Identification of neurological complications in childhood influenza: a random forest model.

BACKGROUND: Among the neurological complications of influenza in children, the most severe is acute necrotizing encephalopathy (ANE), with a high mortality rate and neurological sequelae. ANE is characterized by rapid progression to death within 1-2 days from onset. However, the knowledge about the early diagnosis of ANE is limited, which is often misdiagnosed as simple seizures/convulsions or mild acute influenza-associated encephalopathy (IAE). OBJECTIVE: To develop and validate an early prediction model to discriminate the ANE from two common neurological complications, seizures/convulsions and mild IAE in children with influenza. METHODS: This retrospective case-control study included patients with ANE (median age 3.8 (2.3,5.4) years), seizures/convulsions alone (median age 2.6 (1.7,4.3) years), or mild IAE (median age 2.8 (1.5,6.1) years) at a tertiary pediatric medical center in China between November 2012 to January 2020. The random forest algorithm was used to screen the characteristics and construct a prediction model. RESULTS: Of the 433 patients, 278 (64.2%) had seizures/convulsions alone, 106 (24.5%) had mild IAE, and 49 (11.3%) had ANE. The discrimination performance of the model was satisfactory, with an accuracy above 0.80 from both model development (84.2%) and internal validation (88.2%). Seizures/convulsions were less likely to be wrongly classified (3.7%, 2/54), but mild IAE (22.7%, 5/22) was prone to be misdiagnosed as seizures/convulsions, and a small proportion (4.5%, 1/22) of them was prone to be misdiagnosed as ANE. Of the children with ANE, 22.2% (2/9) were misdiagnosed as mild IAE, and none were misdiagnosed as seizures/convulsions. CONCLUSION: This model can distinguish the ANE from seizures/convulsions with high accuracy and from mild IAE close to 80% accuracy, providing valuable information for the early management of children with influenza.

Modified nusinersen intrathecal injection method: inclusion of a septal needle-free closed infusion connector.

Objective: Nusinersen, an extremely expensive biologic drug (around 100,000 US$ per dose) that needs to be administered intrathecally, is approved for the treatment of 5q-spinal muscular atrophy (SMA). Because of the low muscle tone of the back muscles of pediatric SMA patients, especially type 1 SMA patients, the safe, effective, and fast execution of sheath injection is needed. Therefore, a modified intrathecal injection method was developed accordingly. This paper aims to describe the applicability and safety of this modified method. Methods: The modified intrathecal injection method (MIIM) mainly includes a septal needle-free closed infusion connector between the lumbar puncture needle and the syringe, besides the procedures of routine lumbar puncture. Its applicability and safety were evaluated through clinical observation. Results: A total of 92 children with SMA have successfully received nusinersen treatment at our hospital using the modified method since 2019 without obvious adverse events related to the modified injection method. Based on the clinical feedback of operators, the advantages of the modified method include successfully injecting the total dose of nusinersen with constant injection rate and a more stable fixation of the puncture needle, as well as making the operator more relaxed. However, compared with the routine method, the procedure of the modified method has additional steps. Conclusion: The modified intrathecal injection method is an effective and safe method to inject nusinersen when weighing the pros and cons, and it may also be used for administering intrathecal injections of other expensive medicines or for patients with other strict requirements for intrathecal injection.

Clinical evaluation of acute necrotizing encephalopathy in children.

Objective: Acute necrotizing encephalopathy (ANE) is a rare but severe encephalopathy and is associated with a high morbidity and mortality. We aimed to analyze and compare the clinical features and predictive indicators of pediatric ANE. Materials and methods: This retrospective study included children with ANE diagnosed at Guangzhou Women and Children's Medical Center between November 2018 and January 2020. Pediatric patients' information, including clinical characteristics, laboratory tests, neuroelectrophysiology and brain magnetic resonance imaging (MRI) findings, MRI score, brainstem auditory evoked potential (BAEP) grades, ANE severity scores (ANE-SS), and modified Rankin scale (mRS), were collected. Results: Twelve ANE patients were included. Among them, one patient (8.3%) died from brainstem dysfunction, one (8.3%) recovered and 10 (83.3%) experienced neurological sequelae. All patients had an initial viral infection and neurological symptoms such as acute disturbance of consciousness (ADOC) or seizure, and the interval from onset of the disease to neurological manifestations was 3 (1.25-3) days. MRI score-I ranged from 1 to 3 (1.8 ± 0.7), MRI score-II ranged from 1 to 4 (2.5 ± 1.1). ANE-SS varied from 1 to 6 (3.9 ± 1.3). The scores of mRS were from 0 to 6 (2.9 ± 1.7). Higher MRI score were associated with worse outcomes, while the BAEP grade and ANE-SS score were not significantly associated with mRS. Conclusion: ANE is a severe encephalopathy syndrome with rapid progression, resulting in serious neurological sequelae. Compared with BAEP grade and ANE-SS, brain MRI shows more comprehensive advantages in predicting the prognosis of ANE patients. More in-depth research and better indicators are still needed to support the evaluation and treatment of ANE.

Enterovirus 71 VP1 promotes 5-HT release by upregulating the expression of ERICH3 and methyltransferase ZC3H13.

BACKGROUND AND AIM: The effect of structural viral protein 1 (VP1) on neurological damage caused by enterovirus 71 (EV71) infection is unclear. This study aimed to explore the transcriptome changes in EV infected patients and the role of VP1 on the cell secretion pathway of neuron cells. METHODS: In our cohort, EV infected patients were enrolled, and RNA-seq analysis was used to evaluate the distinct transcript patterns of cerebrospinal fluid (CSF). The EV71 VP1-overexpressing vector (pEGFP-c3-VP1) was generated and transfected into neuron cells. The relationship between Glutamate Rich 3 (ERICH3) and methyltransferase Zinc Finger CCCH-Type Containing 13 (ZC3H13) and their effect on the serotonin (5-HT) release of neuron cells were explored using small interfering RNA. The expression of ERICH3 and ZC3H13 and concentration of 5-HT were determined using real-time PCR, Western blot, and ELISA, respectively. RESULT: The expression of ERICH3 and ZC3H13 were significantly upregulated in EV infected patients with neurological symptoms compared to those without (P < 0.05). The ERICH3 gene had many N6-methyladenosine (m6A) binding sites that can be regulated by m6A modification. Further, the expression of ERICH3 and ZC3H13 were elevated significantly in EV71-VP1 overexpressing neuron cells (P < 0.05). Moreover, ERICH3 or ZC3H13 deficiency could significantly downregulate the release of 5-HT in VP1-overexpressing cells (P < 0.05). Nonetheless, ERICH3 expression was significantly suppressed when ZC3H13 was silenced in neuron cells and vice versa (P < 0.05). CONCLUSIONS: EV71-VP1 can promote 5-HT release by upregulating the expression of ERICH3 and ZC3H13. 5-HT might be a novel therapeutic target for EV71 infection-induced fatal neuronal damage.

Risk Factors for Severe Hand-Foot-Mouth Disease in China: A Systematic Review and Meta-Analysis.

Background: This study aimed to identify potential risk factors for severe hand-foot-mouth disease (HFMD). Methods: The PubMed, Embase, the Cochrane Library, Sinomed, WanFang, CNKI, and VIP databases were searched (up to August 2021). Results: Twenty-nine studies (9,241 and 927,355 patients with severe HFMD and controls, respectively; all from China) were included. EV71 was associated with higher odds of severe HFMD compared with other agents (OR = 4.44, 95%CI: 3.12-6.33, p < 0.001). Being home-raised (OR = 1.99, 95%CI: 1.59-2.50, p < 0.001), higher number of children in the family (OR = 2.09, 95%CI: 1.93-2.27, p < 0.001), poor hand hygiene (OR = 2.74, 95%CI: 1.78-4.23, p < 0.001), and no breastfeeding (OR = 2.01, 95%CI: 1.45-2.79, p < 0.001) were risk factors for severe HFMD. First consulting to a district-level or above hospital (OR = 0.34, 95%CI: 0.25-0.45, p < 0.001) and diagnosis of HFMD at baseline (OR = 0.17, 95%CI: 0.13-0.24, p < 0.001) were protective factors against severe HFMD. Fever, long fever duration, vomiting, lethargy, leukocytosis, tic, and convulsions were each associated with severe HFMD (all p < 0.05), while rash was not. Conclusions: EV71, lifestyle habits, frequent hospital visits, and symptoms are risk factors for severe HFMD in children in China, while early diagnosis and admission to higher-level hospitals are protective factors.

Characterization of Enterovirus Associated m6A RNA Methylation in Children With Neurological Symptoms: A Prospective Cohort Study.

Little is known about the particular changes of N6-methyladenosine (m6A) RNA methylation in enterovirus (EV) infection among children with neurologic symptoms. Here, we determined the characterization of EV associated m6A RNA methylation in this population. A prospective cohort study was conducted from 2018/2 to 2019/12 at the Guangzhou Women and Children's Medical Center. We included EV infected children with and without neurological symptoms. High-throughput m(6)A-RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq analysis were used to evaluate the m6A RNA methylation and transcript expression of cerebrospinal fluid samples. The functional annotation and pathways of differentially methylated m6A genes with synchronously differential expression were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Seven patients were enrolled in the control group, and 13 cases were in the neurological symptoms (NS) group. A total of 3472 differentially expressed genes and 957 m6A modified genes were identified. A conjoint analysis of MeRIP-seq and RNA-seq data found 1064 genes with significant changes in both the m6A modifications and mRNA levels. The different m6A RNA methylation was increased in the transcriptome's CDS regions but decreased in both the 3'UTRs and stop codon among the NS group. Functional annotation like the "oxidative phosphorylation" gene pathway, "Parkinson's disease" and GO terms like "respiratory electron transport chain," "cellular metabolic process," and "oxidation-reduction process" was enriched in symptomatic patients. Our study elucidated the changes of RNA m6A methylation patterns and related cellular functions and signaling pathways in EV patients with neurologic symptoms.

Thyroid Function and Anti-thyroid Antibodies in Pediatric Anti-NMDAR Encephalitis.

Objective: Recent studies found that changes of thyroid antibodies (ATAbs), thyroid hormone, and non-thyroidal illness syndrome (NTIS) characterized by thyroid hormone inactivation with low triiodothyronine and high reverse triiodothyronine followed by suppressed thyroid-stimulating hormone (TSH) in adult anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis were associated with disease severity. This study aimed to explore thyroid function and ATAbs in pediatric anti-NMDAR encephalitis and their clinical association. Methods: We retrospectively analyzed the clinical data of 51 pediatric cases with anti-NMDAR encephalitis hospitalized in Guangzhou Women and Children's Medical Center from August 2016 to 2019. Results: A percentage of 52.9% of patients belonged to the ATAb (+) group, with 26 cases both positive for anti-thyroid peroxidase antibodies (TPOAb) and anti-thyroglobulin antibodies (TGAb), and one patient only positive for TPOAb. A percentage of 62.7% of patients had at least one abnormality in terms of FT3, free thyroxin (FT4), or TSH levels. Meanwhile, 45.1% of patients were diagnosed with NTIS. Among 25 cases retested for thyroid function 2 months after the initial test, the respectively decreased FT3 and FT4 in 13 and 11 cases on admission returned to normal or closer normal than before; TPOAb in eight cases and TGAb in 12 cases were changed from positivity to negativity. Compared with onset, the level of TPOAb and TGAb at relapse remained stable or significantly decreased, respectively. Compared with the ATAb (-) group, the ATAb (+) group had an older onset age, a higher ratio of movement disorders, elevated rate of sleep disorders, increased anti-nuclear antibody positivity rate, and higher ratio of more than one course of intravenous immunoglobulin treatment. There were no significant differences between the NTIS and non-NTIS groups in clinical characteristics. Conclusion: Anti-thyroid antibody positivity, abnormality of FT3, FT4, or TSH levels and NTIS are frequent in pediatric anti-NMDAR encephalitis. Thyroid antibody and thyroid hormone abnormalities could be improved through the course of treatment of anti-NMDAR encephalitis. Cases with ATAbs (+) are at older onset ages and more likely to be treated by intravenous immunoglobulin therapy more than once. Unlike adult anti-NMDAR encephalitis, NTIS might not be associated with the clinical characteristics of anti-NMDAR encephalitis in pediatric patients.

Parameters Indicating Development of Influenza-Associated Acute Necrotizing Encephalopathy: Experiences from a Single Center.

BACKGROUND Influenza-associated acute necrotizing encephalopathy (IANE) can be lethal and disabling and have a sudden onset and deteriorate rapidly but lacks early diagnostic indicators. We aimed to examine the early clinical diagnostic indicators in children with IANE. MATERIAL AND METHODS Acute influenza patients were grouped according to their clinical manifestations: flu alone (FA), flu with febrile seizure (FS), influenza-associated encephalopathy (IAE), and IANE. The clinical features, biomarkers, neuroelectrophysiological results, and neuroimaging examination results were compared. RESULTS A total of 31 patients were included (FA (n=4), FS (n=8), IAE (n=14), and IANE (n=5)). The IANE group, whose mean age was 3.7 years, was more likely to show rapid-onset seizure, acute disturbance of consciousness (ADOC), Babinski's sign, and death/sequela. More patients in the IANE group required tracheal intubation mechanical ventilation and received intravenous immunoglobulins (IVIG) and glucocorticoids. The alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels in the IANE group were significantly higher than in the FS and IAE groups. The aquaporin-4 (AQP-4) antibody and malondialdehyde (MDA) levels in the serum and cerebrospinal fluid (CSF) were notably higher in IANE patients in the acute stage compared with FS and IAE patients. All patients in the IANE group had positive neuroimaging findings. CONCLUSIONS Early clinical warning factors for IANE include rapid-onset seizures in patients under 4 years of age, ADOC, and pathological signs. Increased AQP-4 antibodies and MDA levels in CSF might contribute to early diagnosis. Early magnetic resonance venography (MRV) and susceptibility-weighted imaging (SWI) sequences, or thrombelastography to identify deep vein thrombosis, might indicate clinical deterioration.

Pediatric anti-N-methyl-d-aspartate receptor encephalitis in southern China: Analysis of 111 cases.

OBJECTIVE: To study the clinical features of children diagnosed with anti-NMDAR encephalitis in southern China. METHODS: Clinical data of children diagnosed with anti-NMDAR encephalitis from October 2014 to June 2020 from one national regional medical center were analyzed. Neurological disability was assessed by modified Rankin Scale (mRS) throughout the course of disease. RESULTS: 111 children (M/F = 49/62; mean onset age = 6.8 y) with anti-NMDAR encephalitis were involved. Prodromal events occurred in 34.2% of patients with infectious events being the most common. Seizure was the most common initial symptom, though movement disorder served as the most common event throughout the course of disease. 9.9% of patients had overlapped with other neuronal autoantibodies. Electroencephalogram showed abnormalities with slow wave (100.0%), epileptic discharge (31.5%) and delta brush (8.1%) respectively. 41.4% of patients had abnormal brain MRI, with focal lesions being the most common. None patients had tumor. 80.9% of patients had good response to first line therapy (steroid plus immunoglobulin), while 14 patients accepted second-line therapy (Rituximab) and all had a good response. Boys were significantly more likely to need more course of steroid. 13.8% of patients relapsed. 2 male patients died. mRS score was significantly improved after treatment. 51.4% of patients had a full recovery and 81.7% had mRS score ≤ 2. The median mRS score of boys after treatment was higher than that of girls. Non-infectious prodromal event, past medical history, perivascular lesions in brain MRI, hospital stay, initial mRS score higher than 3, and RTX treatment were independent risk factors associated with poor prognosis, defined as mRS score > 2. CONCLUSION: Of pediatric anti-NMDAR encephalitis in southern China: median onset age around 7 years; girls more common; boys might have poor outcome than girls; seizure or movement disorder respectively being most common onset or course symptom; a few overlapped with other neuronal autoantibodies; rare combined with tumor; most had a good response to immunotherapy and a good prognosis; relapse rate relatively high; fatality rate relatively low; some risk factors associated with poor prognosis.

Influenza-Associated Encephalopathy and Acute Necrotizing Encephalopathy in Children: A Retrospective Single-Center Study.

BACKGROUND Although influenza primarily affects the respiratory system, it can cause severe neurological complications, especially in younger children, but knowledge about the early indicators of acute necrotizing encephalopathy (ANE) is limited. The main purpose of this article is to summarize the clinical characteristics, diagnosis, and treatment of neurological complications of influenza in children, and to identify factors associated with ANE. MATERIAL AND METHODS This was a retrospective study of children with confirmed influenza with neurological complications treated between 01/2014 and 12/2019 at Guangzhou Women and Children's Medical Center. A receiver operating characteristics curve analysis was performed to determine the prognostic value of selected variables. RESULTS Sixty-three children with IAE (n=33) and ANE (n=30) were included. Compared with the IAE group, the ANE group showed higher proportions of fever and acute disturbance of consciousness, higher alanine aminotransferase, higher aspartate aminotransferase, higher creatinine kinase, higher procalcitonin, higher cerebrospinal fluid (CSF) protein, and lower CSF white blood cells (all P<0.05). The areas under the curve (AUCs) for procalcitonin and CSF proteins, used to differentiate IAE and ANE, were 0.790 and 0.736, respectively. The sensitivity and specificity of PCT >4.25 ng/ml to predict ANE were 73.3% and 100.0%, respectively. The sensitivity and specificity of CSF protein >0.48 g/L to predict ANE were 76.7% and 69.7%, respectively. Thirteen (43.3%) children with ANE and none with IAE died (P<0.0001). CONCLUSIONS High levels of CSF protein and serum procalcitonin might be used as early indicators for ANE. All children admitted with neurological findings, especially during the influenza season, should be evaluated for influenza-related neurological complications.

Brainstem folding in an influenza child with Dandy-Walker variant.

BACKGROUND: Influenza in children is a major cause of morbidity and mortality worldwide. Nervous system diseases are a factor relating to increased mortality rate. However, reports of how these underlying diseases contribute to the death of children with influenza are rare. CASE SUMMARY: A 4-year-old-girl developed type A influenza-related encephalopathy (IAE) with seizures, acute disorder of consciousness, and intracranial hypertension (cerebrospinal fluid pressure: 250 mmH2O), and the Dandy-Walker variant was found by her first magnetic resonance imaging (MRI) when admission. Three days later, she suddenly presented anisocoria, acute pulmonary edema, and coma, and the later MRI found that she had compressed brainstem, oblongata "Z-like folding", and swelling bilateral basal ganglia. After admission, the patient were tested for routine and special biomarkers and underwent neuroimaging and neuroelectrophysiology examinations as well as Oseltamivir and intravenous immunogloblin treatments. When predicting that unstable intracranial structures detected by MRI might have disastrous consequences in the progression of IAE, she was transferred into the pediatric intensive care unit and underwent continuous assessment of clinical condition while she did not have instability of basic vital signs; at the same time, her parents were fully informed about the risk and prognosis. Although she was ultimately dead from brain stem failure, the parents expressed understanding and did not trigger a doctor-patient conflict. CONCLUSION: In case of finding an unstable intracranial structure, intensive care should be given to IAE patient and their clinical condition should be monitored continuously.

Delayed diagnosis of X-linked agammaglobulinaemia in a boy with recurrent meningitis.

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a rare inherited primary immunodeficiency disease characterized by the B cell developmental defect, caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK), which may cause serious recurrent infections. The diagnosis of XLA is sometimes challenging because a few number of patients have higher levels of serum immunoglobulins than expected. In this study, we reported an atypical case with recurrent meningitis, delayed diagnosis with XLA by genetic analysis at the second episode of meningitis at the age of 8 years. CASE REPORT: An 8-year-old Chinese boy presented with fever, dizziness and recurrent vomiting for 3 days. The cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) results were suggestive of bacterial meningoencephalitis, despite the negative gram staining and cultures of the CSF. The patient was treated with broad-spectrum antibiotics and responded well to the treatment. He had history of another episode of acute pneumococci meningitis 4 years before. The respective level of Immunoglobulin G (IgG), Immunoglobulin A (IgA) and Immunoglobulin M (IgM) was 4.85 g/L, 0.93 g/L and 0.1 g/L at 1st episode, whereas 1.9 g/L, 0.27 g/L and 0 g/L at second episode. The B lymphocytes were 0.21 and 0.06% of peripheral blood lymphocytes at first and second episode respectively. Sequencing of the BTK coding regions showed that the patient had a point mutation in the intron 14, hemizyous c.1349 + 5G > A, while his mother had a heterozygous mutation. It was a splice site mutation predicted to lead to exon skipping and cause a truncated BTK protein. CONCLUSION: Immunity function should be routinely checked in patients with severe intracranial bacterial infection. Absence of B cells even with normal level of serum immunoglobulin suggests the possibility of XLA, although this happens only in rare instances. Mutational analysis of BTK gene is crucial for accurate diagnosis to atypical patients with XLA.

Enterovirus 71 VP1 promotes mouse Schwann cell autophagy via ER stress­mediated PMP22 upregulation.

Enterovirus 71 (EV71) accounts for the majority of hand, foot and mouth disease­related deaths due to fatal neurological complications. EV71 structural viral protein 1 (VP1) promotes viral replication by inducing autophagy in neuron cells, but the effect of VP1 on myelin cells is unclear. The present study aimed to investigate the role and mechanism of VP1 in autophagy of mouse Schwann cells. An EV71 VP1­expressing vector (pEGFP­C3­VP1) was generated and transfected into mouse Schwann cells. Transmission electron microscopy and western blot analysis for microtubule­associated protein 1 light chain 3 α (LC3) II (an autophagy marker) were used to assess autophagy. Reverse transcription­quantitative PCR and immunofluorescence were performed to determine the expression of peripheral myelin protein 22 (PMP22). Small interfering RNA against PMP22 was used to investigate the role of PMP22 in mouse Schwann cell autophagy. Salubrinal [a selective endoplasmic reticulum (ER) stress inhibitor] was used to determine whether PMP22 expression was affected by ER stress. The present results indicated that VP1 promoted mouse Schwann cell autophagy. Overexpression of VP1 upregulated PMP22. PMP22 deficiency downregulated LC3II and thus inhibited autophagy. Furthermore, PMP22 expression was significantly suppressed by salubrinal. In conclusion, VP1 promoted mouse Schwann cell autophagy through upregulation of ER stress­mediated PMP22 expression. Therefore, the VP1/ER stress/PMP22 autophagy axis may be a potential therapeutic target for EV71 infection­induced fatal neuronal damage.

Clinical manifestations of severe enterovirus 71 infection and early assessment in a Southern China population.

BACKGROUND: Enterovirus 71 (EV-A71) shows a potential of rapid death, but the natural history of the infection is poorly known. This study aimed to examine the natural history of EV-A71 infection. METHODS: This was a prospective longitudinal observational study performed between January 1st and October 31st, 2012, at three hospitals in Guangdong, China. Subjects with positive EV-A71 RNA laboratory test results were included. Disease progression was documented with MRI, autopsies, and follow-up. Symptoms/signs with potential association with risk of death were analyzed. RESULTS: Among the 288 patients, neurologic symptoms and signs were observed (emotional movement disorders, dyskinesia, involuntary movements, autonomic dysfunction, and disturbance of consciousness). Some of them occurred as initial symptoms. Myoclonic jerks/tremors were observed among >50% of the patients; nearly 40% of patients presented fatigue and 25% were with vomiting. Twenty-eight patients (9.7%) presented poor peripheral perfusion within 53.4 ± 26.1 h; 23 patients (8.0%) presented pulmonary edema and/or hemorrhage within 62.9 ± 28.6 h. Seventeen (5.9%) patients were in a coma. Seven (2.4%) patients died within 62.9 ± 28.6 h. Seventy-seven survivors underwent head and spinal cord MRI and 37.7% (29/77) showed abnormalities. Two fatal cases showed neuronal necrosis, softening, perivascular cuffing, colloid, and neuronophagia phenomenon in the brainstem. CONCLUSIONS: Patients with EV-A71 infection showed high complexity of symptoms and onset timing. Death risk may be indicated by autokinetic eyeball, eyeball ataxia, severe coma, respiratory rhythm abnormality, absent pharyngeal reflex, ultrahyperpyrexia, excessive tachycardia, pulmonary edema and/or hemorrhage, and refractory shock and ataxic respiration. Early assessment of these symptoms/signs is important for proper management.

Glucocorticoids Prevent Enterovirus 71 Capsid Protein VP1 Induced Calreticulin Surface Exposure by Alleviating Neuronal ER Stress.

Severe hand-foot-and-mouth disease (HFMD) caused by Enterovirus 71 (EV71) always accompanies with inflammation and neuronal damage in the central nervous system (CNS). During neuronal injuries, cell surface-exposed calreticulin (Ecto-CRT) is an important mediator for primary phagocytosis of viable neurons by microglia. Our data confirmed that brainstem neurons underwent neuronophagia by glia in EV71-induced death cases of HFMD. EV71 capsid proteins VP1, VP2, VP3, or VP4 did not induce apoptosis of brainstem neurons. Interestingly, we found VP1-activated endoplasmic reticulum (ER) stress and autophagy could promote Ecto-CRT upregulation, but ER stress or autophagy alone was not sufficient to induce CRT exposure. Furthermore, we demonstrated that VP1-induced autophagy activation was mediated by ER stress. Meaningfully, we found dexamethasone treatment could attenuate Ecto-CRT upregulation by alleviating VP1-induced ER stress. Altogether, these findings identify VP1-promoted Ecto-CRT upregulation as a novel mechanism of EV71-induced neuronal cell damage and highlight the potential of the use of glucocorticoids to treat severe HFMD patients with CNS complications.

Reversible splenial lesion syndrome in children: Retrospective study and summary of case series.

OBJECTIVE: To describe clinical features of reversible splenial lesion syndrome (RESLES) in children. METHODS: Retrospectively analyzed clinical features of RESLES in children and compared differences between severe and non-severe group, classified by clinical global impression-scale; summarized clinical features of children with mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) from case series. RESULTS: 16 episodes of RESLES occurring in 15 Chinese children were analyzed, with 13 episodes having MERS and 3 episodes with epilepsy. 10 episodes were associated with various pathogens including rotavirus (n=5), adenovirus (n=1), influenza A (n=1), mycoplasma (n=2), and jejunum campylobacter (n=1). The common neurological symptoms included seizure, behavioral changes, altered consciousness and motor deterioration. The lesions of splenium of corpus callosum (SCC), extra-SCC (n=2) or extra-CC (n=1) showed T2-weight and FLAIR hyper-intensity, with the corresponding reduced diffusion. All had complete resolution of radiological changes except 1 episode with small residual. 8 episodes had EEG abnormalities, while elevated white blood count, increased hs-CRP, and hyponatremia were commonly revealed. 7 episodes were given steroid plus therapy, while 3 episodes were treated with antiepileptic drugs. Compared with non-severe group, the number of patients with altered consciousness, EEG abnormalities, motor deterioration, or extra-SCC lesions in severe group was significantly increased. The patients in severe group tended to need longer hospital stay interval. No case caused neurological sequelae, except 1 patient in severe group with recurrent episode and extra-CC lesions having intellectual disability (ID). Five pediatric MERS case series were summarized, including 67 episodes (40 male and 27 female; age ranging 10 m∼13y) from 65 patients, with 33 episodes in Japan, 27 in China, and 7 in Caucasian Australian children, and all patients have a good prognosis except 1 patient with ID (current study). CONCLUSION: Although RESLES in children tend to be a good outcome, the prognosis of patient in severe group, especially with extra-CC lesions, might have neurological sequelae.

[Molecular Epidemiology of Astrovirus Infection Among Hospitalized Infants in Kunming City, China, 2013～2014].

We investigated the infection and molecular-epidemiologic characteristics of human astrovirus (HAstV) of hospitalized infants in Kunming City from the year 2013 to 2014.Infection and genotype of HAstV of 63 samples of diarrheal feces and 42 controls were analyzed by reverse transcription-polymerase chain reaction(RT-PCR).The complete genome sequence of a HAstV strain was amplified and sequenced. The positive rate of HAstV in 63 feces samples was 41.27%(26/63).The main circulating genotype of HAstV was HAstV1.Only 1sample was positive for HAstV in 42controls(2.38%).A complete genome sequence of the HAstV strain was identified as HAstV1 by phylogenetic analyses. These data provide an important theoretical basis for the control of viral diarrhea in infants in Kunming City.