Shikonin ameliorates depressive- and anxiogenic-like behaviors in rats via the suppression of inflammation in the hippocampus.

Shikonin is an active naphthoquinone with antioxidative, anti-inflammatory, and anticancer properties. In this study, we investigated the effects of shikonin on depressive- and anxiety-like behaviors in lipopolysaccharide- (LPS-) induced depression and chronic unpredictable mild stress (CUMS) rat models and explored the potential mechanism. First, a 14-day intraperitoneal administration of shikonin (10 mg/kg) significantly decreased immobility time in forced swimming test (FST) and increased open arm entries in elevated plus maze (EPM) test, without affecting line crossings in open field test (OFT), indicating that shikonin has anti-depressant- and anxiolytic-like effects. Second, chronic shikonin administration (10 mg/kg) reversed depressive- and anxiety-like behaviors in LPS-induced and CUMS depression models, as shown in the sucrose preference test (SPT), FST, EPM, and novel object recognition test (NORT). Finally, shikonin significantly reduced the levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) in hippocampus, indicating that the anti-depressant- and anxiolytic-like effects of shikonin are related to the reduction of neuroinflammation in hippocampus. These findings suggest that shikonin exerts anti-depressant- and anxiolytic-like effects via an anti-inflammatory mechanism of shikonin in the hippocampus.

Melatonin Ameliorates Post-Stroke Cognitive Impairment in Mice by Inhibiting Excessive Mitophagy.

Post-stroke cognitive impairment (PSCI) remains the most common consequence of ischemic stroke. In this study, we aimed to investigate the role and mechanisms of melatonin (MT) in improving cognitive dysfunction in stroke mice. We used CoCl2-induced hypoxia-injured SH-SY5Y cells as a cellular model of stroke and photothrombotic-induced ischemic stroke mice as an animal model. We found that the stroke-induced upregulation of mitophagy, apoptosis, and neuronal synaptic plasticity was impaired both in vivo and in vitro. The results of the novel object recognition test and Y-maze showed significant cognitive deficits in the stroke mice, and Nissl staining showed a loss of neurons in the stroke mice. In contrast, MT inhibited excessive mitophagy both in vivo and in vitro and decreased the levels of mitophagy proteins PINK1 and Parkin, and immunofluorescence staining showed reduced co-localization of Tom20 and LC3. A significant inhibition of mitophagy levels could be directly observed under transmission electron microscopy. Furthermore, behavioral experiments and Nissl staining showed that MT ameliorated cognitive deficits and reduced neuronal loss in mice following a stroke. Our results demonstrated that MT inhibits excessive mitophagy and improves PSCI. These findings highlight the potential of MT as a preventive drug for PSCI, offering promising therapeutic implications.

Antidepressant effect of teriflunomide via oligodendrocyte protection in a mouse model.

Addressing the treatment of depression is crucial; nevertheless, the etiology and pathogenesis remain unelucidated. Therefore, this study investigated the effects of teriflunomide (TF) on corticosterone (CORT)-induced depression-like behaviors in mice. Notably, TF administration resulted in a substantial amelioration of anxiety and depression-like behaviors observed in CORT-treated mice. This was evidenced by behavioral assessments conducted via the sucrose preference test (SPT), open-field test (OFT), novelty-suppressed feeding test (NSFT), forced swimming test (FST), and tail suspension test (TST). The administration of CORT inflicts damage upon oligodendrocytes and neurons within the hippocampus. Our findings indicate that TF offers significant protective effects on oligodendrocytes, mitigating apoptosis both invivo and invitro. Additionally, TF was found to counteract the CORT-induced neuronal loss and synaptic damage, as demonstrated by an increase in Nissl-positive cells across hippocampal regions CA1, CA3, and the dentate gyrus (DG) alongside elevated levels of synapse-related proteins including PSD-95 and synaptophysin. Additionally, TF treatment facilitated a reduction in the levels of apoptosis-related proteins while simultaneously augmenting the levels of Bcl2. Our findings indicate that TF administration effectively mitigates CORT-induced depression-like behaviors and reverses damage to oligodendrocytes and neurons in the hippocampus, suggesting TF as a promising candidate for depression.

Insights into Capacity Fading Mechanism and Coating Modification of High-Nickel Cathodes in Lithium-Ion Batteries.

Developments in electric vehicles and mobile electronic devices are promoting the demand for lithium-ion batteries with higher capacity and longer lifetime. The performances of lithium-ion batteries are crucially affected by cathode materials, among which ternary cathode materials are the most competitive option with the advantages of high capacity, safety, and cost-effectiveness. However, although high-nickel ternary cathode materials can achieve relatively high specific capacity, they generally have unsatisfactory stability during long-term cycling. In this study, the microscopic mechanisms of the cathode failure and the principle of coating modification in lithium-ion batteries have been comprehensively examined. It has been revealed that the irreversible capacity fading is mainly attributed to the interface chemical reaction, which reduces the transition-metal valence states and generates undesired disordered rock-salt phases. This structural phase transformation at the interface induces the dissolution of transition metals and results in irreversible capacity loss of the cathode. To restrain the occurrence of this process, a LiNbO3 coating-modified single-crystal LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode material has been prepared. The electrochemical properties as well as the microstructural evolution of the cathode-electrolyte interface during cycling of both the uncoated and coated samples have been comprehensively characterized and compared through impedance spectroscopy testing, SEM-EDX, STEM, and EELS characterization. Additionally, molecular dynamics simulation results confirmed that LiNbO3 coating can effectively inhibit the dissolution of transition metals while providing stable lithium-ion channels. The experimental results also indicate that the coating modification can effectively improve the cycling stability of the NCM811, with the capacity retention rate for 500 cycles increasing from 19% to 70%. This study is helpful to deepen the understanding of the capacity fading mechanisms, and the coating method is effective at maintaining the structural stability and improving the cycle life of lithium-ion batteries.

Association of Acupuncture and Auricular Acupressure With the Improvement of Sleep Disturbances in Cancer Survivors: A Systematic Review and Meta-Analysis.

Background: Studies on the efficacy of acupuncture and auricular acupressure on sleep disturbances in cancer patients have been growing, but there is no specific and comprehensive systematic review and meta-analysis. This review aims to evaluate the efficacy and safety of acupuncture and auricular acupressure on sleep disturbances in cancer survivors based on existing randomized clinical trials (RCTs). Methods: Four English-language and four Chinese-language biomedical databases were searched for RCTs published from database inception to July 30, 2021. RCTs comparing acupuncture and auricular acupressure with sham control, drug therapy, behavior therapy, or usual care for managing cancer were included. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias (ROB) tool. Mean differences (MDs) and 95% confidence intervals (CIs) were calculated for the effect sizes. Results: Thirteen RCTs with 961 patients were included. The risk of performance bias or reporting bias for most of the included trials was high or unclear. Evidence was not found for short-term effects on sleep scales compared to sham control (MD, 1.98; 95% CI, 0.33-3.64; p = 0.02; I2 = 36%), wait list control (MD, 0.40; 95% CI, -0.87-1.68; p = 0.54; I2 = 49%), drug therapy (MD, 1.18; 95% CI, -3.09-5.46; p = 0.59; I2 = 98%). For long-term effect, two sham-controlled RCTs showed no significance of acupuncture on insomnia scale scores (MD, 1.71; 95% CI, -2.38-5.81; p = 0.41; I2 = 89%). Subgroup analyses suggested no evidence that auricular acupressure (MD, 3.14; 95% CI=1.52, 4.76; p = 0.0001; I2 = 0%) or acupuncture (MD, 0.54; 95% CI=-1.27, 2.34; p = 0.56; I2 = 0%) was associated with the reduction in insomnia scale scores. Conclusions: This systematic review and meta-analysis found no evidence about acupuncture or auricular acupressure in the improvement of sleep disturbances in cancer survivors in terms of short- or long-term effect. Adverse events were minor. The finding was inconsistent with previous research and suggested that more well-designed and large-scale randomized controlled trials are needed to identify the efficacy of acupuncture and auricular acupressure for sleep disturbances in cancer survivors. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, CRD42020171612.

Effectiveness of different acupuncture therapies for chronic cancer pain: A protocol for systematic review and Bayesian network meta-analysis.

BACKGROUND: Pain is a common and distressing symptom experienced by cancer patients. Previous research found acupuncture was associated with significant reductions in pain intensity and opioid use. Acupuncture therapies are various, and the difference in efficacy and safety has never been assessed. This paper aims to assess and rank the effectiveness of the different acupuncture methods and provide an acupuncture treatment guideline for relieving chronic pain in cancer survivors. METHODS: Four English databases (PubMed, Embase, Cochrane library, and Web of Science) and 4 Chinese databases (China National Knowledge Infrastructure, Wanfang Data, and Chinese Biomedical Literature Database) will be searched for randomized controlled trials (RCTs) published from the database inception to November 30, 2021. The primary outcomes will be patient-reported pain intensity measured by the Brief Pain Inventory, Visual Analog Scale, Verbal Rating Scale, Numerical Rating Scale, and other valid outcome measures. The Grading of Recommendations Assessment, and Development and Evaluation System will evaluate the quality of evidence. Bayesian network meta-analysis will be performed in WinBUGS V.1.4.3 to determine the comparative effectiveness of the acupuncture therapies. RESULTS: This study will quantify the effectiveness of each acupuncture intervention for chronic cancer pain with pain scores and the use of analgesics. The adverse events of acupuncture treatment for cancer pain will also be reported. CONCLUSION: The conclusion of our study will help physicians and patients choose suitable acupuncture methods to manage cancer pain.

Transferrin receptors/magnetic resonance dual-targeted nanoplatform for precise chemo-photodynamic synergistic cancer therapy.

Various drug delivery strategies to improve cancer therapeutic efficacy have been actively investigated. One major challenge is to improve the targeting ability. Here elaborately designed nanocarriers (NCs) named as Tf-5-ALA-PTX-NCs are demonstrated to address this problem. In this nanostructure, paclitaxel (PTX) and 5-aminolevulinic acid (5-ALA) were co-encapsulated within magnetic nanocarriers to achieve synergistic chemotherapy and photodynamic therapy, while transferrin (Tf) was conjugated with modified copolymer Pluronic P123 and embedded in the surface of the nanocarriers, which endows nanocarriers with Tf targeting and magnetic targeting to enhance the anti-tumor outcome. Results demonstrated that Tf-5-ALA-PTX-NCs significantly enhanced the targeting drug delivery to MCF-7 cells and synergistically induced apoptosis and death of MCF-7 cells in vitro and highly efficient tumor ablation in vivo. Intriguingly, Tf-5-ALA-PTX-NCs have a controllable "on/off" switch to enhance the drug release. The dual-targeted nanocarriers would be a promising versatile anti-tumor drug delivery and imaging-guided cancer chemo-photodynamic synchronization therapy strategy.

Acupuncture for hypertension with insomnia: Study protocol for a randomized, sham-controlled, subject-and-assessor-blinded trial.

Background: Previous studies show that insomnia and hypertension are closely related. Currently, intervention for hypertension with insomnia has become a research hotspot. Acupuncture, as a representative non-pharmaceutical therapy of traditional Chinese medicine (TCM), has been widely used in improving insomnia and hypertension. However, there are few clinical studies on acupuncture for hypertension with insomnia. Methods: A single-center, subject-and-assessor-blind, randomized, sham-controlled trial has been designed for a study to be conducted in Jiangsu Province Hospital of Chinese Medicine. Sixty eligible patients will be randomly assigned to the treatment group and the control group in a 1:1 ratio. The treatment group will receive acupuncture treatment, while the control group will receive sham acupuncture treatment. Both groups will be treated three times per week for 4 weeks. Data will be collected at baseline and after 4 weeks of treatment and analyzed by using SPSS 25.0. The primary outcome measures are sleep parameters of portable polysomnography before and after treatment. Secondary outcomes are Pittsburgh Sleep Quality Index, Insomnia Severity Index, home blood pressure, and heart rate variability. Discussion: This study aims to evaluate the efficacy of acupuncture using the portable polysomnography combined with sleep scales, and analyze heart rate variability to preliminarily explore the underlying mechanism of acupuncture on hypertension with insomnia. The trail, if proven to be effective, will provide strong scientific evidence to support acupuncture is effective to manage patients for hypertension with insomnia. Clinical trial registration: ChiCTR2200059161.

The top 100 most cited papers in insomnia: A bibliometric analysis.

Objective: The number of citations to a paper represents the weight of that work in a particular area of interest. Several highly cited papers are listed in the bibliometric analysis. This study aimed to identify and analyze the 100 most cited papers in insomnia research that might appeal to researchers and clinicians. Methods: We reviewed the Web of Science (WOS) Core Collection database to identify articles from 1985 to 24 March 2022. The R bibliometric package was used to further analyze citation counts, authors, year of publication, source journal, geographical origin, subject, article type, and level of evidence. Word co-occurrence in 100 articles was visualized using VOS viewer software. Results: A total of 44,654 manuscripts were searched on the Web of Science. Between 2001 and 2021, the top 100 influential manuscripts were published, with a total citation frequency of 38,463. The top countries and institutions contributing to the field were the U.S. and Duke University. Morin C.M. was the most productive author, ranking first in citations. Sleep had the highest number of manuscripts published in the top 100 (n = 31), followed by Sleep Medicine Reviews (n = 9). The most cited manuscript (Bastien et al., Sleep Medicine, 2001; 3,384 citations) reported clinical validation of the Insomnia Severity Index (ISI) as a brief screening indicator for insomnia and as an outcome indicator for treatment studies. Co-occurrence analyses suggest that psychiatric disorders combined with insomnia and cognitive behavioral therapy remain future research trends. Conclusion: This study provides a detailed list of the most cited articles on insomnia. The analysis provides researchers and clinicians with a detailed overview of the most cited papers on insomnia over the past two decades. Notably, COVID-19, anxiety, depression, CBT, and sleep microstructure are potential areas of focus for future research.

Growth of lithium-indium dendrites in all-solid-state lithium-based batteries with sulfide electrolytes.

All-solid-state lithium-based batteries with inorganic solid electrolytes are considered a viable option for electrochemical energy storage applications. However, the application of lithium metal is hindered by issues associated with the growth of mossy and dendritic Li morphologies upon prolonged cell cycling and undesired reactions at the electrode/solid electrolyte interface. In this context, alloy materials such as lithium-indium (Li-In) alloys are widely used at the laboratory scale because of their (electro)chemical stability, although no in-depth investigations on their morphological stability have been reported yet. In this work, we report the growth of Li-In dendritic structures when the alloy material is used in combination with a Li6PS5Cl solid electrolyte and Li(Ni0.6Co0.2Mn0.2)O2 positive electrode active material and cycled at high currents (e.g., 3.8 mA cm-2) and high cathode loading (e.g., 4 mAh cm-2). Via ex situ measurements and simulations, we demonstrate that the irregular growth of Li-In dendrites leads to cell short circuits after room-temperature long-term cycling. Furthermore, the difference between Li and Li-In dendrites is investigated and discussed to demonstrate the distinct type of dendrite morphology.

Size effect of Pt nanoparticles in acid-assisted soot oxidation in the presence of NO.

Pt/Al2O3 catalysts with mean Pt particle size ranged from 2.7 to 7.1 nm were synthesized by chemical reduction method, and the sulfated counterparts were prepared by impregnation of sulfuric acid. The turnover frequency of platinum for soot oxidation under loose contact conditions in a feed flow containing NO and O2 are positively correlated with the size of platinum. The sulfated Pt/Al2O3 exhibits higher catalytic activity for soot oxidation in the presence of NO despite their reduced ability for NO2 production. Such a contradiction is more significant for those catalysts with smaller platinum particles. Herein, the catalysts were characterized by X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET), transmission electron microscopy (TEM), inductive coupled plasma (ICP) emission spectrometry, CO chemisorption, thermogravimetric analysis (TGA), NH3 temperature-programmed desorption (NH3-TPD), NO temperature-programmed oxidation (TPO) and NOx temperature-programmed desorption (TPD). Possible effect of Pt particle size for the catalytic oxidation of soot in the presence of NO was presented based primarily on the promoted NO2 transfer efficiency onto the soot pushed by the acidic catalysts.

Seroprevalence of EV-A71 neutralizing antibodies following the 2011 epidemic in HCMC, Vietnam.

Enterovirus-A71 (EV-A71) cyclically causes hand-foot-mouth disease (HFMD) epidemics in Asian children. An EV-A71 epidemic occurred in Southern Vietnam in 2011, but its scale is not clear. We collected residual sera from non-HFMD Vietnamese inpatients in 2012-2013 to determine seroprevalence of EV-A71 neutralizing antibodies, and measured cross-reactive neutralizing antibody titers against three EV-A71 genogroups. About 23.5% of 1-year-old children in Southern Vietnam has been infected by EV-A71, and the median age of infection was estimated to be 3 years. No significant antigenic variation could be detected among the three EV-A71 genogroups. The high seroprevalence of EV-A71 neutralizing antibody in children living in southern Vietnam indicates the necessity of introducing EV-A71 vaccines in southern Vietnam, particularly for children under 6 months of age. Moreover, it is critical to understand EV-A71 disease burden for formulating national vaccination policy.

Autologous bionic tissue for inguinal hernia repair.

The prosthetic mesh, which is widely used in tension-free hernioplasty, often result in avascular stiff fibrotic scar or mesh shrinkage, causing chronic pain and infection. Here, we developed an autologous bionic tissue (ABT), which was composed of autologous bone marrow-derived mesenchymal stem cells (MSCs), poly (lactic-co-glycolic acid) (PLGA) porous scaffolds, and extracellular matrix (ECM) produced by MSCs for inguinal hernioplasty. In ABT, MSCs produced a variety of ECM composites, such as structural proteins (insoluble collagen, elastin) that provided mechanical properties, macromolecules (hyaluronic acid, glycosaminoglycan) as water and cytokines reservoir, and cell-engaging proteins (fibronectin, laminin). The above ECM composites reached the highest level in 21 days. ECM degradation related cytokines (MMP-9 and its inhibitor TIMP-1) reached the highest level on the 14th day. ECM increased the mechanical properties, elasticity, and flexibility of PLGA. Compared with the PLGA, ABT greatly inhibited inflammatory factors and promoted anti-inflammatory factors (p < 0.05), and gradually reduced the M1/M2 ratio in vivo (p < 0.05). After implantation, the thickness of tissue regeneration (p < 0.05), the number of capillaries or mature vessels (p < 0.05), the mechanical properties of ABT (p < 0.05) were greater than PLGA. MSCs and ECM could reduce the inflammation caused by PLGA, and prevent PLGA from earlier degradation and facilitate host cellular infiltration, thus ABT could greatly promote tissue regeneration in hernia repairs.

Establishment of Asia-Pacific Network for Enterovirus Surveillance.

Enteroviruses (EV), the major pathogens of hand, foot, and mouth disease (HFMD) and herpangina, affect millions of children each year. Most human enteroviruses cause self-limited infections except polioviruses, enterovirus A71 (EV-A71), enterovirus D68 (EV-D68), and several echoviruses (Echo) and coxsackieviruses (CV). Especially, EV-A71 has repeatedly caused large-scale outbreaks in the Asia-Pacific region since 1997. Some Asian countries have experienced cyclical outbreaks of severe EV-A71 infections and initiated development of EV-A71 vaccines. Five EV-A71 vaccine candidates have been clinically evaluated and three of them were approved for marketing in China. However, none of the China-approved products seek marketing approval in other countries. This situation supports a role for collaboration among Asian countries to facilitate clinical trials and licensure of EV-A71 vaccines. Additionally, enterovirus D68 outbreaks have been reported in the US and Taiwan currently and caused severe complications and deaths. Hence, an Asia-Pacific Network for Enterovirus Surveillance (APNES) has been established to estimate disease burden, understand virus evolution, and facilitate vaccine development through harmonizing laboratory diagnosis and data collection. Founded in 2017, the APNES is comprised of internationally recognized experts in the field of enterovirus in Asian countries working to raise awareness of this potentially fatal and debilitating disease. This article demonstrated the summaries of the first expert meeting, 2017 International Workshop on Enterovirus Surveillance and Vaccine Development, held by APNES in Taipei, Taiwan, March 2017.

Genomic analysis of serologically untypable human enteroviruses in Taiwan.

BACKGROUND: Human enteroviruses contain over 100 serotypes. We have routinely conducted enterovirus surveillance in northern Taiwan; but about 10% of isolates could not be serotyped using traditional assays. Next-generation sequencing (NGS) is a powerful tool for genome sequencing. METHODS: In this study, we established an NGS platform to conduct genome sequencing for the serologically untypable enterovirus isolates. RESULTS: Among 130 serologically untypable isolates, 121 (93%) of them were classified into 29 serotypes using CODEHOP (COnsensus-DEgenerate Hybrid Oligonucleotide Primer)-based RT-PCR to amplify VP1 genes (VP1-CODEHOP). We further selected 52 samples for NGS and identified 59 genome sequences from 51 samples, including 8 samples containing two virus genomes. We also detected 23 genome variants (nucleotide identity < 90% compared with genome sequences in the public domain) which were potential genetic recombination, including 9 inter-serotype recombinants and 14 strains with unknown sources of recombination. CONCLUSIONS: We successfully integrated VP1-CODEHOP and NGS techniques to conduct genomic analysis of serologically untypable enteroviruses.

Genomic analysis of enterovirus D68, including one strain isolated from a child with Wilson's disease in Taiwan.

North America experienced life-threatening outbreaks of enterovirus D68 (EV-D68) in 2014. We retrospectively detected EV-D68 from a child with Wilson's disease in 2008 in Taiwan. After comparing this EV-D68/Taiwan/2008 strain with EV-D68 genomes obtained from the public domain, it was classified as genome type 1-B; it is phylogenetically related to the predominant EV-D68 viruses that circulated in 2009 in Vietnam. It is necessary to strengthen EV-D68 detection globally, including in children with acute liver failure. Moreover, harmonization of genomic analysis of EV-D68 is desirable to understand global evolution of EV-D68.

Theranostic micelles combined with multiple strategies to effectively overcome multidrug resistance.

AIM: To develop precise targeting and versatile Fe3O4@SiO2-P123/PTX-ZnPc nanoparticles (FSP-PTX-ZnPc NPs) to reverse paclitaxel (PTX)-induced multidrug resistance in breast cancer. MATERIALS & METHODS: PTX and zinc (II) phthalocyanine (ZnPc) co-loaded FSP-PTX-ZnPc NPs were designed. The resulting multifunctional NPs were evaluated systematically in vitro and in vivo, and the mechanism of drug-resistance reversal was investigated. RESULTS: The NPs enhanced drug uptake in MCF-7/PDR cells by increasing drug solubility and impairing P-glycoprotein efflux. Additionally, magnetic targeting and enhanced permeation and retention (EPR) effect enhanced drug accumulation in tumor, facilitating the chemotherapeutic and photodynamic therapy effects. Moreover, FSP-PTX-ZnPc NPs could penetrate the blood-brain barrier, a desirable trait for brain disease therapy. CONCLUSION: The multifunctional FSP-PTX-ZnPc NPs are an effective tool for overcoming drug resistance in breast cancer.

A Molecular Approach Applied to Enteroviruses Surveillance in Northern Taiwan, 2008-2012.

Traditional methods for detection and serotyping of enterovirus infections are virus isolation and immunofluorescence assay (VI-IFA), which are labor-intensive and time-consuming. Recently, VP1 gene has been targeted to develop a CODEHOP-based RT-PCR (VP1-CODEHOP) for the same purpose. In this study, we conducted a 5-year enterovirus surveillance comparing the VI-IFA and VP1-CODEHOP tests. Throat swabs were collected from 431 pediatric patients and 208(48%) and 250(58%) were tested positive by the VI-IFA and VP1-CODEHOP tests, respectively. Among the 47 cases who had inconsistent results between the VI-IFA and VP1-CODEHOP tests and provided paired sera for serological verifications, correct diagnosis for the VI-IFA and VP1-CODEHOP were 5(11%) and 40(85%) cases, respectively. Therefore, the VP1-CODEHOP is more reliable for detection of human enteroviruses than the VI-IFA. Based on serological verifications for the eight cases who had inconsistent serotypes between the two tests and provided paired sera, five and two showed consistent serotypes with the VP1-CODEHOP and VI-IFA tests, respectively. CVA16, CVA6 and EV71 were the most prevalent serotypes in northern Taiwan, 2008~2012. Moreover, variant CVA2, CVA6 and EV71 viruses were further identified based on phylogenetic analysis of partial VP1 sequences. In conclusion, the VP1-CODEHOP test could be used as the primary method for enterovirus surveillance to support decision-making for outbreak control.

Reemergence of enterovirus 71 epidemic in northern Taiwan, 2012.

BACKGROUND: Enterovirus 71 (EV71) belongs to picornavirus family and could be classified phylogenetically into three major genogroups (A, B and C) including 11 genotypes (A, B1-B5 and C1-C5). Since 1997, EV71 has caused large-scale of epidemics with neurological complications in Asian children. In Taiwan, nationwide EV71 epidemics with different predominant genotypes have occurred cyclically since 1998. A nationwide EV71 epidemic occurred again in 2012. We conducted genetic and antigenic characterizations of the 2012 epidemic. METHODS: Chang Gung Memorial Hospital (CGMH) is a medical center in northern Taiwan. In CGMH, specimens were collected from pediatric inpatients with suspected enterovirus infections for virus isolation. Enterovirus isolates were serotyped and genotyped and sera from EV71 inpatients were collected for measuring neutralizing antibody titers. RESULTS: There were 10, 16 and 99 EV71 inpatients identified in 2010, 2011 and 2012, respectively. There were 82 EV71 isolates genotyped, which identified 17 genotype C4a viruses and 65 genotype B5 viruses. The genotype B5 viruses were not detected until November 2011 and caused epidemics in 2012. Interestingly, the B5-2011 viruses were genetically distinguishable from the B5 viruses causing the 2008 epidemic and are likely introduced from China or Southeastern Asia. Based on antigenic analysis, minor antigenic variations were detected among the B5-2008, B5-2011, C4a-2008 and C4a-2012 viruses but these viruses antigenically differed from genotype A. CONCLUSIONS: Genotype B5 and C4a viruses antigenically differ from genotype A viruses which have disappeared globally for 30 years but have been detected in China since 2008. Enterovirus surveillance should monitor genetic and antigenic variations of EV71.

Epidemiology of enterovirus 71 infections in Taiwan.

Enterovirus 71 (EV71) was first described in USA in 1969 but retrospective studies in The Netherlands further detected EV71 in the clinical specimens collected in 1963. EV71 has one single serotype measured by using hyperimmune animal antisera but can be phylogenetically classified into three genogroups (A, B, and C) including 11 genotypes (A, B1-B5, C1-C5). In Taiwan, EV71 caused a large-scale nationwide epidemic in 1998. Retrospective studies further detected EV71 in clinical specimens collected from hand-foot-mouth disease patients in 1980 and 1986. Therefore, EV71 may have circulated in Taiwan prior to 1980. Since 1998, EV71 has cyclically caused nationwide epidemics with different predominant genotypes in 1998 (genotype C2), 2000-2001 (B4), 2005 (C4), 2008 (B5), and 2012 (B5). Phylogenetic analysis revealed that C4 viruses isolated in 2005 were probably from China, B5 viruses isolated in 2008 were probably from South Eastern Asia, and B5 viruses isolated in 2012 were probably from Xiamen, China. Several studies have collected postinfection sera from children to measure cross-reactive neutralizing antibody titers against different EV71 genotypes and found that antigenic differences between genogroup B and C viruses did not have a clear pattern but that genotype A virus was antigenically different from genogroup B and C viruses. In conclusion, EV71 cyclically caused nationwide epidemics through international importations. EV71 surveillance in Taiwan should combine genetic and serological methods.