lamberink's prediction model has a general discrimination ability. The model overestimated the actual recurrence events when predicting the two-year recurrence risk, but it showed relatively good calibration with five-year prediction. The cutoff value found in this study may be used to guide patients and clinicians towards a decision regarding the withdrawal of AEDs. The model appears to be a useful tool for predicting seizure recurrence for the five-year recurrence risk.
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http://dx.doi.org/10.1016/j.yebeh.2020.106987DOI Listing
January 2021

A novel proangiogenic B cell subset is increased in cancer and chronic inflammation.

Sci Adv 2020 May 13;6(20):eaaz3559. Epub 2020 May 13.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

B cells contribute to immune responses through the production of immunoglobulins, antigen presentation, and cytokine production. Several B cell subsets with distinct functions and polarized cytokine profiles have been reported. In this study, we used transcriptomics analysis of immortalized B cell clones to identify an IgG4 B cell subset with a unique function. These B cells are characterized by simultaneous expression of proangiogenic cytokines including VEGF, CYR61, ADM, FGF2, PDGFA, and MDK. Consequently, supernatants from these clones efficiently promote endothelial cell tube formation. We identified CD49b and CD73 as surface markers identifying proangiogenic B cells. Circulating CD49bCD73 B cells showed significantly increased frequency in patients with melanoma and eosinophilic esophagitis (EoE), two diseases associated with angiogenesis. In addition, tissue-infiltrating IgG4CD49bCD73 B cells expressing proangiogenic cytokines were detected in patients with EoE and melanoma. Our results demonstrate a previously unidentified proangiogenic B cell subset characterized by expression of CD49b, CD73, and proangiogenic cytokines.
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http://dx.doi.org/10.1126/sciadv.aaz3559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220305PMC
May 2020

Factors Affecting Preventive Treatment Outcomes for Patients With Newly Diagnosed Chronic Migraine and Their Compliance With Treatment Recommendations in Chongqing Province, China: An Open-Label Prospective Study With Retrospective Baseline.

Front Neurol 2020 9;11:227. Epub 2020 Apr 9.

Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

This study aims to investigate the factors affecting the efficacy of first oral prophylaxis in patients with chronic migraine (CM) and to assess patient compliance with their medication regimens. To identify the therapeutic effect of prevention medication in 740 patients with newly diagnosed CM that did not receive any preventive treatments after 4 weeks in an open-label prospective study with retrospective baseline from January 2016 to January 2018, the factors that may affect the outcomes of preventive treatment were analyzed based on the demographic characteristics, migraine characteristics, family history of headache, and history of medication overuse. Moreover, the patients were followed up to evaluate their compliance with and the side effects of the medication at 4 weeks and at 12 weeks. After 4 weeks of prophylaxis, 94.3% ( = 698) of the patients persisted with taking the medicine. The treatment was effective for 61.7% of CM patients ( = 431) and ineffective for 38.3% ( = 267). The results showed that the effectiveness of the preventive treatment was related to the number of headaches per month, and the effect was better for patients with headaches for 15-20 days/month than for those with headaches for 26-30 days/month (OR = 2.78, 95% CI: 1.26-5.75, = 0.006). After 12 weeks of treatment, only 34.5% ( = 255) of the patients persisted with taking the medicine. The most common reason for non-compliance in CM patients is appointment difficulty in a headache clinic (31.8%). The effect of CM prophylaxis was related to the frequency of headache. Only 34.5% of the patients continued to take medicine after 12 weeks of treatment, suggesting that patient compliance needs to be enhanced in the prophylaxis of CM. For the Chinese headache society, the best way to increase patient compliance should be treatment at dedicated headache centers and timely visits to headache specialists.
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http://dx.doi.org/10.3389/fneur.2020.00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161669PMC
April 2020

Tonsillar microbial diversity, abundance, and interrelations in atopic and non-atopic individuals.

Allergy 2020 08 19;75(8):2133-2135. Epub 2020 Apr 19.

Department of Paediatrics and Adolescent Medicine, Turku University Hospital and University of Turku, Turku, Finland.

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http://dx.doi.org/10.1111/all.14306DOI Listing
August 2020

The tolerability and safety profile of eslicarbazepine acetate in neurological disorders.

J Neurol Sci 2020 06 11;413:116772. Epub 2020 Mar 11.

Department of Neurology, West China Hospital, Sichuan University, Wai Nan Guo Xue Lane 37 #, Chengdu 610041, Sichuan, China. Electronic address:

Objectives: This study aimed to assess the tolerability and safety profile of eslicarbazepine acetate (ESL).

Methods: Placebo controlled, double-blind randomized controlled trials (RCTs) were enrolled by searching Pubmed, Embase, Cochrane Online Library, and clinicaltrial.gov. Studies evaluating the safety of ESL on any neurological disorders were included. Adverse events (AEs), serious AEs and AEs-related withdrawals were pooled by direct or indirect meta-analysis.

Results: A total of 4067 patients in 13 RCTs (5 for refractory partial epilepsy, 2 for bipolar I disorder, 1 for migraine, 1 for fibromyalgia, 2 for diabetic neuropathic pain, and 2 for post-herpetic neuralgia) were included. Meta-analysis revealed that ESL treatment had a higher incidence of serious AEs and AEs-related withdrawals than the placebo. Of 35 reported AEs, 13 were significantly associated with ESL treatment, including blurred vision, diplopia, vertigo, nausea, vomiting, fatigue, dizziness, somnolence, headache, rash, hyponatraemia, increased gamma-glutamyl transferase, and dysarthria. Subgroup analysis revealed that dizziness was the only AE significant at 400 mg/day, while diplopia, nausea, vomiting, dizziness, somnolence, rash, and hyponatremia at 800 mg/day, and blurred vision, diplopia, vertigo, nausea, vomiting, fatigue, dizziness, somnolence, headache, rash, and hyponatremia at 1200 mg/day were significant. Adjunctive use of ESL in refractory epilepsy significantly led to higher risk for vestibulocerebellar AEs than other disorders.

Conclusions: ESL treatment was related to a range of AEs, especially at high doses or when used as adjunctive therapy in epilepsy. While the majority of AEs of ESL were related to the vestibulocerebellar system, hyponatremia and rash should also be noted by clinicians.
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http://dx.doi.org/10.1016/j.jns.2020.116772DOI Listing
June 2020

JASPAR 2020: update of the open-access database of transcription factor binding profiles.

Nucleic Acids Res 2020 01;48(D1):D87-D92

Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway.

JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) for TFs across multiple species in six taxonomic groups. In this 8th release of JASPAR, the CORE collection has been expanded with 245 new PFMs (169 for vertebrates, 42 for plants, 17 for nematodes, 10 for insects, and 7 for fungi), and 156 PFMs were updated (125 for vertebrates, 28 for plants and 3 for insects). These new profiles represent an 18% expansion compared to the previous release. JASPAR 2020 comes with a novel collection of unvalidated TF-binding profiles for which our curators did not find orthogonal supporting evidence in the literature. This collection has a dedicated web form to engage the community in the curation of unvalidated TF-binding profiles. Moreover, we created a Q&A forum to ease the communication between the user community and JASPAR curators. Finally, we updated the genomic tracks, inference tool, and TF-binding profile similarity clusters. All the data is available through the JASPAR website, its associated RESTful API, and through the JASPAR2020 R/Bioconductor package.
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http://dx.doi.org/10.1093/nar/gkz1001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145627PMC
January 2020

Nanoparticle-Coupled Topical Methotrexate Can Normalize Immune Responses and Induce Tissue Remodeling in Psoriasis.

J Invest Dermatol 2020 05 31;140(5):1003-1014.e8. Epub 2019 Oct 31.

Department of Immunology, University Hospital Zurich, Zurich, Switzerland. Electronic address:

Methotrexate (MTX) is an antiproliferative drug used for treating inflammatory diseases, including psoriasis. Nevertheless, its use in localized therapy is hindered because of poor transdermal penetration. We show that MTX coupled with gold nanoparticles (GNPs) demonstrates superior antiinflammatory efficacy than MTX alone in an imiquimod-induced mouse model, significantly reducing γδ T cells, CD4 T cells, and neutrophils. Furthermore, it was well tolerated upon systemic and topical administration. In an AGR129 human xenograft mouse model, two-week topical treatment with MTX-GNPs inhibited skin hyperplasia significantly better than topical calcipotriol-betamethasone and led to profound tissue remodeling, involving the upregulation of extracellular matrix reorganization and the downregulation of cornification and keratinization processes. The number of resident T cells in the grafts, as well as interleukin-17 production, drastically decreased upon MTX-GNP treatment. While both MTX and MTX-GNPs directly prevented the proliferation and induced apoptosis of T cells, the suppression of cytokine production was a shared mechanism of GNP and MTX-GNPs. In conclusion, MTX-GNPs influence immune and stromal components of the skin, leading to the potent inhibition of pathogenesis in preclinical psoriasis. MTX-GNPs surpass the efficacy of conventional MTX and standard of care, emerging as a non-steroidal, topical alternative for psoriasis treatment.
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http://dx.doi.org/10.1016/j.jid.2019.09.018DOI Listing
May 2020

CNEr: A toolkit for exploring extreme noncoding conservation.

PLoS Comput Biol 2019 08 26;15(8):e1006940. Epub 2019 Aug 26.

Computational Regulatory Genomics Group, MRC London Institute of Medical Sciences, United Kingdom.

Conserved Noncoding Elements (CNEs) are elements exhibiting extreme noncoding conservation in Metazoan genomes. They cluster around developmental genes and act as long-range enhancers, yet nothing that we know about their function explains the observed conservation levels. Clusters of CNEs coincide with topologically associating domains (TADs), indicating ancient origins and stability of TAD locations. This has suggested further hypotheses about the still elusive origin of CNEs, and has provided a comparative genomics-based method of estimating the position of TADs around developmentally regulated genes in genomes where chromatin conformation capture data is missing. To enable researchers in gene regulation and chromatin biology to start deciphering this phenomenon, we developed CNEr, a R/Bioconductor toolkit for large-scale identification of CNEs and for studying their genomic properties. We apply CNEr to two novel genome comparisons-fruit fly vs tsetse fly, and two sea urchin genomes-and report novel insights gained from their analysis. We also show how to reveal interesting characteristics of CNEs by coupling CNEr with existing Bioconductor packages. CNEr is available at Bioconductor (https://bioconductor.org/packages/CNEr/) and maintained at github (https://github.com/ge11232002/CNEr).
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http://dx.doi.org/10.1371/journal.pcbi.1006940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730951PMC
August 2019

Impact of high-altitude therapy on type-2 immune responses in asthma patients.

Allergy 2020 01 3;75(1):84-94. Epub 2019 Nov 3.

Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland.

Background: Asthma patients present with distinct immunological profiles, with a predominance of type 2 endotype. The aim of this study was to investigate the impact of high-altitude treatment on the clinical and immunological response in asthma.

Methods: Twenty-six hospitalized asthma patients (nine eosinophilic allergic; EA, nine noneosinophilic allergic; NEA and eight noneosinophilic nonallergic; NN) and nine healthy controls in high altitude for 21 days were enrolled in the study. We assessed eosinophils, T cells, Tregs, and innate lymphoid cells (ILC) from peripheral blood using flow cytometry.

Results: The number of eosinophils (both resting and activated) and chemoattractant receptor homolog expressed on Th2 cells (CRTH2)-expressing CD4 and CD8 T cells decreased significantly in EA patients after altitude treatment. The frequency of CRTH2 Tregs as decreased significantly in all the asthma phenotypes as well as the frequency of ILC2 was significantly reduced in EA after altitude treatment. After 21 days of altitude therapy, CRTH2-expressing ILC2, CD4 and CD8 T cells and Treg cells showed attenuated responses to exogenous PGD2. Furthermore, PGD2 signaling via CRTH2 was found to diminish the suppressive function of CRTH2 Tregs which partially normalized during high-altitude treatment. Improved asthma control was particularly evident in allergic asthma patients and correlated with decreased frequencies of CRTH2 Treg cells in EA patients. Serum IL-5 and IL-13 decreased during climate treatment in asthma patients with high baseline levels.

Conclusions: Asthma treatment in high altitude reduced the type 2 immune response, corrected the increased CRTH2 expression and its dysregulated functions.
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http://dx.doi.org/10.1111/all.13967DOI Listing
January 2020

Neurological Involvement in Primary Systemic Vasculitis.

Front Neurol 2019 26;10:430. Epub 2019 Apr 26.

Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Primary systemic vasculitis can affect every structure in both the central and peripheral nervous system, causing varied neurological manifestations of neurological dysfunction. Early recognition of the underlying causes of the neurological symptoms can facilitate timely treatment and improve the prognosis. This review highlights the clinical manifestations of primary systemic vasculitis in the nervous system.
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http://dx.doi.org/10.3389/fneur.2019.00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498988PMC
April 2019

Author Correction: Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates.

Nat Commun 2019 03 6;10(1):1167. Epub 2019 Mar 6.

MRC London Institute of Medical Sciences (LMS), Du Cane Road, London, W12 0NN, UK.

The original version of this Article contained an error in the hyperlink for the online repository http://mulvdb.org which was incorrectly given as http://mulv.lms.mrc.ac.uk. This has been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-09109-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403331PMC
March 2019

Gene expression signatures of circulating human type 1, 2, and 3 innate lymphoid cells.

J Allergy Clin Immunol 2019 06 28;143(6):2321-2325. Epub 2019 Feb 28.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.01.047DOI Listing
June 2019

Gene expression signatures of circulating human type 1, 2, and 3 innate lymphoid cells.

J Allergy Clin Immunol 2019 06 28;143(6):2321-2325. Epub 2019 Feb 28.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.01.047DOI Listing
June 2019

Long fragments achieve lower base quality in Illumina paired-end sequencing.

Sci Rep 2019 02 27;9(1):2856. Epub 2019 Feb 27.

Functional Genomics Center Zurich, ETH Zurich/University of Zurich, Zurich, Switzerland.

Illumina's technology provides high quality reads of DNA fragments with error rates below 1/1000 per base. Sequencing runs typically generate millions of reads in which the vast majority of the reads has an average error rate below 1/1000. However, some paired-end sequencing data show the presence of a subpopulation of reads where the second read (R2) has lower average qualities. We show that the fragment length is a major driver of increased error rates in the R2 reads. Fragments above 500 nt tend to yield lower base qualities and higher error rates than shorter fragments. We use publicly available Illumina data to demonstrate that the fragment length dependency of the R2 read qualities exists in various library protocols, in different labs and using different sequencer models. Our finding extends the understanding of the Illumina read quality and has implications on error models for Illumina reads. It also sheds a light on the importance of controlling the fragment size during library preparation.
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http://dx.doi.org/10.1038/s41598-019-39076-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393434PMC
February 2019

Predictors of seizure reduction outcome after vagus nerve stimulation in drug-resistant epilepsy.

Seizure 2019 Mar 15;66:53-60. Epub 2019 Feb 15.

Department of Neurology, West China Hospital, Sichuan University, Wai Nan Guo Xue Lane 37 #, Chengdu 610041, Sichuan, China. Electronic address:

Purpose: To evaluate the predictors of seizure reduction outcome after vagus nerve stimulation (VNS) in patients with drug-resistant epilepsy (DRE).

Methods: A meta-analysis was performed using relevant research from databases such as PubMed, Embase, Cochrane Online Library, and Clinicaltrials.gov. Studies were selected according to predefined inclusion and exclusion criteria. The quality of studies was evaluated by using the Newcastle-Ottawa Scale (NOS) scale. All data was pooled by STATA 12.0 software for meta-analysis.

Results: The review considered 1281 articles, and 16 articles with NOS score ≥6 were included in the analysis. The meta-analysis showed that at 6 m, 1, 2, 3, 4, 6 and 12 years after implantation, 33.99, 43.42, 46.50, 63.31, 52.71, 54.64, 70.37 and 82.90% of patients exhibited >50% reduction of seizure frequency after VNS. The duration of epilepsy showed a significant difference between the good responders and poor responders (p = 0.038), whereas age at VNS implantation (p = 0.305), age at seizure onset (p = 0.530), seizure type (p = 0.11), etiology (p = 0.187), and history of previous epilepsy surgery (p = 0.075) were not predictors of seizure reduction outcome after VNS. Several features about the electroencephalogram (EEG) feature and heart rhythm complexity (HRV) have not been analyzed by a sufficient number of studies.

Conclusions: DRE patients with shorter duration of epilepsy may be better candidates for VNS rather than those who are younger at onset and implantation. Several EEG or HRV features may have predictive value but more research is needed.
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http://dx.doi.org/10.1016/j.seizure.2019.02.010DOI Listing
March 2019

Safety and tolerability of calcitonin-gene-related peptide binding monoclonal antibodies for the prevention of episodic migraine - a meta-analysis of randomized controlled trials.

Cephalalgia 2019 Aug 21;39(9):1164-1179. Epub 2019 Feb 21.

Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Aim: To systematically evaluate the safety and tolerability of calcitonin-gene-related peptide binding monoclonal antibodies from the results of randomized controlled trials.

Methods: Online databases were searched on calcitonin-gene-related peptide binding monoclonal antibodies for the prevention of episodic migraine. Overall withdrawal, withdrawal due to adverse events, adverse events, serious adverse events and specific adverse events were extracted from the included studies. A meta-analysis was performed with Revman 5.3.0 software.

Results: Ten studies that investigated four drugs (galcanezumab, erenumab, fremanezumab and eptinezumab) with 5817 participants were included in this study. Serious adverse events, overall withdrawals, withdrawal due to adverse events and any adverse events were not significantly associated with monoclonal antibody treatment. Injection site pain and erythema were significantly higher in the calcitonin-gene-related peptide binding monoclonal antibodies treatment group than in the placebo group. The rates of serious adverse events were significantly higher in the galcanezumab 120 mg group. Injection site erythema was associated with galcanezumab 120 mg and 240 mg. Injection site pain and nasopharyngitis were associated with galcanezumab 150 mg and 5 mg, respectively. Overall adverse events were significantly higher with erenumab 70 mg and 140 mg. Treatment-related adverse events were significantly higher with fremanezumab 225 mg/month and 675 mg/quarter.

Conclusions: This study provides data on the safety and tolerability profiles of calcitonin-gene-related peptide binding monoclonal antibodies and confirms their potential use as preventive treatments for episodic migraine. In addition to the acceptable withdrawal rates, serious adverse events were rare, and the severity of most adverse events was mild to moderate. Injection site reaction may be the major adverse event associated with galcanezumab.
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http://dx.doi.org/10.1177/0333102419829007DOI Listing
August 2019

Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid.

J Allergy Clin Immunol 2019 06 22;143(6):2190-2201.e9. Epub 2019 Jan 22.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland. Electronic address:

Background: Group 2 innate lymphoid cells (ILC2s) play critical roles in induction and exacerbation of allergic airway inflammation. Thus clarification of the mechanisms that underlie regulation of ILC2 activation has received significant attention. Although innate lymphoid cells are divided into 3 major subsets that mirror helper effector T-cell subsets, counterpart subsets of regulatory T cells have not been well characterized.

Objective: We sought to determine the factors that induce regulatory innate lymphoid cells (ILCregs).

Methods: IL-10 ILCregs induced from ILC2s by using retinoic acid (RA) were analyzed with RNA-sequencing and flow cytometry. ILCregs were evaluated in human nasal tissue from healthy subjects and patients with chronic rhinosinusitis with nasal polyps and lung tissue from house dust mite- or saline-treated mice.

Results: RA induced IL-10 secretion by human ILC2s but not type 2 cytokines. IL-10 ILCregs, which were converted from ILC2s by means of RA stimulation, expressed a regulatory T cell-like signature with expression of IL-10, cytotoxic T lymphocyte-associated protein 4, and CD25, with downregulated effector type 2-related markers, such as chemoattractant receptor-homologous molecule on T2 cells and ST2, and suppressed activation of CD4 T cells and ILC2s. ILCregs were rarely detected in human nasal tissue from healthy subjects or lung tissue from saline-treated mice, but numbers were increased in nasal tissue from patients with chronic rhinosinusitis with nasal polyps and in lung tissue from house dust mite-treated mice. Enzymes for RA synthesis were upregulated in airway epithelial cells during type 2 inflammation in vivo and by IL-13 in vitro.

Conclusion: We have identified a unique immune regulatory and anti-inflammatory pathway by which RA converts ILC2s to ILCregs. Interactions between airway epithelial cells and ILC2s play an important roles in the generation of ILCregs.
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http://dx.doi.org/10.1016/j.jaci.2018.12.1018DOI Listing
June 2019

Role of Der p 1-specific B cells in immune tolerance during 2 years of house dust mite-specific immunotherapy.

J Allergy Clin Immunol 2019 03 5;143(3):1077-1086.e10. Epub 2018 Dec 5.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland. Electronic address:

Background: Long-term follow-up of allergen-specific B cells in terms of immunoglobulin isotype expression, plasmablast differentiation, and regulatory B (Breg) cell development during allergen-specific immunotherapy (AIT) has not been reported.

Objective: Allergen-specific B-cell responses during 2 years of house dust mite AIT were compared between responder and nonresponder patients.

Methods: B cells specific for Der p 1 were detected by using the fluorochrome-labeled allergen method. The frequency of IgA-, IgG- and IgG-switched Der p 1-specific B cells, plasmablasts, and IL-10- and IL-1 receptor antagonist (IL-1RA)-producing Breg cells were investigated and correlated to clinical response to AIT.

Results: Sixteen of 25 patients completed the 2-year study. Eleven responder patients showed a successful response to AIT, as measured by a decrease in symptom-medication scores from 13.23 ± 0.28 to 2.45 ± 0.24 (P = .001) and a decrease in skin prick test reactivity to house dust mite from 7.0 ± 1.3 to 2.7 ± 0.5 mm (P = .001). IgG and IgA Der p 1-specific B cells showed a significant increase after AIT, with a significantly greater frequency in responders compared with nonresponders in the IgG but not the IgA fraction. The frequency of plasmablasts and IL-10- and/or IL-1RA-producing Breg cells was greater among responders compared with nonresponders after 2 years. The increased frequency of Der p 1-specific IgG4 B cells, plasmablasts, and IL-10 and dual-positive IL-10IL-1RA Breg cells significantly correlated with improved clinical symptoms over the course of AIT.

Conclusion: Allergen-specific B cells in patients responding to AIT are characterized by increased numbers of IgA- and IgG-expressing Der p 1-specific B cells, plasmablasts, and IL-10 and/or IL-1RA Breg cells.
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http://dx.doi.org/10.1016/j.jaci.2018.10.061DOI Listing
March 2019

Laundry detergents and detergent residue after rinsing directly disrupt tight junction barrier integrity in human bronchial epithelial cells.

J Allergy Clin Immunol 2019 05 27;143(5):1892-1903. Epub 2018 Nov 27.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, and the Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland. Electronic address:

Background: Defects in the epithelial barrier have recently been associated with asthma and other allergies. The influence of laundry detergents on human bronchial epithelial cells (HBECs) and their barrier function remain unknown.

Objective: We investigated the effects of laundry detergents on cytotoxicity, barrier function, the transcriptome, and the epigenome in HBECs.

Methods: Air-liquid interface cultures of primary HBECs from healthy control subjects, patients with asthma, and patients with chronic obstructive pulmonary disease were exposed to laundry detergents and detergent residue after rinsing. Cytotoxicity and epithelial barrier function were evaluated. RNA sequencing, Assay for Transposase Accessible Chromatin with high-throughput sequencing, and DNA methylation arrays were used for checking the transcriptome and epigenome.

Results: Laundry detergents and rinse residue showed dose-dependent toxic effects on HBECs, with irregular cell shape and leakage of lactate dehydrogenase after 24 hours of exposure. A disrupted epithelial barrier function was found with decreased transepithelial electrical resistance, increased paracellular flux, and stratified tight junction (TJ) immunostaining in HBECs exposed to laundry detergent at 1:25,000 dilutions or rinse residue at further 1:10 dilutions. RNA sequencing analysis showed that lipid metabolism, apoptosis progress, and epithelially derived alarmin-related gene expression were upregulated, whereas cell adhesion-related gene expression was downregulated by laundry detergent at 1:50,000 dilutions after 24 hours of exposure without substantially affecting chromatin accessibility and DNA methylation.

Conclusion: Our data demonstrate that laundry detergents, even at a very high dilution, and rinse residue show significant cell-toxic and directly disruptive effects on the TJ barrier integrity of HBECs without affecting the epigenome and TJ gene expression.
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http://dx.doi.org/10.1016/j.jaci.2018.11.016DOI Listing
May 2019

Combination of flunarizine and transcutaneous supraorbital neurostimulation improves migraine prophylaxis.

Acta Neurol Scand 2019 Mar 11;139(3):276-283. Epub 2018 Dec 11.

Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Objective: This study is aimed to access the efficacy and safety of combination therapy of flunarizine plus transcutaneous supraorbital neurostimulation (tSNS) compared with either flunarizine or tSNS alone for migraine prophylaxis.

Methods: Patients with episodic migraine were enrolled and randomized into 3 groups. Flunarizine 5 mg per day, or tSNS for 20 minutes daily or combination of both were prescribed consecutively for 3 months. The primary outcome measures were changes in migraine days and 50% responder rate of monthly migraine days. Secondary outcome measures were the changes in migraine intensity and intake of rescue medication. Finally, satisfaction to treatment and adverse effect were evaluated as well.

Results: A total of 154 were randomized and included in the analysis. After 3 months, the monthly migraine days were decreased in 3 groups and more significant in the combination group. The 50% responder rate was significantly higher (78.43%) in the combination therapy than monotherapy of flunarizine (46.15%) or tSNS (39.22%) alone. Greater reduction of migraine intensity and intake of rescue medication was observed in combination group. There was no difference of adverse events between flunarizine group and combination group (P = .89).

Conclusion: Adding tSNS to flunarizine can improve the therapeutic efficacy of migraine prophylaxis without increasing the adverse effects. In addition, tSNS is effective and safe for migraine treatment and can be a valid option for migraineurs who are reluctant to take oral medications or for patients who experience a low-migraine frequency and/or intensity that prophylactic therapy is not indicated but desire to acquire medical intervention.
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http://dx.doi.org/10.1111/ane.13050DOI Listing
March 2019

Tight junction, mucin, and inflammasome-related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice.

Allergy 2019 02 5;74(2):294-307. Epub 2018 Nov 5.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

Background: Asthma is a chronic respiratory disease with marked clinical and pathophysiological heterogeneity. Specific pathways are thought to be involved in the pathomechanisms of different inflammatory phenotypes of asthma; however, direct in vivo comparison has not been performed.

Methods: We developed mouse models representing three different phenotypes of allergic airway inflammation-eosinophilic, mixed, and neutrophilic asthma via different methods of house dust mite sensitization and challenge. Transcriptomic analysis of the lungs, followed by the RT-PCR, western blot, and confocal microscopy, was performed. Primary human bronchial epithelial cells cultured in air-liquid interface were used to study the mechanisms revealed in the in vivo models.

Results: By whole-genome transcriptome profiling of the lung, we found that airway tight junction (TJ), mucin, and inflammasome-related genes are differentially expressed in these distinct phenotypes. Further analysis of proteins from these families revealed that Zo-1 and Cldn18 were downregulated in all phenotypes, while increased Cldn4 expression was characteristic for neutrophilic airway inflammation. Mucins Clca1 (Gob5) and Muc5ac were upregulated in eosinophilic and even more in neutrophilic phenotype. Increased expression of inflammasome-related molecules such as Nlrp3, Nlrc4, Casp-1, and IL-1β was characteristic for neutrophilic asthma. In addition, we showed that inflammasome/Th17/neutrophilic axis cytokine-IL-1β-may transiently impair epithelial barrier function, while IL-1β and IL-17 increase mucin expressions in primary human bronchial epithelial cells.

Conclusion: Our findings suggest that differential expression of TJ, mucin, and inflammasome-related molecules in distinct inflammatory phenotypes of asthma may be linked to pathophysiology and might reflect the differences observed in the clinic.
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http://dx.doi.org/10.1111/all.13619DOI Listing
February 2019

Prevalence and risk factors of depression and anxiety among patients with convulsive epilepsy in rural West China.

Acta Neurol Scand 2018 Dec 7;138(6):541-547. Epub 2018 Sep 7.

Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.

Objectives: To explore the prevalence and risk factors of depression and anxiety in patients with convulsive epilepsy (PWE) in rural West China.

Methods: PWE from rural West China were evaluated for depression and anxiety with the Neurological Disorders Depression Inventory for Epilepsy (C-NDDI-E; Chinese version) and the Generalized Anxiety Disorder-7 (GAD-7; Chinese version). We also assessed their quality of life using the Quality of Life in Epilepsy Inventory (QOLIE-31) and their level of social support using the Social Support Rating Scale (SSRS). We used logistic regression analysis to identify independent risk factors of depression and anxiety and analysis of variance (ANOVA) to investigate the association between quality of life and depression and anxiety.

Results: Of the 458 PWE in our study, 33.4% have anxiety and 52.6% have depression. SSRS (P = 0.03) and seizure frequency (P = 0.007) are independent risk factors of anxiety, and annual income of the patients (P < 0.001) is an independent risk factor of depression. PWE with both depression and anxiety have significantly lower QOLIE-31 total and subtotal scores.

Conclusions: PWE have a high prevalence of depression and anxiety in rural West China, which may be impacting their quality of life. PWE with depression and anxiety got a worse quality of life, and depression had a greater impact on quality of life for PWE than anxiety. The risk factors of depression and anxiety include seizure frequency and social support, while annual income is an additional risk factor of depression. Identifying risk factors early may be helpful in the timely management of these symptoms.
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http://dx.doi.org/10.1111/ane.13016DOI Listing
December 2018