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Pediatric out-of-hospital cardiac arrest (OHCA) is a rare event with severe sequelae. Although the survival to hospital-discharge (STHD) rate has improved from 2–6% to 17.6–40.2%, only 1–4% of OHCA survivors have a good neurological outcome. This study investigated the characteristics of case management before and after admittance to the emergency department (ED) associated with outcomes of pediatric OHCA in an ED. This was a retrospective study of data collected from our ED resuscitation room logbooks dating from 2005 to 2016. All records of children under 18 years old with OHCA were reviewed. Outcomes of interest included sustained return of spontaneous circulation (SROSC), STHD, and neurological outcomes. From the 12-year study period, 152 patients were included. Pediatric OHCA commonly affects males (55.3%, n = 84) and infants younger than 1 year of age (47.4%, n = 72) at home (76.3%, n = 116). Most triggers of pediatric OHCA were respiratory in nature (53.2%, n = 81). Sudden infant death syndrome (SIDS) (29.6%, n = 45), unknown medical causes (25%, n = 38), and trauma (10.5%, n = 16) were the main causes of pediatric OHCA. Sixty-two initial cardiac rhythms at the scene were obtained, most of which were asystole and pulseless electrical activity (PEA) (93.5%, n/all: 58/62). Upon ED arrival, cardiopulmonary resuscitation (CPR) was continued for 32.66 ± 20.71 min in the ED and 34.9% (n = 53) gained SROSC. Among them, 13.8% (n = 21) achieved STHD and 4.6% (n = 7) had a favorable neurological outcome. In multivariate analyses, fewer ED epinephrine doses ( p  < 0.05), witness of OHCA ( p  = 0.001), and shorter ED CPR duration ( p  = 0.007) were factors that increased the rate of SROSC at the ED. A longer emergency medical service (EMS) scene interval ( p  = 0.047) and shorter ED CPR interval ( p  = 0.047) improved STHD.

CD1d-restricted invariant natural killer T cells (iNKT cells) may play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Interleukin (IL)-15 is a pro-inflammatory cytokine which is over-expressed in SLE patients. In the present study, we investigated the iNKT cell expansion of mononuclear cells (MNCs) from SLE patients following 10 days’ culture with α-galactosylceramide (α-Galcer) and /or IL-15. We sought to determine the phenotypic and functional characteristics of the expanded iNKT cells compared to healthy controls and correlated with disease activity. We observed that 1. The percentages of Vα24+/Vβ11+ iNKT cells following 10-day incubation was lower in SLE groups compared to controls; 2. The percentages and absolute numbers of Vα24+/Vβ11+ iNKT cells were expanded by α-galactosylceramide (α-Galcer), and further enhanced with IL-15 in SLE patient, but the effect of IL-15 was much lower than controls; 3.IL-15 +α-Galcer expanded CD3+/CD56+ NKT-like cells from SLE patients, especially with active disease 4. The CD161+ Vα24+/Vβ11+ iNKT cells in SLE were more responsive to α-Galcer stimulation than the CD161- counterpart; 5. IL-15 decreased apoptosis of α-Galcer activated SLE iNKT cells; 6. IL-15 enhanced CD69, CD1d and CD11a expression on α-Galcer treated iNKT cells; 7. The IL-4 production of iNKT cells was decreased in SLE patients compared to controls; 8. IL-15 increased IFN-γ and IL-4 production of SLE iNKT cells; 8. IL-15 failed to augment the ability of iNKT cells to aid NK-mediated K562 cytolysis in SLE patients; 9. CD161 positivity, granzyme B and perforin expression of α-Galcer+IL-15 expanded iNKT cells correlated with C3 levels in SLE patients. Taken together, our results demonstrated numeric and functional deficiency of iNKT cells and their response to IL-15 in SLE patients. Our finding may provide insight for using adoptive iNKT cell therapy in autoimmune diseases.

A detailed understanding of the metabolic processes governing rapid growth in early life is still lacking. The aim of this study was to investigate the age-related metabolic changes in healthy children throughout early childhood. Healthy children from a birth cohort were enrolled in this study from birth through 4 years of age. Urinary metabolites were assessed at 6 months, and 1, 2, 3, and 4 yr of age by using 1H-nuclear magnetic resonance (NMR) spectroscopy coupled with multivariate statistical analysis including principal components analysis (PCA) and partial least-squares discriminant analysis (PLS-DA). Metabolic pathway analysis was performed using the MetPA web tool. A total of 105 urine samples from 30 healthy children were collected and analyzed. Metabolites contributing to the discrimination between age groups were identified by using supervised PLS-DA (Q2 = 0.60; R2 = 0.66). A significantly higher urinary trimethylamine N-oxide (TMAO) and betaine level was found in children aged 6 months. Urinary glycine and glutamine levels declined significantly after 6 months of age and there was a concomitant compensatory increase in urinary creatine and creatinine. Metabolic pathway analysis using MetPA revealed similar nitrogen metabolism associated energy production across all ages assessed. Pathways associated with amino acid metabolism were significantly different between infants aged 6 months and 1 year, whereas pathways associated with carbohydrate metabolism were significantly different between children at ages 2 and 3 years. Urine metabolomics ideally represents dynamic metabolic changes across age. Urinary metabolic profiles change significantly within the first year of life, which can potentially provide crucial information about infant nutrition and growth.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the deposition of immune complexes (ICs) in various organs, especially the kidney, leading to lupus nephritis, one of the major and therapeutically challenging manifestations of SLE. Among the various cytokines induced in SLE, type I interferons (IFN-Is) play crucial roles in mediating immunopathogenesis, and anti-IFN-I treatment has been approved for SLE treatment. The uptake of ICs by macrophages results in macrophage activation, which initiates, triggers, and exaggerates immune responses in SLE. After observing the induction of an IFN-stimulated gene, LY6E, in monocytes from SLE patients, we demonstrated the colocalization of both LY6E and a macrophage marker in kidneys from pristane-induced lupus-prone mice and from patients with lupus nephritis. By studying mouse bone marrow-derived macrophages, we showed that LY6E regulated IFN-α- and IC-induced production and secretion of mature interleukin-1β (mIL-1β), foam cell formation and several mitochondria-associated mechanisms, such as the release of mitochondrial DNA (mtDNA) but not mitochondrial RNA (mtRNA) into the cytosol, the generation of mitochondrial reactive oxygen species (mtROS) and ROS, the activation of caspase 1, NLRP3, and the stimulator of interferon genes (STING) signaling pathway, and the activation of cytidine/uridine monophosphate kinase 2 (CMPK2), which were involved in LY6E-mediated immunomodulatory effects. In addition, synergistic effects of a combination of IL-1β and IFN-α and of IL-1β and ICs on the induction of the expression of IFN-stimulated genes were observed. In addition to revealing the proinflammatory roles and mechanisms of LY6E in macrophages, given that various subgroups of macrophages have been identified in the kidneys of patients with lupus nephritis, targeted treatment aimed at LY6E may be a potential therapeutic for lupus nephritis.

Monocytes (Mos) and macrophages (Mφs) are key players in the innate immune system and are critical in coordinating the initiation, expansion, and regression of many autoimmune diseases. In addition, they display immunoregulatory effects that impact inflammation and are essential in tissue repair and regeneration. Juvenile idiopathic arthritis (JIA) is an umbrella term describing inflammatory joint diseases in children. Accumulated evidence suggests a link between Mo and Mφ activation and JIA pathogenesis. Accordingly, topics regarding the signals and mechanisms regulating Mo and Mφ activation leading to pathologies in patients with JIA are of great interest. In this review, we critically summarize recent advances in the understanding of how Mo and Mφ activation is involved in JIA pathogenesis and focus on the signaling pathways and mechanisms participating in the related cell activation processes.

Natural killer (NK) cells may play an important role in the pathogenesis of SLE. Interleukin(IL)-15, an NK-enhancing cytokine, is over-expressed in SLE patients. In the present study, we examined the effect of IL-15 on NK cytotoxicity of SLE patients, and the expression of various activating and inhibitory NK receptors on NK cells from SLE patients in relation to disease activity. We also sought to determine how IL-15 would affect the NK receptor expression on NK cells from SLE patients. PBMCs were collected from 88 SLE patients with inactive disease activity (SLEDAI score<6) and active disease activity (SLEDAI score≥6), 26 age-matched healthy adults were used as controls. PBMC were incubated in the presence or absence of IL-15 (10ng/ml) for eighteen hours. CD3-CD56+ lymphoctes were gated using flow cytometry and further divided into CD56dim and CD56bright subsets according to the MFI of CD56. We observed that 1. Serum IL-15 was elevated in SLE patients, and higher in active disease than in inactive disease; 2. NK cytotoxicity of SLE patients was deficient compared to controls and showed an impaired response to IL-15 compared to controls; 3.CD69, CD94, NKG2A, NKp30, and CD158b on NK cells from SLE patients were higher than controls, and could be further enhanced by IL-15; 4. NKp46 expression from SLE patients was higher than controls, but down-regulated by IL-15; 5.Deficient NKG2D and NKAT-2 expression were found on NK cells from SLE patients, which were enhanced by IL-15; 6. A unique NKp46- subset and CD158b+ subsets were observed in NK cells from SLE patients but not controls. 7. Unlike controls, CD158k on NK cells from SLE patients failed to respond to IL-15. Taken together, we demonstrated the aberrant NCR and iNKR expression on NK cells and their distinct response to IL-15 in SLE patients. As IL-15 predominantly aggravates the aberrant NKR expression found in SLE, IL-15 antagonist may have therapeutic benefits in SLE patients.

Vitamin D has been implicated in the pathogenesis of skeletal disorders and various autoimmune disorders. Vitamin D can be consumed from the diet or synthesized in the skin upon ultraviolet exposure and hydroxylation in the liver and kidneys. In its bioactive form, vitamin D exerts a potent immunomodulatory effect and is important for bone health. Juvenile idiopathic arthritis (JIA) is a collection of inflammatory joint diseases in children that share the manifestation of inflamed synovium, which can result in growth arrest, articular deformity, bone density loss, and disability. To evaluate the potential effect of vitamin D on JIA disease manifestations and outcomes, we review the role of vitamin D in bone metabolism, discuss the mechanism of vitamin D in modulating the innate and adaptive immune systems, evaluate the clinical significance of vitamin D in patients with JIA, and summarize the supplementation studies.

Background Mitochondria is prone to oxidative damage by endogenous and exogenous sources of free radicals, including particulate matter (PM). Given the role of mitochondria in inflammatory disorders, such as asthma and chronic obstructive pulmonary disease, we hypothesized that supplementation of vitamin D may play a protective role in PM-induced mitochondrial oxidative damages of human bronchial epithelial BEAS-2B cells. Methods BEAS-2B cells were pretreated with 1,25(OH) 2 D 3 , an active form of vitamin D, for 1 h prior to 24-hour exposure to PM (SRM-1648a). Oxidative stress was measured by flow cytometry. Mitochondrial functions including mitochondrial membrane potential, ATP levels, and mitochondrial DNA copy number were analyzed. Additionally, mitochondrial ultrastructure was examined using transmission electron microscopy. Intracellular and mitochondrial calcium concentration changes were assessed using flow cytometry based on the expression of Fluo-4 AM and Rhod-2 AM, respectively. Pro-inflammatory cytokines, including IL-6 and MCP-1, were quantified using ELISA. The expression levels of antioxidants, including SOD1, SOD2, CAT, GSH, and NADPH, were determined. Results Our findings first showed that 24-hour exposure to PM led to the overproduction of reactive oxygen species (ROS) derived from mitochondria. PM-induced mitochondrial oxidation resulted in intracellular calcium accumulation, particularly within mitochondria, and alterations in mitochondrial morphology and functions. These changes included loss of mitochondrial membrane integrity, disarrayed cristae, mitochondrial membrane depolarization, reduced ATP production, and increased mitochondrial DNA copy number. Consequently, PM-induced mitochondrial damage triggered the release of certain inflammatory cytokines, such as IL-6 and MCP-1. Similar to the actions of mitochondrial ROS inhibitor MitoTEMPO, 1,25(OH) 2 D 3 conferred protective effects on mtDNA alterations, mitochondrial damages, calcium dyshomeostasis, thereby decreasing the release of certain inflammatory cytokines. We found that greater cellular level of 1,25(OH) 2 D 3 upregulated the expression of enzymatic (SOD1, SOD2, and CAT) and non-enzymatic (GSH and NADPH) antioxidants to modulate cellular redox homeostasis. Conclusion Our study provides new evidence that 1,25(OH) 2 D 3 acts as an antioxidant, enhancing BEAS-2B antioxidant responses to regulate mitochondrial ROS homeostasis and mitochondrial function, thereby enhancing epithelial defense against air pollution exposure.

A correct interpretation of sensitization to common allergens is critical in determining susceptibility to allergic diseases. The aim of this study was to investigate the patterns of sensitization to food and inhalant allergens, and their relation to the development of atopic diseases in early childhood. Children aged 0 through 4 years from a birth cohort in the Prediction of Allergies in Taiwanese Children (PATCH) study were enrolled. Specific IgE antibody against food and inhalant allergens were measured and their association between total serum IgE levels and atopic diseases were assessed. A total of 182 children were regular followed up at clinics for a four-year follow-up period. The prevalence of food allergen sensitization increased markedly after 6 months of age, reaching up to 47% at 1.5 years of age and then declined significantly to 10% in parallel with a considerable increase in the prevalence of sensitization to inhalant allergens up to 25% at age 4. Food allergen sensitization appeared to be mainly associated with the elevation of serum total IgE levels before age 2. A combined sensitization to food and inhalant allergens had an additive effect on serum IgE levels after age 2, and was significantly associated with the risk of developing atopic diseases at age 4. Sensitization to food occurs early in life, in parallel with the rising prevalence of sensitization to inhalant allergens at older age. A combined sensitization to food and inhalant allergens not only has an additive increase in serum IgE antibody production but also increases the risk of developing allergic respiratory diseases in early childhood.

Adalimumab, a TNF-alpha inhibitor, is approved to treat juvenile idiopathic arthritis (JIA), helping control disease activity and reduce flare frequency. This study aims to investigate predictors of treatment response, including anti-drug antibodies. We reviewed 65 JIA patients (mean age 10.47 ± 3.90 years; 61.5% male) receiving adalimumab for an average of 2.64 ± 0.56 years, with demographics, laboratory parameters, therapeutic regimens, and treatment outcomes recorded. Disease status was evaluated using the Wallace criteria up to 36 months post-treatment initiation, and anti-adalimumab antibody levels were measured after 6 months of treatment. Enthesitis-related arthritis was the most common subtype (64.6%). Inactive disease status was achieved by 83.1% of patients, with 59.3% experiencing relapse. Detectable anti-adalimumab antibody at six months (p = 0.023) and temporomandibular joint (TMJ) involvement (p = 0.038) identified those less likely to achieve inactive disease. An antibody level cutoff of 7.426 ng/mL best predicted response (AUC = 0.808; p = 0.008), while high anti-adalimumab antibody levels after treatment (p = 0.032) and an injection intervals over two weeks (p = 0.042) were predictors of future flares. Our results highlight that the presence of anti-adalimumab antibodies six months after treatment is a risk factor for poor response to adalimumab therapy.