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Objective. Infectious diseases usually spread rapidly. This study aims to develop a model that can provide fine-grained early warnings of infectious diseases using real hospital data combined with disease transmission characteristics, weather, and other multi-source data. Methods. Based on daily data reported for infectious diseases collected from several large general hospitals in China between 2012 and 2020, seven common infectious diseases in medical institutions were screened and a multi self-regression deep (MSRD) neural network was constructed. Using a recurrent neural network as the basic structure, the model can effectively model the epidemiological trend of infectious diseases by considering the current influencing conditions while taking into account the historical development characteristics in time-series data. The fitting and prediction accuracy of the model were evaluated using mean absolute error (MAE) and root mean squared error. Results. The proposed approach is significantly better than the existing infectious disease dynamics model, susceptible-exposed-infected-removed (SEIR), as it addresses the concerns of difficult-to-obtain quantitative data such as latent population, overfitting of long time series, and considering only a single series of the number of sick people without considering the epidemiological characteristics of infectious diseases. We also compare certain machine learning methods in this study. Experimental results demonstrate that the proposed approach achieves an MAE of 0.6928 and 1.3782 for hand, foot, and mouth disease and influenza, respectively. Conclusion. The MRSD-based infectious disease prediction model proposed in this paper can provide daily and instantaneous updates and accurate predictions for epidemic trends. [ABSTRACT FROM AUTHOR]

The hand foot, and mouth disease (HFMI)) epidemic has become a serious public health problem worldwide with a high economic and health burden. In addition, the prevalence of (HFMI) varies greatly between cities. Therefore, this paper aims to reveal high-risk cities for HFMD and associated meteorological and air pollution factors in Guangdong Province during 2014-2018. Data on the incidence of HFMD mid meteorological and air pollution. factors were obtained from the Guangdong Provincial Center for Disease Control and Prevention and Guangdong Meteorological Service. Three different grey incidence analysis (GIA) were used, namely Deng's grey incidence analysis, absolute degree of GIA, and second synthetic degree of GIA. Additionally, GMC (1,1) model was used to predict the trend of HFMD in 2019-2028. According to the second synthetic degree of GIA, the top three cities most affected by HFMD are Zhuhai, Guangzhou, and Foshan. However, the prediction model .found that the incidence of HFMD in Guangdong Province will generally decline in the next 10 years, indicating that the prevention and control measures are still relatively in place. Deng's grey incidence analysis found that CO, %O2, PM2.5, PM10), and wind scale are closely related to the incidence of HFMD. It is recommended to closely monitor weather change and urban air quality and take protective measures against HFMD in advance. The results of this study hare substantial implications for the control of HFMD. [ABSTRACT FROM AUTHOR]

Hand, foot, and mouth disease (HFMD) is a global infectious disease severely threatening children's health. It has been recognized that climate factors play an important role in the transmission of HFMD. In this paper, the bootstrap test in the geographically weighted regression (GWR) literature is extended to geographically and temporally weighted regression (GTWR) models for identifying homogeneous explanatory variables and spatiotemporally heterogeneous ones. The resulting mixed GTWR model is then used to investigate spatiotemporal effect of climate factors on the HFMD incidence in Inner Mongolia, China, a provincial autonomous region with extensive area and different climatic conditions. The results demonstrate that the effect of relative humidity is global over space and time, while that of air temperature, air pressure and wind speed varies spatiotemporally. The extended bootstrap test provides a solid statistical basis for model selection. The findings from the study may provide not only a deep understanding of spatiotemporal variation characteristics of the climatic effect on the HFMD incidence, but also some useful evidences for taking measures of the disease prevention and control at the county level in different seasons. [ABSTRACT FROM AUTHOR]

Aim: The aim of this paper is to present an interesting case of viral myocarditis complicated by sepsis, its sequelae, including multi-organ dysfunction syndrome, and the approach to manage it successfully. Background: Viral myocarditis is an inflammatory disease of myocardium, often leading to residual heart disease. Commonly, dengue and Coxsackie B viruses are the causative agents. Patients usually present with dyspnea, fever, and signs of heart failure. A possibility of bacterial sepsis should not be overlooked, given similar presentations may occur. Case description: A 21-year-old male presented with acute onset breathlessness, fever, chills, and severe neck pain. On a detailed workup, he was found to have features suggestive of viral myocarditis, bacterial sepsis, with bilateral pleural loculations, a posterior epidural spinal abscess. Elimination of infectious foci, along with a decision to stick to the ongoing antibiotics, instead of stepping up to the last available ones proved beneficial. Meticulous balance of diuretics and inotropes saved the patient's life from what turned out to be coxsackie myocarditis. Conclusion: Here, we present the case of a young male who came in with congestive heart failure due to Coxsackie myocarditis and his condition complicated by severe sepsis. Clinical significance: Up to 10% of the cases of coxsackie myocarditis progress to chronic dilated cardiomyopathy. The management is usually conservative, and antiviral agents have shown no role in speedy recovery. Elimination of infectious foci aggressively is of prime importance in the treatment of bacterial sepsis. A careful balance of inotropes, diuretics, and fluid management is needed to get the patient into remission in such cases. [ABSTRACT FROM AUTHOR]

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The prediction model is a major component within public health cyber‐physical systems, which supports decisions on prevention and control of diseases. Hand, foot, and mouth disease (HFMD) is one of the most common global infectious diseases with the highest incidence rate. Previous HFMD prediction models are mainly based on the time series that counted in equal‐grained time intervals. However, there are details in the time series counted in fine‐grained time intervals. To benefit from both equal‐grained and fine‐grained data, we proposed a dual‐grained representation (DGR) model. The DGR first represents inputted data to temporal patterns. Then, the represented patterns are consolidated to generate predictions. Experimental comparisons of the short‐term prediction performance are figured out by using real outpatient collections in Xiamen, China. [ABSTRACT FROM AUTHOR]

Introduction: Hand, foot, and mouth disease caused by enterovirus A71 (EV-A71) is more frequently associated with neurological complications and deaths compared to other enteroviruses.Areas covered: The authors discuss current understanding of the neuropathogenesis of EV-A71 based on various clinical, human, and animal model studies. The authors discuss the important advancements in virus entry, virus dissemination, and neuroinvasion. The authors highlight the role of host immune system, host genetic factors, viral quasispecies, and heparan sulfate in EV-A71 neuropathogenesis.Expert opinion: Comparison of EV-A71 with EV-D68 and PV shows similarity in primary target sites and dissemination to the central nervous system. More research is needed to understand cellular tropisms, persistence of EV-A71, and other possible invasion routes. EV-A71 infection has varied clinical manifestations which may be attributed to multiple receptors usage. Future development of antivirals and vaccines should target neurotropic enteroviruses. Repurposing drug and immunomodulators used in combination could reduce the severity of EV-A71 infection. Only a few drugs have been tested in clinical trials, and in the absence of antiviral and vaccines (except China), active virus surveillance, good hand hygiene, and physical distancing should be advocated. A better understanding of EV-A71 neuropathogenesis is critical for antiviral and multivalent vaccines development. [ABSTRACT FROM AUTHOR]

Hand, foot, and mouth disease (HFMD) is a highly contagious disease with several outbreaks in Asian-Pacific countries, including Thailand. With such epidemic characteristics and potential economic impact, HFMD is a significant public health issue in Thailand. Generally, contagious/infectious diseases' transmission dynamics vary across geolocations due to different socioeconomic situations, demography, and lifestyles. Hence, a nationwide comprehensive model of the disease's epidemic dynamics can provide information to understand better and predict a potential outbreak of this disease and efficiently and effectively manage its impact. However, there is no nationwide and comprehensive (i.e., the inclusion of reinfections in the model) model of HFDM dynamics for Thailand. This paper has endeavoured to promote nationwide comprehensive modelling of HFMD's epidemic dynamics and comprehend the reinfection cases. We have formulated the SEIRS epidemiological model with dynamic vitals, including reinfections, to explore this disease's prevalence. We also introduced periodic seasonality to reproduce the seasonal effect. The pattern of spread of this disease is uneven across the provinces in Thailand, so we used K -means clustering algorithm to cluster those provinces into three groups (i.e., highly, moderately, and least affected levels). We also analysed health records collected from district hospitals, which suggest significant reinfection cases. For example, we found that 11% (approximately) of infectious patients return for repeat treatment within the study period. We also performed sensitivity analysis which indicates that the basic reproduction number ( R 0 ) is sensitive to the rate of transmission (β) and the rate at which infected people recover (γ). By fitting the model with HFMD confirmed data for the provinces in each cluster, the basic reproduction number ( R 0 ) was estimated to be 2.643, 1.91, and 3.246 which are greater than 1. Based on this high R 0 , this study recommends that this disease will persist in the coming years under identical cultural and environmental conditions. [ABSTRACT FROM AUTHOR]

Hand, Foot, and Mouth Disease (HFMD) is an outbreak infectious disease that can easily spread among children under the age of five. The most common causative agents of HFMD are enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), but infection caused by EV71 is more associated with fatalities due to severe neurological disorders. The present diagnosis methods rely on physical examinations by the doctors and further confirmation by laboratories detection methods such as viral culture and polymerase chain reaction. Clinical signs of HFMD infection and other childhood diseases such as chicken pox, and allergies are similar, yet the genetics and pathogenicity of the viruses are substantially different. Thus, there is an urgent need for an early screening of HFMD using an inexpensive and user-friendly device that can directly detect the causative agents of the disease. This paper reviews current HFMD diagnostic methods based on various target types, such as nucleic acid, protein, and whole virus. This was followed by a thorough discussion on the emerging sensing technologies for HFMD detection, including surface plasmon resonance, electrochemical sensor, and surface enhanced Raman spectroscopy. Lastly, optical absorption spectroscopic method was critically discussed and proposed as a promising technology for HFMD screening and detection. [Display omitted] • The HFMD diagnostic methods measure various target types including nucleic acid, protein, and whole virus. • The current lab-based HFMD diagnostic methods have limitations of relatively high cost, lack of simplicity, and time-consuming. • Present emerging biosensor technologies for HFMD detection offer direct measurements, user-friendly, lab-free and tag-free. • Optical spectroscopy is proposed due to its simplicity, without requiring ligand development and ligand immobilization. [ABSTRACT FROM AUTHOR]

As the proportion of non-enterovirus 71 and non-coxsackievirus A16 which proportion of composition in the hand, foot, and mouth pathogenic spectrum gradually increases worldwide, the attention paid to other enteroviruses has increased. As a member of the species enterovirus A, coxsackievirus A14 (CVA14) has been epidemic around the world until now since it has been isolated. However, studies on CVA14 are poor and the effective population size, evolutionary dynamics, and recombination patterns of CVA14 are not well understood. In this study, 15 CVA14 strains were isolated from HFMD patients in mainland China from 2009 to 2019, and the complete sequences of CVA14 in GenBank as research objects were analyzed. CVA14 was divided into seven genotypes A-G based on an average nucleotide difference of the full-length VP1 coding region of more than 15%. Compared with the CVA14 prototype strain, the 15 CVA14 strains showed 84.0–84.7% nucleotide identity in the complete genome and 96.9–97.6% amino acid identity in the encoding region. Phylodynamic analysis based on 15 CVA14 strains and 22 full-length VP1 sequences in GenBank showed a mean substitution rate of 5.35 × 10−3 substitutions/site/year (95% HPD: 4.03–6.89 × 10−3) and the most recent common ancestor (tMRCA) of CVA14 dates back to 1942 (95% HPD: 1930–1950). The Bayesian skyline showed that the effective population size had experienced a decrease–increase–decrease fluctuation since 2004. The phylogeographic analysis indicated two and three possible migration paths in the world and mainland China, respectively. Four recombination patterns with others of species enterovirus A were observed in 15 CVA14 strains, among which coxsackievirus A2 (CVA2), coxsackievirus A4 (CVA4), coxsackievirus A6 (CVA6), coxsackievirus A8 (CVA8), and coxsackievirus A12 (CVA12) may act as recombinant donors in multiple regions. This study has filled the gap in the molecular epidemiological characteristics of CVA14, enriched the global CVA14 sequence database, and laid the epidemiological foundation for the future study of CVA14 worldwide. [ABSTRACT FROM AUTHOR]

This paper reports a high incidence of HFMD in children and adults, occurred in summer-autumn 2012 in the northeastern part of Romania. We present a few cases with some atypical clinical manifestations. [ABSTRACT FROM AUTHOR]

Although most patients with acute viral myocarditis recover spontaneously, some patients progress to heart failure. Perturbations in innate immunity may partially explain the heterogeneity of clinical outcomes. As the most abundant immune cells in the heart, cardiac macrophages have heterogeneous origins, including embryonic‐derived resident macrophages (ResMϕs) and monocyte‐derived macrophages (MoMFs). However, the time course change and role of cardiac macrophage subsets has not been fully explored. In the present study, we found that BALB/c mice had prolonged MoMF accumulation and low proportions of ResMϕs that could not be restored to normal levels. MoMFs of BALB/c mice generally exhibit an M1‐dominant functional phenotype. Moreover, the preferential depletion of MoMF by a C‐C chemokine receptor type 2 (CCR2) inhibitor resulted in improved acute myocarditis and chronic fibrosis, as well as the recovery of ResMϕs number and reduced CD4+ T cell expansion. Hence, immunomodulatory therapy that targets the balance among cardiac macrophages and modulates their function is expected to prevent the progression of cardiac injury to overt heart failure and improve adverse outcomes. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a common multifactorial autoimmune disease resulting from the destruction of insulin-producing -cells in the pancreas as a consequence of dysregulated immune responses.[1] In the past few years, there has been a flurry of discoveries and advancements in our understanding of the immunopathogenic mechanisms at the basis of T1D development and progression. Herein, conventional dendritic cells display a pivotal role in inducing T1D upon pathogen infections as these cells can capture and present -cell-derived proteins and/or viral antigens, initiating the diabetogenic T cell-specific immune response[7] (Figure 1). Anti-viral innate immunity: Is it where type 1 diabetes really begins?. [Extracted from the article]

Hand, foot and mouth disease (HFMD) is a susceptible viral infectious disease to infants and children, which led to millions of cases and hundreds of deaths annually in China. Existing predictive methods commonly learn the development patterns from historical observations. However, almost all these methods are neglect the immediate impact of exogenous factors on HFMD transmission. To solve the limitation, we consider the approximately unidirectional influences from temperature to confirmed cases and then propose a transfer one-step-ahead learning (Tr-OSH) method to establish their association. The Tr-OSH method first extract the unidirectional representation from temperature observations, and subsequently transfer the obtained representation for HFMD cases prediction. Moreover, we notice the independent correlation of each time step and period, and generate the independent representation by the relevance to upcoming values. Intensive experiments on real-world HFMD datasets demonstrate that our Tr-OSH method much efficaciously improves prediction accuracy. [ABSTRACT FROM AUTHOR]

Aim: To study the associations between baseline blood glucose levels (BGL), glycemic variability and clinical outcomes in patients with severe acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT). Methods: We performed a secondary analysis of the Randomized Evaluation of Normal versus Augmented Level of RRT (RENAL) study. A multivariate Cox regression model was used to assess the association between baseline BGL, glycemic variability and clinical outcomes. The primary outcome was all-cause mortality, and secondary outcomes were duration of hospital and intensive care unit (ICU) stay. Results: Baseline BGL data were available in 1404 out of 1508 patients from the RENAL study. Among them, 627 patients died within 90 days of randomization. Compared to patients in the second quartile (BGL 5.8–7.2 mmol/L), patients in the first quartile (BGL < 5.8 mmol/L) had increased mortality rate (90-day HR 1.48; p = 0.001; 28-day HR 1.47; p = 0.042). However, there were no significant differences in ICU and hospital length of stay (LOS) (p = 0.82 and p = 0.33, respectively). Glycemic variability data were from 1345 out of 1404 patients who had data for BG values within 28 days. Higher coefficient of variation (CV) (HR 1.02; P trend = 0.002) and standard deviation value (SD) (HR 1.29; P trend = 0.027) were associated with higher risk of death at day 90. Conclusions: We identified a low BGL within the normal physiological range at baseline and greater CV and SD values as significant modifiable risk factors for mortality in severe AKI patients in ICU, which may be a target for intervention. [ABSTRACT FROM AUTHOR]

Coxsackievirus B2 (CVB2) is an enterovirus B (EV‐B) species and can cause aseptic meningitis, myocarditis and hand, foot, and mouth disease (HFMD). We characterized a novel CVB2 (YN31V3) associated with HFMD in Yunnan, Southwest China, in 2019. Although YN31V3 and other Mainland China epidemic strains mainly belonged to genotype C, YN31V3 formed an independent branch. The genome sequence of the strain YN31V3 from this study showed a 12.91% nucleotide difference to its closest strain RW41‐2/YN/CHN/2012. Recombination analyses showed that the newly isolated YN31V3 was probably a recombinant, which was closely related to CVB2 strains in the genomic P1 region and other EV‐B strains in the P2 and P3 regions, respectively. YN31V3 strain had a temperature‐sensitive phenotype. The challenge of suckling BALB/c mice with YN31V3 could cause symptoms of disease and severe pathological lesions. Highlights: Coxsackievirus B2 strain YN31V3 associated with hand, foot, and mouth disease was isolated and analyzed in Southwest China.The isolate YN31V3 belonged to a novel clade.The sequence diversity of coxsackievirus B2 affects its clinical manifestations and tissue tropism.It is essential to persistent surveillance of enterovirus. [ABSTRACT FROM AUTHOR]

Background: Measles caused by measles virus (MeV) is a highly contagious viral disease which has also been associated with complications including pneumonia, myocarditis, encephalitis, and subacute sclerosing panencephalitis. The current study isolated 33 strains belonging to 2 groups, outbreak and sporadic strains, in 13 cities of Shandong province, China from 2013 to 2019. Comparison of genetic characterization among 15 outbreak strains and 18 sporadic strains was performed by analyzing nucleotide sequences of the C-terminal region of N protein gene (N-450). Results: All 33 stains belonged to genotype H1. The outbreak strains and sporadic strains distributed crossly in phylogenetic tree. Sequences alignment revealed some interesting G to A transversion which changed the amino acids on genomic sites 1317, 1422, and 1543. The nucleotide and amino acid similarities among outbreak isolates were 98–100% (0–10 nucleotide variations) and 97.7–100%, respectively; They were 97.3–100% and 96.6–100%, respectively for sporadic isolates. Evolutionary genetics analysis revealed that the mean evolution rates of outbreak and sporadic isolates were 1.26 N 10− 3 and 1.48 N 10− 3 substitutions per site per year separately, which were similar with corresponding data before 2012. Local transmission analysis suggested that there were three transmission chains in this study, two of them originated from Japan. Outbreak cases and sporadic cases emerged alternatively and were reciprocal causation on the transmission chains. Conclusions: Our study investigated the phylogeny and evolutional genetics of MeV during a 7-year surveillance, and compared epidemic and genetic characteristics of outbreak strains and sporadic strains. These results underscore the importance of evolutionary study alongside with sporadic cases in discovering and tracing possible outbreaks, especially in the stage of measles elimination. [ABSTRACT FROM AUTHOR]

Background: Acute flaccid paralysis (AFP) surveillance was conducted as part of the World Health Organization's strategy for completely eradicating poliomyelitis and leaving non-polio enteroviruses NPEVs as one of the main potential causes of AFP. We aimed to detect NPEV in association with AFP. Methods: We used 459 isolates reported to be Negative Polio and some NPEVs by the World Health Organization Polio Regional Reference Laboratory (Thailand), which had been obtained during polio surveillance programmes conducted in Thailand in 2013–2014. Of 459 isolates, 35 belonged to the genus Enterovirus by RT-PCR and genotyping by DNA sequencing. Results: This study found 17 NPEV genotypes, with 3, 13 and 1 belonging to enterovirus (EV) species A (EV-A), EV-B, and EV-C, respectively. The EV-A types identified included coxsackievirus A2 (CA2), CA4, and EV71, typically associated with hand, foot and mouth diseases. EV-B is the most prevalent cause of AFP in Thailand, while CA21 was the only type of EV-C detected. The EV-B species (13/35; 76.5%) constituted the largest proportion of isolates, followed by EV-A (3/35; 17.6%) and EV-C (1/35; 5.9%). For the EV-B species, Echovirus (E) 30 and CVB were the most frequent isolates. E30, CVB, E14, and E6 were considered endemic strains. Conclusion: NPEVs, e.g. CA4, are reported for the first time in Thailand. Despite some limitations to this study, this is the first report on the circulation patterns of NPEVs associated with AFP in Thailand. AFP surveillance has unearthed many unknown NPEVs and, the cases of death due to AFP occur annually. Therefore, it is important to study NPEVs in the wake of the eradication of poliovirus in the context of the continued incidence of paralysis. [ABSTRACT FROM AUTHOR]

After infection with Coxsackievirus B3 (CB3), H-2 congenic strains of mice on an A- background develop an immunologically mediated myocarditis associated with autoantibodies directed mainly against cardiac myosin. We tested these autoantibodies for cross- reactivity with the virus. Using immunoblotting and virus neutralizing assays with affinity purified antibodies and absorbed sera, we found that the autoantibodies to heart myosin did not cross react with CB3. In addition, myosin autoantibodies induced by immunization with cardiac myosin did not react with the virus. Western immunoblotting revealed that the anti-CB3 antibodies in the infected mice are directed against the capsid protein VP 2. We conclude that CB3 antigens do not stimulate an immune response that cross-reacts with cardiac myosin. [ABSTRACT FROM AUTHOR]

Huntingtin-interacting protein family members are evolutionarily conserved from yeast to humans, and they are known to be key factors in clathrin-mediated endocytosis. Here we identified the Caenorhabditis elegans protein huntingtin-interacting proteinrelated 1 (HIPR-1) as a host factor essential for Orsay virus infection of C. elegans. Ablation of HIPR-1 resulted in a greater than 10,000-fold reduction in viral RNA, which could be rescued by ectopic expression of HIPR-1. Viral RNA replication from an endogenous transgene replicon system was not affected by lack of HIPR-1, suggesting that HIPR-1 plays a role during an early, prereplication virus life-cycle stage. Ectopic expression of HIPR-1 mutants demonstrated that neither the clathrin light chain-binding domain nor the clathrin heavy chain-binding motif were needed for virus infection, whereas the inositol phospholipid-binding and F-actin-binding domains were essential. In human cell culture, deletion of the human HIP orthologs HIP1 and HIP1R led to decreased infection by Coxsackie B3 virus. Finally, ectopic expression of a chimeric HIPR-1 harboring the human HIP1 ANTH (AP180 N-terminal homology) domain rescued Orsay infection in C. elegans, demonstrating conservation of its function through evolution. Collectively, these findings further our knowledge of cellular factors impacting viral infection in C. elegans and humans. [ABSTRACT FROM AUTHOR]

Copyright of Al-Mustansiriyah Journal for Pharmaceutical Sciences is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Hand, foot, and mouth disease (HFMD) is a common infectious disease occurring in children under 5 years of age worldwide, and Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CVA-16) are identified as the predominant pathogens. In recent years, Coxsackievirus A6 (CVA-6) and Coxsackievirus A10 (CVA-10) have played more and more important role in a series of HFMD outbreaks. This study aimed to understand the epidemic characteristics associated with HFMD outbreak in Guangzhou, 2018.Methods: The clinical and laboratory data of 1220 enterovirus-associated HFMD patients in 2018 were analysed in this study. Molecular diagnostic methods were performed to identify its serotypes. Phylogenetic analyses were depicted based on the complete VP1 gene.Results: There were 21 enterovirus serotypes detected in Guangzhou in 2018. Three serotypes of enterovirus, CVA-6 (364/1220, 29.8%), CVA-10 (305/1220, 25.0%), and CVA-16 (397/1220, 32.5%), were identified as the causative pathogens and accounted for 87.3% among all 1220 HFMD patients. In different seasons, CVA-6 was the predominant pathogen of HFMD during autumn, and CVA-10 as well as CVA-16 were more prevalent in summer. Patients infected by CVA-6, CVA-10 or CVA-16 showed similar clinical features and laboratory characteristics, and the ratios of severe HFMD were 5.8, 5.9, and 1.5% in the three serotypes. Phylogenetic analyses of VP1 sequences showed that the CVA-6, CVA-10, and CVA-16 sequences belonged to the sub-genogroup E2, genogroup E, and genogroup B1, respectively.Conclusions: CVA-6, CVA-10, and CVA-16 were the predominant and co-circulated serotypes in Guangzhou China, 2018, which should be the new target for prevention and control of HFMD. Our findings provide useful information for diagnosis, treatment, and prevention of HFMD. [ABSTRACT FROM AUTHOR]

The thymus is the main organ of the lymphatic system, in which T cells undergo a rigorous selection to ensure that their receptors (TCRs) will be functional and will not react against the self. Genes encoding for TCR chains are fragmented and must be rearranged by a process of somatic recombination generating TCR rearrangement excision circles (TRECs). We recently documented coxsackievirus B4 (CV-B4) infection of Swiss albino mouse thymus in the course of in utero transmission. In the current study, we intended to evaluate thymic output in this experimental model. For this purpose, pregnant Swiss albino mice were inoculated with CV-B4 at day 10 or 17 of gestation, and thymus and spleen were sampled from offspring at different time points and then subjected to quantification of TREC molecules and Ptk7 gene expression. Results showed a pronounced effect of in utero CV-B4 infection on the thymus with an increase in the cellularity and, consequently, the weight of the organ. sj and DβTREC analysis, by real-time PCR, revealed a significant decrease following CV-B4 infection compared to controls, a decrease which gets worse as time goes by, both in the thymus and in the periphery. Those observations reflect a disturbance in the export of T cells to the periphery and their accumulation within the thymus. The evaluation of Ptk7 transcripts in the thymus, for its part, showed a decrease in expression, especially following an infection at day 10 of gestation, which supports the hypothesis of T cell accumulation in a mature stage in the thymus. The various effects observed correlate either negatively or positively with the viral load in the thymus and spleen. Disruption in thymic export may indeed interfere with T cell maturation. We speculate that this may lead to a premature release of T cells and the possibility of circulating autoreactive or proliferation-impaired T cell clones. [ABSTRACT FROM AUTHOR]

Myocarditis is an infectious-inflammatory disease with viral infections being one of the most common infectious cause. When it is superimposed to an individual genetic background, myocarditis may progress into a chronic heart muscle disorder, most often dilated cardiomyopathy (DCM), with a natural history similar to classic forms of genetic or idiopathic dilated cardiomyopathies. We present the case of a 30-year-old patient, with a persistent infectious episode in the last 8 weeks, pain and swelling in the large joints. At admission the patient had fever, tachycardia and a grade 2/6 systolic mitral murmur. Laboratory findings revealed inflammatory syndrome, hepatocytolysis syndrome and microalbuminuria. The electrocardiogram (ECG) showed possible right atrial tachycardia. The echocardiography revealed a globally enlarged heart with reduced ejection fraction and diffuse hypokinesia. When discussing the etiology of the DCM, the following were taken into consideration: a tachycardiomyopathy, ischemic etiology, genetic component, autoimmune etiology (elevated anti-Ro titer), and myocarditis. The diagnosis of myocarditis was confirmed by the cardiac magnetic resonance imaging which showed diffuse fibrosis of the interstitial space and an important increase of the extracellular volume. This case is distinguished by a particular immunological panel requiring dynamic monitoring in order to diagnose a possible associated autoimmune pathology. [ABSTRACT FROM AUTHOR]

The article presents a case report of a 3-month-old male infant with a perimembranous ventral septal defect with no previous illness history. The patient was diagnosed with the common subepidermal blistering skin disease bullous pemphigoid (BP), that characteristically affects the elderly population, but who responded well to oral and topical corticosteroids and oral erythromycin. Also noted is the uncommon status of infantile BP for pediatricians and dermatologists.

Objective: To study the characteristics of the acute heart failure patients admitted in paediatric intensive care unit of Pak Emirates Military Hospital Rawalpindi and record their outcomes in terms of mortality and discharge. Study Design: Cross sectional study. Place and Duration of Study: Pak Emirates Military Hospital Rawalpindi, Paediatric Intensive Care Unit (PICU). Study was conducted, from Sep 2017 to Mar 2017. Methodology: All consecutive paediatric intensive care unit admissions with diagnosis of acute heart failure were prospectively studied till discharge or death. Following data was collected prospectively: regarding age; gender; diagnosis at the time of admission; the need for mechanical ventilation; paediatric intensive care unit length of stay and the outcome in terms of mortality and discharge. Descriptive statistics were calculated for all variables. Results: During the study period 59 children were treated for heart failure. Admissions from the emergency department were 64.4%. The median age was 6 months. The leading cause of heart failure came out to be acute viral myocarditis (45.8%) followed by congenital heart diseases (39%). The average length of stay was 4.56 ± 1.62 (range 1 to 10 days). There were 13.6% of the patients who required mechanical ventilation. Out of the total 59 patients, 12 patients (20.3%) expired. Conclusion: Congestive heart failure cases were found to be similar to the demographics reported earlier from Pakistan and other developing countries that included the Asian and African countries. [ABSTRACT FROM AUTHOR]

Background: Acute myocarditis (AM) can be defined as an inflammatory disease of the myocardium and characterized by large heterogeneity of clinical presentation. Myocarditis is becoming increasingly recognized as a contributor to unexplained mortality, and is thought to be a major cause of sudden cardiac death in the first two decades of life. The present study aimed to search the assessment of repolarization dispersion measured from the 12-lead surface electrocardiogram (including Tp-e interval, Tp-e/QT and Tp-e/QTc ratios) in AM patients.Methods: Totally 56 patients (mean age was 22 ± 3.7 years and 67% of the patients were male) with AM and 56 control subjects (23 ± 4.7 years and 64% of the patients were male) were enrolled. Tp-e intervals, Tp-e/QT and Tp-e/corrected QT (QTc) ratios were calculated from 12-lead electrocardiogram.Results: Heart rate, QT and QTc values were similar between groups. QRS interval was lower in AM group compared to the control group (p <  0.001). Tp-e, Tp-e/QT and Tp-e/ QTc were significantly higher in AM group (p <  0.001, p <  0.001, p = 0.03 respectively) and they were significantly correlated with high troponin and high sensitive C reactive protein levels. In hospital follow-up time was 6 ± 2 days. Four patients have non sustained ventricular tachyarrhythmias and 1 patient dead because of cardiac arrest.Conclusions: Our study demonstrated that Tp-e intervals, Tp-e/QT and Tp-e/QTc ratios were higher in patients with AM than control subjects. The increased frequency of ventricular arrhythmias can be clarified by increased indexes of ventricular repolarization parameters in patients with AM. [ABSTRACT FROM AUTHOR]

Coxsackievirus B3 (CVB3) is the primary cause of viral myocarditis. An early and abundant neutrophil accumulation in the myocardium is a hallmark of early CVB3 infection. Yet the relative contribution of neutrophils to host susceptibility to CVB3 myocarditis remains largely unknown. Herein, peripheral neutrophil depletion was implemented in a BALB/c mouse model of acute CVB3 myocarditis using the specific 1A-8 (anti-Ly6G) or a RB6-8C5 (anti-Gr-1) mAb covering a wide range. Anti-Ly6G treatment led to systemic neutropenia throughout the disease, but did not alter virus replication, disease susceptibility and histopathological changes in the heart and pancreas of mice. In contrast, depletion of both neutrophils and monocytes/macrophages by anti-Gr-1 mAb prior to and after infection significantly promoted susceptibility of mice to CVB3 infection which was associated with exacerbated cardiac and pancreatic viral load. However, depletion of Gr1+ cells significantly suppressed acute myocarditis and pancreatic acini destruction at day 7 post infection via reducing Ly6Chigh monocyte population in the circulation. Additionally, cardiac interstitial fibrosis was not affected by neutrophil depletion, whereas Gr-1+ cells other than neutrophils increased cardiac fibrosis at day 21 p.i. by increasing cardiac expression of profibrotic cytokine TNF-α and TGF-β. Thus, Neutrophil function is most likely not essential for CVB3 control and peripheral neutrophils play dispensable role in the pathogenesis of acute myocarditis and pancreatitis during CVB3 infection. Whereas Gr-1+ cells other than neutrophils play a major role in limiting viral replication while promoting myocardial and pancreatic inflammatory injury and fibrosis. [ABSTRACT FROM AUTHOR]

This article presents information on the research paper "Hand-Foot-and-Mouth Disease," by J. Alsop, T.H. Flewett and J.R. Foster. The paper reports on an outbreak in 24 patients. The disease was mild and persisted for less than a week. The majority of patients were under 4 years of age. The eruption consisted of small vesicles which affected the mouth, hands and feet, and in a few patients there was a maculo papular rash on the buttocks. Coxsackie group A type 16 virus was isolated from vesicle fluid from the hands of one patient.

This study aimed to analyze the epidemiological characteristics of hand, foot and mouth disease (HFMD) during 2008-14 in Wenzhou, China. The epidemiological data of HFMD retrieved from the Wenzhou Center for Disease Control and Prevention were retrospectively analyzed. HFMD infections with enterovirus 71 (EV71), Cox A16 or other pathogens were further verified by polymerase chain reaction (PCR) and real-time PCR. A total of 213 617 cases of HFMD were reported between 2008 and 2014 in Wenzhou. The average incidence was 384.31 of 100 000, and the fatality rate was 0.14‰. The incidence of HFMD peaked between April and July, and it occurred more frequently in males than in females. Approximately 92.68% of the HFMD patients were children aged <5 years. Nearly 80% of the cases were diagnosed within 2 days after onset. The major HFMD pathogen was EV71. This study suggested that appropriate comprehensive prevention and control measures should be taken to avoid the spread of HFMD. [ABSTRACT FROM AUTHOR]

Enteroviruses are among the most common viral infectious agents of humans and are primarily transmitted by the fecal–oral route. However, the events associated with enterovirus infections of the human gastrointestinal tract remain largely unknown. Here, we used stem cell-derived enteroids from human small intestines to study enterovirus infections of the intestinal epithelium. We found that enteroids were susceptible to infection by diverse enteroviruses, including echovirus 11 (E11), coxsackievirus B (CVB), and enterovirus 71 (EV71), and that contrary to an immortalized intestinal cell line, enteroids induced antiviral and inflammatory signaling pathways in response to infection in a virus-specific manner. Furthermore, using the Notch inhibitor dibenzazepine (DBZ) to drive cellular differentiation into secretory cell lineages, we show that although goblet cells resist E11 infection, enteroendocrine cells are permissive, suggesting that enteroviruses infect specific cell populations in the human intestine. Taken together, our studies provide insights into enterovirus infections of the human intestine, which could lead to the identification of novel therapeutic targets and/or strategies to prevent or treat infections by these highly clinically relevant viruses. [ABSTRACT FROM AUTHOR]

Alice in Wonderland Syndrome (AIWS) is a perceptual disorder, principally involving visual and somesthetic integration, firstly reported by Todd, on the literary suggestion of the strange experiences described by Lewis Carroll in Alice in Wonderland books. Symptoms may comprise among others aschematia and dysmetropsia. This syndrome has many different etiologies; however EBV infection is the most common cause in children, while migraine affects more commonly adults. Many data support a strict relationship between migraine and AIWS, which could be considered in many patients as an aura or a migraine equivalent, particularly in children. Nevertheless, AIWS seems to have anatomical correlates. According to neuroimaging, temporoparietal-occipital carrefour (TPO-C) is a key region for developing many of AIWS symptoms. The final part of this review aims to find the relationship between AIWS symptoms, presenting a pathophysiological model. In brief, AIWS symptoms depend on an alteration of TPO-C where visual-spatial and somatosensory information are integrated. Alterations in these brain regions may cause the cooccurrence of dysmetropsia and disorders of body schema. In our opinion, the association of other symptoms reported in literature could vary depending on different etiologies and the lack of clear diagnostic criteria. [ABSTRACT FROM AUTHOR]

Background: Coxsackievirus A9 (CV-A9) is a pathogenic enterovirus type within the family Picornaviridae. CV-A9 infects A549 human epithelial lung carcinoma cells by attaching to the αVβ6 integrin receptor through a highly conserved Arg-Gly-Asp (RGD) motif, which is located at the exposed carboxy-terminus of the capsid protein VP1 detected in all studied clinical isolates. However, genetically-modified CV-A9 that lacks the RGD motif (CV-A9- RGDdel) has been shown to be infectious in some cell lines but not in A549, suggesting that RGD-mediated integrin binding is not always essential for efficient entry of CV-A9. Methods: Two cell lines, A549 and SW480, were used in the study. SW480 was the study object for the integrin-independent entry and A549 was used as the control for integrin-dependent entry. Receptor levels were quantitated by cell sorting and quantitative PCR. Antibody blocking assay and siRNA silencing of receptor-encoding genes were used to block virus infection. Peptide phage display library was used to identify peptide binders to CV-A9. Immunofluorescence and confocal microscopy were used to visualize the virus infection in the cells. Results: We investigated the receptor use and early stages of CV-A9 internalization to SW480 human epithelial colon adenocarcinoma cells. Contrary to A549 infection, we showed that both CV-A9 and CV-A9-RGDdel internalized into SW480 cells and that function-blocking anti-αV integrin antibodies had no effect on the binding and entry of CV-A9. Whereas siRNA silencing of β6 integrin subunit had no influence on virus infection in SW480, silencing of β2-microglobulin (β2M) inhibited the virus infection in both cell lines. By using a peptide phage display screening, the virus-binding peptide identical to the N-terminal sequence of HSPA5 protein was identified and shown to block the virus infection in both A549 and SW480 cell lines. HSPA5 was also found to co-localize with CV-A9 at the SW480 cell periphery during the early stages of infection by confocal microscopy. Conclusions: The data suggest that while αVβ6 integrin is essential for CV-A9 in A549 cell line, it is not required in SW480 cell line in which β2M and HSPA5 alone are sufficient for CV-A9 infection. This suggests that the choice of CV-A9 receptor(s) is dependent on the tissue/cellular environment. [ABSTRACT FROM AUTHOR]

Background: The hand foot and mouth disease (HFMD) is a human syndrome caused by intestinal viruses like that coxsackie A virus 16, enterovirus 71 and easily developed into outbreak in kindergarten and school. Scientifically and accurately early detection of the start time of HFMD epidemic is a key principle in planning of control measures and minimizing the impact of HFMD. The objective of this study was to establish a reliable early detection model for start timing of hand foot mouth disease epidemic in Dalian and to evaluate the performance of model by analyzing the sensitivity in detectability. Methods: The negative binomial regression model was used to estimate the weekly baseline case number of HFMD and identified the optimal alerting threshold between tested difference threshold values during the epidemic and non-epidemic year. Circular distribution method was used to calculate the gold standard of start timing of HFMD epidemic. Results: From 2009 to 2014, a total of 62022 HFMD cases were reported (36879 males and 25143 females) in Dalian, Liaoning Province, China, including 15 fatal cases. The median age of the patients was 3 years. The incidence rate of epidemic year ranged from 137.54 per 100,000 population to 231.44 per 100,000population, the incidence rate of non-epidemic year was lower than 112 per 100,000 population. The negative binomial regression model with AIC value 147.28 was finally selected to construct the baseline level. The threshold value was 100 for the epidemic year and 50 for the non- epidemic year had the highest sensitivity(100%) both in retrospective and prospective early warning and the detection time-consuming was 2 weeks before the actual starting of HFMD epidemic. Conclusions: The negative binomial regression model could early warning the start of a HFMD epidemic with good sensitivity and appropriate detection time in Dalian. [ABSTRACT FROM AUTHOR]

Background: Recurrence of hand, foot and mouth disease (HFMD) pandemics continues to threaten public health. Despite increasing awareness and efforts, effective vaccine and drug treatment have yet to be available. Probiotics have gained recognition in the field of healthcare worldwide, and have been extensively prescribed to babies and young children to relieve gastrointestinal (GI) disturbances and diseases, associated or not with microbial infections. Since the faecal-oral axis represents the major route of HFMD transmission, transient persistence of probiotic bacteria in the GI tract may confer some protection against HFMD and limit transmission among children. Methods: In this work, the antiviral activity of two commercially available probiotics, namely Lactobacillus reuteri Protectis (L. reuteri Protectis) and Lactobacillus casei Shirota (L. casei Shirota), was assayed against Coxsackieviruses and Enterovirus 71 (EV71), the main agents responsible for HFMD. In vitro infection set-ups using human skeletal muscle and colon cell lines were designed to assess the antiviral effect of the probiotic bacteria during entry and post-entry steps of the infection cycle. Results: Our findings indicate that L. reuteri Protectis displays a significant dose-dependent antiviral activity against Coxsackievirus type A (CA) strain 6 (CA6), CA16 and EV71, but not against Coxsackievirus type B strain 2. Our data support that the antiviral effect is likely achieved through direct physical interaction between bacteria and virus particles, which impairs virus entry into its mammalian host cell. In contrast, no significant antiviral effect was observed with L. casei Shirota. Conclusions: Should the antiviral activity of L. reuteri Protectis observed in vitro be translated in vivo, such probiotics-based therapeutic approach may have the potential to address the urgent need for a safe and effective means to protect against HFMD and limit its transmission among children. [ABSTRACT FROM AUTHOR]

Enterovirus B species (EV-B) are responsible for a vast number of mild and serious acute infections. They are also suspected of remaining in the body, where they cause persistent infections contributing to chronic diseases such as type I diabetes. Recent studies of the infectious entry pathway of these viruses revealed remarkable similarities, including non-clathrin entry of large endosomes originating from the plasma membrane invaginations. Many cellular factors regulating the efficient entry have recently been associated with macropinocytic uptake, such as Rac1, serine/threonine p21-activated kinase (Pak1), actin, Na/H exchanger, phospholipace C (PLC) and protein kinase Cα (PKCα). Another characteristic feature is the entry of these viruses to neutral endosomes, independence of endosomal acidification and low association with acidic lysosomes. The biogenesis of neutral multivesicular bodies is crucial for their infection, at least for echovirus 1 (E1) and coxsackievirus A9 (CVA9). These pathways are triggered by the virus binding to their receptors on the plasma membrane, and they are not efficiently recycled like other cellular pathways used by circulating receptors. Therefore, the best "markers" of these pathways may be the viruses and often their receptors. A deeper understanding of this pathway and associated endosomes is crucial in elucidating the mechanisms of enterovirus uncoating and genome release from the endosomes to start efficient replication. [ABSTRACT FROM AUTHOR]

The replication of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), which are the major cause of hand, foot and mouth disease (HFMD) in children, can be inhibited by the capsid binder GPP3. Here, we present the crystal structure of CVA16 in complex with GPP3, which clarifies the role of the key residues involved in interactions with the inhibitor. Based on this model, in silico docking was performed to investigate the interactions with the two next-generation capsid binders NLD and ALD, which we show to be potent inhibitors of a panel of enteroviruses with potentially interesting pharmacological properties. A meta-analysis was performed using the available structural information to obtain a deeper insight into those structural features required for capsid binders to interact effectively and also those that confer broad-spectrum anti-enterovirus activity. [ABSTRACT FROM AUTHOR]

Coxsackievirus infection can lead to viral myocarditis and its sequela, dilated cardiomyopathy, which represent major causes of cardiovascular mortality worldwide in children. Yet, the host genetic susceptible factors and the underlying mechanisms by which viral infection damages cardiac function remain to be fully resolved. Dysferlin is a transmembrane protein highly expressed in skeletal and cardiac muscles. In humans, mutations in the dysferlin gene can cause limb-girdle muscular dystrophy type 2 B and Miyoshi myopathy. Dysferlin deficiency has also been linked to cardiomyopathy. Defective muscle membrane repair has been suggested to be an important mechanism responsible for muscle degeneration in dysferlin-deficient patients and animals. Using both naturally occurring and genetically engineered dysferlin-deficient mice, we demonstrated that loss of dysferlin confers increased susceptibility to coxsackievirus infection and myocardial damage. More interestingly, we found that dysferlin is cleaved following coxsackieviral infection through the proteolytic activity of virally encoded proteinases, suggesting an important mechanism underlying virus-induced cardiac dysfunction. Our results in this study not only identify dysferlin deficiency as a novel host risk factor for viral myocarditis but also reveal a key mechanism by which coxsackievirus infection impairs cardiac function, leading to the development of dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]

Coxsackievirus type B3 (CVB3) is a cardiotropic enterovirus. Infection causes cardiomyocyte necrosis and myocardial inflammation. The damaged tissue that results is replaced with fibrotic or calcified tissue, which can lead to permanently altered cardiac function. The extent of pathogenesis among individuals exposed to CVB3 is dictated by a combination of host genetics, viral virulence, and the environment. Here, we aimed to identify genes that modulate cardiopathology following CVB3 infection. 129S1 mice infected with CVB3 developed increased cardiac pathology compared to 129X1 substrain mice despite no difference in viral burden. Linkage analysis identified a major locus on chromosome 7 (LOD: 8.307, P<0.0001) that controlled the severity of cardiac calcification and necrosis following infection. Sub-phenotyping and genetic complementation assays identified Abcc6 as the underlying gene. Microarray expression profiling identified genotype-dependent regulation of genes associated with mitochondria. Electron microscopy examination showed elevated deposition of hydroxyapatite-like material in the mitochondrial matrices of infected Abcc6 knockout (Abcc6-/-) mice but not in wildtype littermates. Cyclosporine A (CsA) inhibits mitochondrial permeability transition pore opening by inhibiting cyclophilin D (CypD). Treatment of Abcc6 -/- mice with CsA reduced cardiac necrosis and calcification by more than half. Furthermore, CsA had no effect on the CVB3-induced phenotype of doubly deficient CypD-/-Abcc6-/- mice. Altogether, our work demonstrates that mutations in Abcc6 render mice more susceptible to cardiac calcification following CVB3 infection. Moreover, we implicate CypD in the control of cardiac necrosis and calcification in Abcc6-deficient mice, whereby CypD inhibition is required for cardioprotection. [ABSTRACT FROM AUTHOR]

Introduction: Kawasaki disease (KD) most commonly develops in infants, although its specific cause is still unclear. We report here a rare case of adult-onset KD which revealed to be concurrently infected by Coxsackievirus A4. Case presentation: The patient was a 37-year-old Japanese man who presented with fever, exanthema, changes in the peripheral extremities, bilateral non-exudative conjunctival injection, and changes in the oropharynx, signs that meet the diagnostic criteria for KD defined by the Centers for Disease Control and Prevention. In this case, the patient had a significantly high antibody titer for Coxsackievirus A4, which led us to presume that the occurrence of KD was concurrent Coxsackievirus A4 infection. Conclusion: We reported a very rare case of KD which suggests that the disease can be concurrent Coxsackievirus A4 infection. Although KD is an acute childhood disease, with fever as one of the principal features, KD should also be considered in the differential diagnosis when adult patients present with a fever of unknown cause associated with a rash. [ABSTRACT FROM AUTHOR]

The infectious activity of coxsackievirus B1 (CV-B1) in Taiwan was high from 2008 to 2010, following an alarming increase in severe neonate disease in the United States (US). To examine the relationship between CV-B1 strains isolated in Taiwan and those from other parts of the world, we performed a phylodynamic study using VP1 and partial 3Dpol (414 nt) sequences from 22 strains of CV-B1 isolated in Taiwan (1989–2010) and compared them to sequences from strains isolated worldwide. Phylogenetic trees were constructed by neighbor-joining, maximum likelihood, and Bayesian Monte Carlo Markov Chain methods. Four genotypes (GI–IV) in the VP1 region of CV-B1 and three genotypes (GA–C) in the 3Dpol region of enterovirus B were identified and had high support values. The phylogenetic analysis indicates that the GI and GIII strains in VP1 were geographically distributed in Taiwan (1993–1994) and in India (2007–2009). On the other hand, the GII and GIV strains appear to have a wider spatiotemporal distribution and ladder-like topology A stair-like phylogeny was observed in the VP1 region indicating that the phylogeny of the virus may be affected by different selection pressures in the specified regions. Further, most of the GI and GII strains in the VP1 tree were clustered together in GA in the 3D tree, while the GIV strains diverged into GB and GC. Taken together, these data provide important insights into the population dynamics of CV-B1 and indicate that incongruencies in specific gene regions may contribute to spatiotemporal patterns of epidemicity for this virus. [ABSTRACT FROM AUTHOR]

Prevention of viral-induced respiratory disease begins with an understanding of the factors that increase or decrease susceptibility to viral infection. The primary receptor for most adenoviruses is the coxsackievirus and adenovirus receptor (CAR), a cell-cell adhesion protein normally localized at the basolateral surface of polarized epithelia and involved in neutrophil transepithelial migration. Recently, an alternate isoform of CAR, CAREx8, has been identified at the apical surface of polarized airway epithelia and is implicated in viral infection from the apical surface. We hypothesized that the endogenous role of CAREx8 may be to facilitate host innate immunity. We show that IL-8, a proinflammatory cytokine and a neutrophil chemoattractant, stimulates the protein expression and apical localization of CAREx8 via activation of AKT/S6K and inhibition of GSK3β. Apical CAREx8 tethers infiltrating neutrophils at the apical surface of a polarized epithelium. Moreover, neutrophils present on the apical-epithelial surface enhance adenovirus entry into the epithelium. These findings suggest that adenovirus evolved to co-opt an innate immune response pathway that stimulates the expression of its primary receptor, apical CAREx8, to allow the initial infection the intact epithelium. In addition, CAREx8 is a new target for the development of novel therapeutics for both respiratory inflammatory disease and adenoviral infection. [ABSTRACT FROM AUTHOR]

Adenoviruses are common pathogens. The localization of their receptors coxsackievirus and adenovirus receptor, and desmoglein-2 in cell-cell junction complexes between polarized epithelial cells represents a major challenge for adenovirus infection from the apical surface. Structural proteins including hexon, penton base and fiber are excessively produced in serotype 5 adenovirus (Ad5)-infected cells. We have characterized the composition of structural protein complexes released from Ad5 infected cells and their capacity in remodeling cell-cell junction complexes. Using T84 cells as a model for polarized epithelium, we have studied the effect of Ad5 structural protein complexes in remodeling cell-cell junctions in polarized epithelium. The initial Ad5 infection in T84 cell culture was inefficient. However, progressive distortion of cell-cell junction in association with fiber release was evident during progression of Ad5 infection. Incubation of T84 cell cultures with virion-free supernatant from Ad5 infected culture resulted in distortion of cell-cell junctions and decreased infectivity of Ad5-GFP vector. We used gel filtration chromatography to fractionate fiber containing virion–free supernatant from Ad5 infected culture supernatant. Fiber containing fractions were further characterized for their capacity to inhibit the infection of Ad5-GFP vector, their composition in adenovirus structural proteins using western blot and LC-MS/MS and their capacity in remolding cell-cell junctions. Fiber molecules in complexes containing penton base and hexon, or mainly hexon were identified. Only the fiber complexes with relatively high content of penton base, but not the fiber-hexon complexes with low penton base, were able to penetrate into T84 cells and cause distortion of cell-cell junctions. Our findings suggest that these two types of fiber complexes may play different roles in adenoviral infection. [ABSTRACT FROM AUTHOR]

Objective: Mercury is a ubiquitous environmental contaminant with toxic outcomes over a range of exposures. In this study, we investigated the effects of mercury exposure on early immune responses to coxsackievirus B3 (CVB3) infection in a murine model of autoimmune heart disease. Materials and methods: Female BALB/c mice, susceptible to CVB3-induced autoimmune myocarditis, were treated with mercuric chloride (200 μg/kg body weight every other day for 2 weeks) prior to infection with CVB3. Six hours post-infection, immune cells were isolated from the spleen and peritoneum for flow cytometry, gene expression, and cytokine profiling. Thirty-five days post-infection, hearts were collected for histological examination of immune cell infiltration. Results: As for male mice, mercury exposure significantly increased autoimmune myocarditis and immune infiltration into the heart. During the innate response 6 h post-infection, mercury increased expression of co-stimulatory molecules and innate immune receptors on peritoneal macrophages. At the same time point, the alternatively activated macrophage gene, arginase, was increased while the classically activated macrophage gene, inducible nitric oxide synthase, was unaffected. Expression of activation markers were decreased on peritoneal B cells with mercury exposure while T cells were unaffected. Mercury increased production of pro-inflammatory mediators in the spleen. Macrophage-recruiting chemokines and activating cytokines, such as CCL2, CCL4, and IL-6, were increased with mercury following CVB3 infection. Conclusions: Thus, mercury treatment exacerbates autoimmune myocarditis in female mice and alters early innate signaling on peritoneal macrophages. Mercury also modulates the cytokine profile in the spleen toward a macrophage-activating milieu, and upregulates alternatively activated macrophage genes, providing evidence that mercury exposure promotes inflammation in the context of infection. [ABSTRACT FROM AUTHOR]

Viral myocarditis, which is most prevalently caused by coxsackievirus B3 (CVB3) infection, is a serious clinical condition characterized by cardiac inflammation. Inflammasome plays an essential role in the regulation of diverse inflammatory responses by serving as a platform for caspase-1 activation and caspase-1-dependent proteolytic maturation and secretion of IL-1β. Although inflammasome has been reported to be crucial for the development of many inflammatory diseases, its role in the pathogenesis of viral myocarditis is still elusive. The present study aims to investigate whether CVB3 infection activates inflammasome and whether the activation of inflammasome contributes to CVB3-induced myocarditis. Our results showed that CVB3 infection induced inflammasome activation both in vitro and in vivo. With the inhibition of inflammasome activation, the severity of CVB3-induced myocarditis was significantly alleviated as evidenced by less weight loss, decreased serological indexes of creatine kinase and creatine kinase-MB activities, as well as less severe myocardial injury. Of importance, echocardiography results showed that inhibition of inflammasome activation also efficiently improved cardiac function as revealed by enhanced left ventricular ejection fraction and left ventricular fractional shortening. Despite that CVB3 infection significantly increased the expression of both retinoic acid-inducible gene 1 and NOD-like receptor family, pyrin domain containing 3 (NLRP3) in cardiac myocytes, CVB3-induced inflammasome activation was NLRP3-, but not retinoic acid-inducible gene 1, dependent. Further study showed that reactive oxygen species production and K+ efflux were critical for the activation of NLRP3 inflammasome upon CVB3 infection. Collectively, our study demonstrated a crucial role of the NLRP3 inflammasome in the pathogenesis of CVB3-induced myocarditis, and modulation of inflammasome activation might represent a promising therapeutic strategy for viral myocarditis. [ABSTRACT FROM AUTHOR]

Coxsackievirus A16 (CA16) is one of the main causative pathogens of hand, foot and mouth disease (HFMD). Viral replication typically results in host cell apoptosis. Although CA16 infection has been reported to induce apoptosis in the human rhabdomyosarcoma (RD) cell line, it remains unclear whether CA16 induces apoptosis in diverse cell types, especially neural cells which have important clinical significance. In the current study, CA16 infection was found to induce similar apoptotic responses in both neural cells and non-neural cells in vitro, including nuclear fragmentation, DNA fragmentation and phosphatidylserine translocation. CA16 generally is not known to lead to serious neurological symptoms in vivo. In order to further clarify the correlation between clinical symptoms and cell apoptosis, two CA16 strains from patients with different clinical features were investigated. The results showed that both CA16 strains with or without neurological symptoms in infected patients led to neural and muscle cell apoptosis. Furthermore, mechanistic studies showed that CA16 infection induced apoptosis through the same mechanism in both neural and non-neural cells, namely via activation of both the mitochondrial (intrinsic) pathway-related caspase 9 protein and the Fas death receptor (extrinsic) pathway-related caspase 8 protein. Understanding the mechanisms by which CA16 infection induces apoptosis in both neural and non-neural cells will facilitate a better understanding of CA16 pathogenesis. [ABSTRACT FROM AUTHOR]

Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load. [ABSTRACT FROM AUTHOR]

An increase in the incidence of hand, foot and mouth disease (HFMD) cases has been observed in the Hunan province of mainland China since 2009 with a particularly higher level of severe cases in 2010–2012. Intestinal viruses of the picornaviridae family are responsible for the human syndrome associated with HFMD with enterovirus 71 (EV71) and Coxsackievirus A16 (Cox A16) being the most common causative strains. HFMD cases associated with EV71 are generally more severe with an increased association of morbidity and mortality. In this study, the etiology surveillance data of HFMD cases in Hunan province from March 2010 to October 2012 were analyzed to determine if there is a statistically relevant linear correlation exists between the detection rate of EV71 in mild cases and the proportion of severe cases among all HFMD patients. As the cases progressed from mild to severe to fatal, the likelihood of EV71 detection increased (25.78%, 52.20% and 84.18%, respectively). For all cases in the timeframe evaluated in this study, the presence of virus was detected in 63.21% of cases; among cases showing positivity for virus, EV71 infection accounted for 50.14%. These results provide evidence to support the observed higher morbidity and mortality associated with this outbreak and emphasizes the importance of early detection in order to implement necessary prevention measures to mitigate disease progression. [ABSTRACT FROM AUTHOR]