Long-term PM2.5 exposure is associated with asthma prevalence and exhaled nitric oxide levels in children.

BACKGROUND: Exhaled nitric oxide concentration (FENO) is a marker of airway inflammation. This study aimed to evaluate the association of air pollution exposure with FENO levels and asthma prevalence with respiratory symptoms in school children. METHODS: We analyzed 4736 school children who reside in six townships near industrial areas in central Taiwan. We evaluated asthmatic symptoms, FENO, and conducted the environmental questionnaire. The personal exposure of PM2.5, NO, and SO2 was estimated using land-use regression models data on children's school and home addresses. RESULTS: Annual exposure to PM2.5 was associated with increased odds of physician-diagnosed asthma (OR = 1.595), exercise-induced wheezing (OR = 1.726), itchy eyes (OR = 1.417), and current nasal problems (OR = 1.334) (P < 0.05). FENO levels in the absence of infection were positively correlated with age, previous wheezing, allergic rhinitis, atopic eczema, near the road, and for children with high exposure to PM2.5 (P < 0.05). An increase of 1 µg/m3 PM2.5 exposure was significantly associated with a 1.0% increase in FENO levels for children after adjusting for potential confounding variables, including exposures to NO and SO2. CONCLUSIONS: Long-term exposures to PM2.5 posed a significant risk of asthma prevalence and airway inflammation in a community-based population of children. IMPACT: Annual exposure to PM2.5 was associated with increased odds of physician-diagnosed asthma and nasal problems and itchy eyes. Long-term exposures to PM2.5 were significantly associated with FENO levels after adjusting for potential confounding variables. This is first study to assess the association between FENO levels and long-term air pollution exposures in children near coal-based power plants. An increase of 1 µg/m3 annual PM2.5 exposure was significantly associated with a 1.0% increase in FENO levels. Long-term exposures to PM2.5 posed a significant risk of asthma prevalence and airway inflammation in a community-based population of children.

Asthma control associated with anxiety and depression in asthmatic children following post-acute COVID-19.

BACKGROUND: Poor asthma control may adversely affect mental health. Our study investigates the correlation between inadequate asthma control, exhaled nitric oxide (FENO) levels, and anxiety and depression among pediatric asthma patients with COVID-19. METHODS: This prospective case-control study enrolled 520 asthmatic children (8-15 years), including 336 patients diagnosed with COVID-19 after rapid antigen testing at home and 184 age-matched asthmatic patients without COVID-19 infection. FENO and spirometry were performed 1 month after COVID-19 infection. Scores for Child Anxiety-Related Disorders (SCARED) and depression screen derived from Patient Health Questionnaire-9 (PHQ-9) to assess their mental health status. Childhood asthma control test (C-ACT), FENO levels, and spirometry were correlated with the SCARED and PHQ-9 questionnaires. RESULTS: SCARED subscales, including generalized anxiety disorder, social anxiety disorder, school avoidance, and depression scores from PHQ-9, exhibited a significant increase in asthmatic patients diagnosed with COVID-19 (p < .05). Among asthmatic children with SARS-CoV-2 infection, the poor asthma control group exhibited the highest SCARED and PHQ-9 measurements (p < .01). Multiple linear regression analysis indicated that reduced C-ACT scores and elevated FENO levels in asthmatic children with COVID-19 were significant risk factors for both anxiety and depression scores (p < .05). Lower C-ACT scales were associated with high scores of SCARED (r = -0.471) and PHQ-9 (r = -0.329) in asthmatic children (p < .001). CONCLUSIONS: The current study emphasizes the need for healthcare professionals to closely monitor asthma control in asthmatic children to prevent heightened risks of depression and anxiety during the ongoing COVID-19 pandemic.

Relationship between the Number of Repeats in the Neck Regions of L-SIGN and Augmented Virus Replication and Immune Responses in Dengue Hemorrhagic Fever.

C-type lectins play a crucial role as pathogen-recognition receptors for the dengue virus, which is responsible for causing both dengue fever (DF) and dengue hemorrhagic fever (DHF). DHF is a serious illness caused by the dengue virus, which exists in four different serotypes: DEN-1, DEN-2, DEN-3, and DEN-4. We conducted a genetic association study, during a significant DEN-2 outbreak in southern Taiwan, to explore how variations in the neck-region length of L-SIGN (also known as CD209L, CD299, or CLEC4M) impact the severity of dengue infection. PCR genotyping was utilized to identify polymorphisms in variable-number tandem repeats. We constructed L-SIGN variants containing either 7- or 9-tandem repeats and transfected these constructs into K562 and U937 cells, and cytokine and chemokine levels were evaluated using enzyme-linked immunosorbent assays (ELISAs) following DEN-2 virus infection. The L-SIGN allele 9 was observed to correlate with a heightened risk of developing DHF. Subsequent results revealed that the 9-tandem repeat was linked to elevated viral load alongside predominant T-helper 2 (Th2) cell responses (IL-4 and IL-10) in K562 and U937 cells. Transfecting K562 cells in vitro with L-SIGN variants containing 7- and 9-tandem repeats confirmed that the 9-tandem repeat transfectants facilitated a higher dengue viral load accompanied by increased cytokine production (MCP-1, IL-6, and IL-8). Considering the higher prevalence of DHF and an increased frequency of the L-SIGN neck's 9-tandem repeat in the Taiwanese population, individuals with the 9-tandem repeat may necessitate more stringent protection against mosquito bites during dengue outbreaks in Taiwan.

Profiling humoral responses to COVID-19 immunization in Kawasaki disease using SARS-CoV-2 variant protein microarrays.

Kawasaki disease (KD) is a form of acute systemic vasculitis syndrome that predominantly occurs in children under the age of 5 years. Its etiology has been postulated due to not only genetic factors but also the presence of foreign antigens or infectious agents. To evaluate possible associations between Kawasaki disease (KD) and COVID-19, we investigated humoral responses of KD patients against S-protein variants with SARS-CoV-2 variant protein microarrays. In this study, plasma from a cohort of KD (N = 90) and non-KD control (non-KD) (N = 69) subjects in categories of unvaccinated-uninfected (pre-pandemic), SARS-CoV-2 infected (10-100 days after infection), and 1-dose, 2-dose, and 3-dose BNT162b2 vaccinated (10-100 days after vaccination) was collected. The principal outcomes were non-KD-KD differences for each category in terms of anti-human/anti-His for binding antibodies and neutralizing percentage for surrogate neutralizing antibodies. Binding antibodies against spikes were lower in the KD subjects with 1-dose of BNT162b2, and mean differences were significant for the P.1 S-protein (non-KD-KD, 3401; 95% CI, 289.0 to 6512; P = 0.0252), B.1.617.2 S-protein (non-KD-KD, 4652; 95% CI, 215.8 to 9087; P = 0.0351) and B.1.617.3 S-protein (non-KD-KD, 4874; 95% CI, 31.41 to 9716; P = 0.0477). Neutralizing antibodies against spikes were higher in the KD subjects with 1-dose of BNT162b2, and mean percentage differences were significant for the 1-dose BNT162b2 B.1.617.3 S-protein (non-KD-KD, -22.89%; 95% CI, -45.08 to -0.6965; P = 0.0399), B.1.1.529 S-protein (non-KD-KD, -25.96%; 95% CI, -50.53 to -1.376; P = 0.0333), BA.2.12.1 S-protein (non-KD-KD, -27.83%; 95% CI, -52.55 to -3.115; P = 0.0195), BA.4 S-protein (non-KD-KD, -28.47%; 95% CI, -53.59 to -3.342; P = 0.0184), and BA.5 S-protein (non-KD-KD, -30.42%; 95% CI, -54.98 to -5.869; P = 0.0077). In conclusion, we have found that KD patients have a comparable immunization response to healthy individuals to SARS-CoV-2 infection and COVID-19 immunization.

Pathogenesis and Preventive Tactics of Immune-Mediated Non-Pulmonary COVID-19 in Children and Beyond.

The COVID-19 pandemic has evolved to immune escape and threatened small children and the elderly with a higher severity and fatality of non-pulmonary diseases. These life-threatening non-pulmonary COVID-19 diseases such as acute necrotizing encephalopathies (ANE) and multisystem inflammatory syndrome in children (MIS-C) are more prevalent in children. However, the mortality of multisystem inflammatory syndrome in adults (MIS-A) is much higher than that of MIS-C although the incidence of MIS-A is lower. Clarification of immunopathogenesis and genetic susceptibility of inflammatory non-pulmonary COVID-19 diseases would provide an appropriate guide for the crisis management and prevention of morbidity and fatality in the ongoing pandemic. This review article described three inflammatory non-pulmonary COVID-19 diseases including (1) meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) post-infectious multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A). To prevent these life-threatening non-pulmonary COVID-19 diseases, hosts carrying susceptible genetic variants should receive prophylactic vaccines, avoid febrile respiratory tract infection, and institute immunomodulators and mitochondrial cocktails as early as possible.

Functions and therapeutic targets of Siglec-mediated infections, inflammations and cancers.

Siglecs, sialic acid (SA)-binding immunoglobulin (Ig)-like lectins, belong to a family of Ig-like lectins. All Siglecs have at least two domains including an extracellular domain with variable (V) and constant (C)-set immunoglobulin (Ig) regions, and a transmembrane domain. Some of the Siglecs (Siglec-2-12, -17, -E, -F and -G) with three domains including immunoreceptor tyrosine-based inhibitory motif associated with Src homology 2 (SH2) tyrosine phosphatases (SHP1/2) usually deliver an inhibitory signal. Certain Siglecs (Siglec-14, -15, -16 and -H) containing no intracellular domain carry certain basic amino acid in transmembrane domain coupled with immunoreceptor tyrosine-based activating motif for cell activation. The number of Siglec-encoding genes has been correlated to lifespan of mammals, indicating its evolutional advantage on acquisition of Siglecs in humans. Certain polymorphisms of Siglecs have been associated with premature delivery, infection, schizophrenia, allergy, dementia or chronic obstructive pulmonary disease. Siglecs mainly expressing on leukocytes could interact with cis- or trans-SA ligands for cell-cell and host-organism interactions on infections, inflammations and cancers. Amplifying or eliminating the SA-Siglec interactions is a promising strategy to treat cancers, infections and inflammations, based on SA modifications in different linkages or nanoparticle decoration, and on the antibodies in conjugation of chimeric receptor design or toxins.

Bio-Scaffolds as Cell or Exosome Carriers for Nerve Injury Repair.

Central and peripheral nerve injuries can lead to permanent paralysis and organ dysfunction. In recent years, many cell and exosome implantation techniques have been developed in an attempt to restore function after nerve injury with promising but generally unsatisfactory clinical results. Clinical outcome may be enhanced by bio-scaffolds specifically fabricated to provide the appropriate three-dimensional (3D) conduit, growth-permissive substrate, and trophic factor support required for cell survival and regeneration. In rodents, these scaffolds have been shown to promote axonal regrowth and restore limb motor function following experimental spinal cord or sciatic nerve injury. Combining the appropriate cell/exosome and scaffold type may thus achieve tissue repair and regeneration with safety and efficacy sufficient for routine clinical application. In this review, we describe the efficacies of bio-scaffolds composed of various natural polysaccharides (alginate, chitin, chitosan, and hyaluronic acid), protein polymers (gelatin, collagen, silk fibroin, fibrin, and keratin), and self-assembling peptides for repair of nerve injury. In addition, we review the capacities of these constructs for supporting in vitro cell-adhesion, mechano-transduction, proliferation, and differentiation as well as the in vivo properties critical for a successful clinical outcome, including controlled degradation and re-absorption. Finally, we describe recent advances in 3D bio-printing for nerve regeneration.

Umbilical Cord Mesenchymal Stromal Cell-Derived Exosomes Rescue the Loss of Outer Hair Cells and Repair Cochlear Damage in Cisplatin-Injected Mice.

Umbilical cord-derived mesenchymal stromal cells (UCMSCs) have potential applications in regenerative medicine. UCMSCs have been demonstrated to repair tissue damage in many inflammatory and degenerative diseases. We have previously shown that UCMSC exosomes reduce nerve injury-induced pain in rats. In this study, we characterized UCMSC exosomes using RNA sequencing and proteomic analyses and investigated their protective effects on cisplatin-induced hearing loss in mice. Two independent experiments were designed to investigate the protective effects on cisplatin-induced hearing loss in mice: (i) chronic intraperitoneal cisplatin administration (4 mg/kg) once per day for 5 consecutive days and intraperitoneal UCMSC exosome (1.2 µg/µL) injection at the same time point; and (ii) UCMSC exosome (1.2 µg/µL) injection through a round window niche 3 days after chronic cisplatin administration. Our data suggest that UCMSC exosomes exert protective effects in vivo. The post-traumatic administration of UCMSC exosomes significantly improved hearing loss and rescued the loss of cochlear hair cells in mice receiving chronic cisplatin injection. Neuropathological gene panel analyses further revealed the UCMSC exosomes treatment led to beneficial changes in the expression levels of many genes in the cochlear tissues of cisplatin-injected mice. In conclusion, UCMSC exosomes exerted protective effects in treating ototoxicity-induced hearing loss by promoting tissue remodeling and repair.

Intravenous immunoglobulin therapy enhances suppressive regulatory T cells and decreases innate lymphoid cells in children with immune thrombocytopenia.

BACKGROUND: This study aimed to investigate the relationship between CD4+ regulatory T cells (Tregs) and innate lymphoid cells (ILCs) in children with primary immune thrombocytopenia (ITP) undergoing high-dose intravenous immunoglobulin (IVIG) therapy. METHODS: We enrolled a cohort of 30 children with newly diagnosed ITP and 30 healthy controls and collected blood samples for levels of Tregs, ILCs, relevant cytokines, and Treg suppression assay at the diagnosis, two days, four weeks, and one year (only platelet count) after high-dose IVIG treatment. IVIG partial responders was defined by a platelet count less than 100 × 109 /L at 12 months after IVIG treatment. RESULTS: Children with newly diagnosed ITP exhibited elevated levels of ILC1, ILC2, ILC3, Th17, myeloid dendritic cells (DCs), plasmacytoid DCs, and serum IFN-γ and IL-17A levels, accompanied by a decrease in IL-10-producing Tregs. High-dose IVIG therapy reversed these aberrations. Platelet counts positively correlated with Tregs (rho = 0.72) and negatively correlated with both ILC1 (rho = -0.49) and ILC3 (rho = -0.60) (P < 0.05). Significantly lower Tregs and higher ILC1, ILC3, DCs, and serum IL-17A levels were noted in the partial responders (n = 8) versus responders (n = 22; P < 0.05). We found that Tregs suppressed proliferation of ILCs and CD4+ T cells in CD25-depleted peripheral PBMCs and enhanced the apoptosis of CD4+ CD45RO+ T cells in vitro following IVIG therapy. CONCLUSIONS: Effective high-dose IVIG therapy for children with newly diagnosed ITP appears to result in the induction of Tregs, which suppresses ILC proliferation in vitro and is associated with platelet response.

Allergen-specific immunotherapy enhances CD8+ CD25+ CD137+ regulatory T cells and decreases nasal nitric oxide.

BACKGROUND: 4-1BB (CD137), a member of the inducible tumor necrosis factor receptor (TNFR) family, is expressed on regulatory T (Treg) cells and regulates Treg cells to control allergic inflammation. Pam3CSK4, a synthetic TLR2 ligand that can expand CD8+ Treg function, is a promising adjuvant for allergen immunotherapy (IT). We examined whether Dermatophagoides pteronyssinus (Der p) IT and Pam3CSK4 could enhance CD8+  CD25+  CD137+ Treg suppressive function to decrease nasal nitric oxide (nNO) levels. METHODS: Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biopsies were obtained from 40 mite-sensitive perennial allergic rhinitis (PAR) patients before and after one year of Der p IT and 30 non-allergic control subjects. CD137 expression on CD8+  CD25+ T cells and suppressive function of CD8+  CD25+  CD137+ Tregs was measured using flow cytometry. Cytokine levels were analyzed by ELISA. Inducible nitric oxide synthase production by nasal epithelial cells after co-culturing with CD8+  CD25+  CD137+ T cells was analyzed by Western blotting. RESULTS: Der p IT improved nasal symptom scores, decreased nNO levels, and increased CD137 expression on CD8+ T cells in PBMCs and nasal mucosa. Pam3CSK4 expanded the CD8+  CD25+  CD137+ population in PBMCs. Pam3CSK4-stimulated CD8+  CD25+  CD137+ Tregs induced IL-10 and TGF-ß and suppressed CD4+  CD25- T-cell proliferation mainly by cell contact inhibition. CD8+  CD25+  CD137+ Tregs cultured with nasal epithelial cells suppressed Der p 2-induced iNOS production. Silencing CD137 in sorted CD8+  CD25+ T cells decreased Pam3CSK4-activated Foxp3 expression. CONCLUSION: Der p IT expanded CD8+  CD25+  CD137+ Tregs and decreased nNO levels. Induced CD137 expression on CD8+  CD25+ Tregs by Pam3CSK4 stimulation may help suppress allergic inflammation during IT.