Clinical outcomes of pediatric Anti-NMDA receptor encephalitis.

OBJECTIVE: To investigate the clinical features and long-term outcomes of pediatric Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: Thirty-two anti-NMDAR encephalitis patients with positive anti-NMDAR antibody test results were recruited. Clinical outcomes were evaluated using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) and the modified Rankin Scale (mRS). RESULTS: The median age of onset was 9.0 years (range, 0.7-17.2 years). Twenty-four patients (75.0%) were female. All patients received first-line immunotherapy including intravenous immunoglobulin and/or steroid therapy. The second-line immunotherapy was administered to 22 patients (68.8%). Clinical outcomes were evaluated in 27 patients who were followed for longer than 6 months after onset, among whom the median follow-up duration was 31.2 months (range, 6.3-82.9 months). The proportion of patients with ≤2 points on the mRS at their 12-month follow-up was 79.2% (19/24). The CASE scores of these 19 patients ranged from 0 to 5, with language and memory deficits accounting for most of these disabilities. When the outcome was assessed according to onset age (<12 years or 12-18 years), the younger group tended to show a slower recovery over their clinical course. CONCLUSIONS: Despite overall favorable clinical outcomes, mild cognitive problems, including language and memory, may persist in pediatric anti-NMDAR encephalitis patients. A specific outcome measure, such as CASE, should be adopted to delineate clinical outcomes and aid the development of individualized treatment plans.

Elevated fecal calprotectin levels are associated with severity of atopic dermatitis in children.

BACKGROUND: Recent data suggested that imbalance in gut microbiota and gastrointestinal inflammation are associated with the childhood allergic disease. Fecal calprotectin has been used for a non-invasive marker of gut inflammation. OBJECTIVE: The aim of this study was to investigate the relationships between fecal calprotectin level and the clinical severity of atopic dermatitis (AD) in children. METHODS: We enrolled 65 subjects with AD. The concentration of calprotectin was measured in each subject's fecal sample. RESULTS: The geometric mean fecal calprotectin level of the total subjects was 33.1(10.1-108.9) µg/g. Among the 65 subjects, 44(67.7%) showed calprotectin levels lower than 50µg/g(Group 1), and 21(32.3%) were higher than 50µg/g(Group 2). The mean SCORAD index was significantly higher in Group 2 than Group 1(31.0±16.0 vs 22.2±15.3, p=0.046). The geometric mean serum total IgE levels was higher in Group 2 compared to Group 1(361.4[31.6-992.3]IU/mL vs 175.9[44.3-699.2]IU/mL, p=0.040). The mean blood eosinophils were significantly higher in Group 2 than in Group 1(497.7[239.8-1032.8]/µL vs 281.5[121.5-652.0]/µL, p=0.034). The incidence of exposure to environmental tobacco smoke was significantly higher in Group 2 compared to Group 1(76.2% vs 47.7%, p=0.036). Geometric mean fecal calprotectin level in severe AD was significantly higher than that of mild-to-moderate AD(66.7[13.5-330.3]µg/g vs 29.4[10.1-85.6]µg/g, p=0.044). The fecal calprotectin level significantly correlated with the SCORAD index(r=0.303, p=0.014). CONCLUSIONS: Higher fecal calprotectin levels were observed in subjects with severe AD. Elevated fecal calprotectin level as a gastrointestinal inflammatory marker may associate with childhood AD. Measurement of fecal calprotectin might be useful for assessment of severity of childhood AD.

Neuroprotective Effect of Lacosamide on Hypoxic-Ischemic Brain Injury in Neonatal Rats.

BACKGROUND AND PURPOSE: Lacosamide (LCM) is an antiepileptic drug that enhances the slow inactivation of sodium channels and modulates collapsin response mediator protein-2. LCM was recently demonstrated to exert a neuroprotective effect in a murine model of traumatic brain injury and status epilepticus. Assuming the same underlying excitotoxicity-related brain injury mechanism, we hypothesized that LCM would have a neuroprotective effect in hypoxic-ischemic brain injury. METHODS: We divided rats into three groups at each testing session: pre- or postfed with LCM, fed with normal saline, and sham. A hypoxic-ischemic brain injury was induced by subjecting 7-day-old rats to right carotid artery coagulation followed by 2.5 h of exposure to 8% oxygen. The animals were killed on postnatal day 12 to evaluate the severity of brain damage. Open field testing was also performed between week 2 and week 6, and the Morris water maze test was performed in week 7 after hypoxia-ischemia. RESULTS: The incidence of liquefactive cerebral infarction was lower in rats prefed with LCM at 100 mg/kg/dose, with the mortality rate being higher at higher doses (200 and 300 mg/kg/dose). The infarct areas were smaller in LCM-prefed rats in several brain regions including the hemisphere, hippocampus, cortex, and striatum. Spatial learning and memory function were better in LCM-prefed rats (p<0.05). No effect was observed in postfed rats. CONCLUSIONS: This study suggests that LCM pretreatment exerts a neuroprotective effect on hypoxia-ischemia in neonatal rats. The obtained results suggest that LCM pretreatment could be used as an effective neuroprotective method for neonates under hypoxic-ischemic conditions including heart surgery.

Application of genetically engineered Salmonella typhimurium for interferon-gamma-induced therapy against melanoma.

Salmonella have been experimentally used as anti-cancer agents, because they show selective growth in tumours. In this study, we genetically modified attenuated Salmonella typhimurium to express and secrete interferon-gamma (IFN-γ) as a tumouricidal agent to enhance the therapeutic efficacy of Salmonella. IFN-γ was fused to the N-terminal region (residues 1-160) of SipB (SipB160) for secretion from bacterial cells. Attenuated S. typhimurium expressing recombinant IFN-γ (S. typhimurium (IFN-γ)) invaded the melanoma cells and induced cytotoxicity. Subcutaneous administration of S. typhimurium (IFN-γ) also efficiently inhibited tumour growth and prolonged the survival of C57BL/6 mice bearing B16F10 melanoma compared with administration of phosphate-buffered saline (PBS), unmodified S. typhimurium or S. typhimurium expressing empty vector (S. typhimurium [Vec]) in a natural killer (NK) cell-dependent manner. Moreover, genetically modified Salmonella, including S. typhimurium (IFN-γ), showed little toxicity to normal tissues with no observable adverse effects. However, S. typhimurium (IFN-γ)-mediated tumour suppression was attributed to direct killing of tumour cells rather than to stable anti-tumour immunity. Collectively, these results suggest that tumour-targeted therapy using S. typhimurium (IFN-γ) has potential for melanoma treatment.

Norovirus in benign convulsions with mild gastroenteritis.

BACKGROUND: Benign convulsions with gastroenteritis (CwG) are defined as afebrile convulsions accompanying symptoms of gastroenteritis without evidence of laboratory derangement. Although the main pathogen has been known as rotavirus, since the introduction of rotavirus vaccine, associated viruses with CwG may have changed. Thus, we evaluated the viral association of CwG for patients admitting for recent 2.5 years. METHODS: All patients hospitalized for CwG between November 2012 and May 2015 were included in our study. Stool specimens were tested with reverse transcription polymerase chain reaction for detecting norovirus and astrovirus and with enzyme immunoassay for rotavirus and enteric adenovirus. Clinical data was gathered via chart review. RESULTS: Fifty patients were included. Except four patients who failed to collect stool samples, 46 patients were tested. Causative diarrheal viruses were detected in 38 patients and they were 29 norovirus, four rotavirus, four adenovirus, and one astrovirus. Norovirus was commonly identified during the months of November and December. No difference of the clinical characteristics and laboratory value was noted according to the number of seizure episodes. CONCLUSIONS: Norovirus is a common pathogen in CwG. Understanding the viral associations can facilitate recognition of CwG.

Common variants in the CRP promoter are associated with a high C-reactive protein level in Kawasaki disease.

Kawasaki disease (KD) is an acute self-limiting form of vasculitis that afflicts infants and children and manifests as fever and signs of mucocutaneous inflammation. Children with KD show various laboratory inflammatory abnormalities, such as elevations in their white blood cell (WBC) count, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). We here performed a genome-wide association study (GWAS) of 178 KD patients to identify the genetic loci that influence 10 important KD laboratory markers: WBC count, neutrophil count, platelet count, CRP, ESR, hemoglobin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and total protein. A total of 165 loci passed our arbitrary stage 1 threshold for replication (p < 1 × 10(-5)). Of these, only 2 SNPs (rs12068753 and rs4786091) demonstrated a significant association with the CRP level in replication study of 473 KD patients (p < 0.05). The SNP located at the CRP locus (rs12068753) demonstrated the most significant association with CRP in KD patients (beta = 4.73 and p = 1.20 × 10(-6) according to the stage 1 GWAS; beta = 3.65 and p = 1.35 × 10(-8) according to the replication study; beta = 3.97 and p = 1.11 × 10(-13) according to combined analysis) and explained 8.1% of the phenotypic variation observed. However, this SNP did not demonstrate any significant association with CRP in the general population (beta = 0.37 and p = 0.1732) and only explained 0.1% of the phenotypic variation in this instance. Furthermore, rs12068753 did not affect the development of coronary artery lesions or intravenous immunoglobulin resistance in KD patients. These results indicate that common variants in the CRP promoter can play an important role in the CRP levels in KD.

Saethre­Chotzen syndrome with an atypical phenotype: identification of TWIST microdeletion by array CGH.

Saethre­Chotzen syndrome is a very rare autosomal dominant congenital disorder characterized by craniosynostosis and acrocephalosyndactyly. It is caused by a mutation in TWIST1, located on chromosome 7p21. A shortage of functional TWIST1 protein affects the development and maturation of cells in the skull, face, and limbs. The patient described in this report displayed craniofacial features classic for Saethre­Chotzen syndrome, including craniosynostosis, low-set ears, small pinna with prominent crura, a high-arched palate, and a simian crease on the left hand. He did not have the limb anomalies commonly seen in patients with Saethre­Chotzen syndrome, and the results of conventional chromosome analysis were normal. However, results of a microarray-based comparative genomic hybridization (array CGH) study confirmed the karyotype of46,XY.7p21.1p15.3(15,957,375-20,331,837)x1, a region that includes TWIST1. Subsequent fluorescent in situ hybridization analysis confirmed this result. No other chromosome was involved in the rearrangement. This case illustrates the important contribution of array CGH to the identification of TWIST microdeletions, even in a patient not showing the phenotype typical of Saethre­Chotzen syndrome.

Relationships of methacholine and adenosine monophosphate responsiveness with serum vascular endothelial growth factor in children with asthma.

BACKGROUND: Airway hyperresponsiveness, which is a characteristic feature of asthma, is usually measured by means of bronchial challenge with direct or indirect stimuli. Vascular endothelial growth factor (VEGF) increases vascular permeability and angiogenesis, leads to mucosal edema, narrows the airway diameter, and reduces airway flow. OBJECTIVE: To examine the relationships between serum VEGF level and airway responsiveness to methacholine and adenosine monophosphate (AMP) in children with asthma. METHODS: Peripheral blood eosinophil counts, serum eosinophil cationic protein (ECP) concentrations, and serum VEGF concentrations were measured in 31 asthmatic children and 26 control subjects. Methacholine and AMP bronchial challenges were performed on children with asthma. RESULTS: Children with asthma had a significantly higher mean (SD) level of VEGF than controls (361.2 [212.0] vs 102.7 [50.0] pg/mL; P < .001). Blood eosinophil counts and serum ECP levels significantly correlated inversely with AMP provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC20) (r = -0.474, P =.01; r = -0.442, P =.03, respectively), but not with methacholine PC20 (r = -0.228, P = .26; r = -0.338, P =.10, respectively). Serum VEGF levels significantly correlated with airway responsiveness to AMP (r = -0.462; P = .009) but not to methacholine (r = -0.243; P = .19). CONCLUSIONS: Serum VEGF levels were increased in children with asthma and were related to airway responsiveness to AMP but not to methacholine. Increased VEGF levels in asthmatic children may result in increased airway responsiveness by mechanisms related to airway inflammation or increased permeability of airway vasculature.

Increased serum interleukin-5 and vascular endothelial growth factor in children with acute mycoplasma pneumonia and wheeze.

Acute mycoplasma pneumonia may be accompanied by wheeze in some children considered not to have asthma. The aim of the present study was to evaluate cytokine secretion in children with acute mycoplasma pneumonia and wheeze. We studied 58 patients with mycoplasma pneumonia (12 with wheeze, Group 1; 46 without wheeze, Group 2) and 36 patients of non-mycoplasma pneumonia (Group 3). Serum levels of interleukin (IL)-4, IL-5, interferon (IFN)-gamma, and vascular endothelial growth factor (VEGF) were measured using an enzyme-linked immunosorbent assay kits. The mean +/- SD IL-5 level of Group 1 was 97.1 +/- 73.0 pg/ml, which was significantly higher than that of Group 2 (28.2 +/- 32.2 pg/ml) and that of Group 3 (35.7 +/- 42.0 pg/ml). The mean +/- SD VEGF level of Group 1 was 687.5 +/- 385.8 pg/ml, which was significantly higher than that of Group 2 (310.0 +/- 251.9 pg/ml) and that of Group 3 (402.3 +/- 279.5 pg/ml). No significant differences in serum levels of IL-4, IFN-gamma, and IgE were observed between the groups. Our results show that children with mycoplasma pneumonia and wheeze have significantly higher serum levels of IL-5 and VEGF. These increased immune responses may be associated with the pathophysiological mechanisms by which the Mycoplasma pneumoniae contribute to the development of wheeze during acute mycoplasma pneumonia.

Comparison of cytokine responses in nasopharyngeal aspirates from children with viral lower respiratory tract infections.

AIM: To determine whether nasopharyngeal aspirates (NPAs) cytokine response is different according to the causative viruses in children with lower respiratory tract infections (LRTI). METHODS: NPAs from 277 children with LRTI caused by respiratory virus were evaluated. Based on the proven viral agents, LRTI patients were divided into four groups. Levels of IL-4, IL-5 and IFN-gamma were determined by ELISA. RESULTS: Patients with influenza virus infection demonstrated significantly lower IL-4 and IL-5 levels than those with other three groups. Patients with respiratory syncytial virus (RSV) infection showed an increase in production of IL-4 and IL-5, and a decrease in the IFN-gamma level when compared to patients with influenza virus infection. Interestingly, a similar Th2 response was seen in patients with parainfluenza virus or adenovirus infection. CONCLUSION: These results demonstrate that respiratory viruses can induce different local cytokine responses. However, Th2 biased responses are not unique for RSV but seem to be predominant in respiratory viruses of young children.