Nasopharyngeal airway long noncoding RNAs of infants with bronchiolitis and subsequent risk of developing childhood asthma.

BACKGROUND: Severe bronchiolitis (ie, bronchiolitis requiring hospitalization) during infancy is a major risk factor for developing childhood asthma. However, the biological mechanisms linking these 2 conditions remain unclear. OBJECTIVE: We sought to investigate the longitudinal relationship between nasopharyngeal airway long noncoding RNA (lncRNA) in infants with severe bronchiolitis and subsequent asthma development. METHODS: In this multicenter prospective cohort study of infants with severe bronchiolitis, we performed RNA sequencing of nasopharyngeal airway lncRNAs at index hospitalization. First, we identified differentially expressed lncRNAs (DE-lncRNAs) associated with asthma development by age 6 years. Second, we investigated the associations of DE-lncRNAs with asthma-related clinical characteristics. Third, to characterize the function of DE-lncRNAs, we performed pathway analysis for mRNA targeted by DE-lncRNAs. Finally, we examined the associations of DE-lncRNAs with nasal cytokines at index hospitalization. RESULTS: Among 343 infants with severe bronchiolitis (median age, 3 months), we identified 190 DE-lncRNAs (false-discovery rate [FDR] < 0.05) associated with asthma development (eg, LINC02145, RAMP2-AS1, and PVT1). These DE-lncRNAs were associated with asthma-related clinical characteristics (FDR < 0.05), for example, respiratory syncytial virus or rhinovirus infection, infant eczema, and IgE sensitization. Furthermore, DE-lncRNAs were characterized by asthma-related pathways, including mitogen-activated protein kinase, FcɛR, and phosphatidylinositol 3-kinase (PI3K)-protein kinase B signaling pathways (FDR < 0.05). These DE-lncRNAs were also associated with nasal cytokines (eg, IL-1ß, IL-4, and IL-13; FDR < 0.05). CONCLUSIONS: In a multicenter cohort study of infants with severe bronchiolitis, we identified nasopharyngeal airway lncRNAs associated with childhood asthma development, characterized by asthma-related clinical characteristics, asthma-related pathways, and nasal cytokines. Our approach identifies lncRNAs underlying the bronchiolitis-asthma link and facilitates the early identification of infants at high risk of subsequent asthma development.

Epidermal clearance of Candida albicans is mediated by IL-17 but independent of fungal innate immune receptors.

IL-17 plays important roles in host defense against Candida albicans at barrier surfaces and during invasive infection. However, the role of IL-17 in host defense after colonization of the epidermis, a main site of C. albicans infection, remains poorly understood. Using a murine model of epicutaneous candidiasis without skin abrasion, we found that skin inflammation triggered by epidermal C. albicans colonization was self-limiting with fungal clearance completed by day 7 after inoculation in wild-type mice or animals deficient in IL-17A or IL-17F. In contrast, marked neutrophilic inflammation in the epidermis and impaired fungal clearance were observed in mice lacking both IL-17A and IL-17F. Clearance of C. albicans was independent of Dectin-1, Dectin-2, CARD9 (caspase-recruitment domain family, member 9), TLR2 (Toll-like receptor 2) and MyD88 in the epidermal colonization model. We found that group 3 innate lymphoid cells (ILC3s) and γδT cells were the major IL-17 producers in the epicutaneous candidiasis model. Analyses of Rag2-/- mice and Rag2-/-Il2rg-/- mice revealed that production of IL-17A and IL-17F by ILC3s was sufficient for C. albicans clearance. Finally, we found that depletion of neutrophils impaired C. albicans clearance in the epidermal colonization model. Taken together, these findings indicate a critical and redundant function of IL-17A and IL-17F produced by ILC3s in host defense against C. albicans in the epidermis. The results also suggest that epidermal C. albicans clearance is independent of innate immune receptors or that these receptors act redundantly in fungal recognition and clearance.

Trends in mortality and morbidity in patients with bullous pemphigoid before and after approval of intravenous immunoglobulin in Japan: an interrupted time-series analysis.

BACKGROUND: Intravenous immunoglobulin (IVIg) has been reported to be an effective treatment for bullous pemphigoid. However, the impact of IVIg approval on real-world outcomes remains unclear. OBJECTIVES: To investigate the effect of IVIg approval on patients with bullous pemphigoid using a national inpatient database. METHODS: Using the Japanese Diagnosis Procedure Combination database, we identified 14 229 patients admitted to hospital for bullous pemphigoid and treated with systemic corticosteroids between July 2010 and March 2020. We conducted an interrupted time-series analysis to compare in-hospital mortality and morbidity between the patients admitted before and after the approval of reimbursement of IVIg for bullous pemphigoid in the Japanese universal health insurance system in November 2015. RESULTS: In-hospital mortality was 5.5% before and 4.5% after the approval of IVIg reimbursement. After the IVIg approval, 18% of the patients were treated with IVIg. Based on the interrupted time-series analysis, in-hospital mortality significantly decreased at the time of approval [-1.2%, 95% confidence interval (CI) -2.0 to -0.3, P = 0.009] and a downward trend was observed after the approval (-0.4% annual rate, 95% CI -0.7 to -0.1, P = 0.005). In-hospital morbidity also demonstrated a downward trend after the approval. CONCLUSIONS: IVIg approval is associated with lower in-hospital mortality and morbidity in inpatients with bullous pemphigoid.

Treatments and outcomes of generalized pustular psoriasis: A cohort of 1516 patients in a nationwide inpatient database in Japan.

BACKGROUND: Because generalized pustular psoriasis (GPP) is rare, there are few studies reporting treatments and outcomes for large numbers of patients. OBJECTIVE: To report treatments and outcomes in a large cohort of patients hospitalized with GPP. METHODS: Using a Japanese national inpatient database, we identified 1516 patients with GPP who required hospitalization between July 2010 and March 2019. We categorized patients into 3 medication groups: biologics (294 patients), oral agents without biologics (948 patients), and systemic corticosteroids only (274 patients). We investigated their characteristics, treatments, and outcomes. RESULTS: Mean age was 66 years (interquartile range: 52-77 years). Fifty patients (3.3%) were admitted to the intensive care unit, 125 (8.2%) required blood pressure support, and 63 (4.2%) died. Patients who received biologics were younger and had fewer comorbidities. In-hospital mortality was lower in the biologics group (1.0% [biologics group] vs 3.7% [oral-agents group] vs 9.1% [corticosteroids-only group]; P < .001) as was morbidity (5.4% vs 8.2% vs 12%, respectively; P = .02). Among those who received biologics, IL-17 inhibitor use increased over time, with in-hospital mortality and morbidity comparable to those of tumor necrosis factor inhibitors. LIMITATIONS: Retrospective study design. Some patients received multiple medications. CONCLUSION: Biologic treatments showed favorable outcomes compared with other treatments.

Keratinocyte IL-36 Receptor/MyD88 Signaling Mediates Malassezia-Induced IL-17-Dependent Skin Inflammation.

BACKGROUND: Among skin commensal fungi, lipophilic Malassezia species exist on nearly all human skin surfaces. The pathophysiology of Malassezia-associated skin diseases remains poorly understood due in part to the lack of appropriate animal models. Our objective was to investigate the mechanisms underlying Malassezia-induced skin inflammation using a novel murine model that physiologically recapitulates Malassezia skin infection. METHODS: Mice were inoculated epicutaneously with Malassezia yeasts without barrier disruption and in the absence of external lipid supplementation. Skin inflammation, lesional fungal loads, and expression of cytokines and antimicrobial peptides were evaluated in wild-type and mutant mouse strains. RESULTS: Malassezia-induced skin inflammation and epidermal thickening were observed on day 4 after inoculation in wild-type mice. High fungal burdens were detected in the cornified layer on day 2 and decreased thereafter with near complete clearance by day 7 after inoculation. Malassezia-induced skin inflammation and fungal clearance by the host were interleukin-17 (IL-17) dependent with contribution of group 3 innate lymphoid cells. Moreover, IL-17-dependent skin inflammation was mediated through IL-36 receptor and keratinocyte MyD88 signaling. CONCLUSION: Using a new skin infection model, it is shown that Malassezia-induced IL-17- dependent skin inflammation and control of fungal infection are mediated via keratinocyte IL-36 receptor/MyD88 signaling.

Clinical course and outcomes of pemphigus vulgaris and foliaceus: A retrospective study using a nationwide database in Japan.

Pemphigus is a life-threatening autoimmune blistering disease. Patient characteristics, treatment courses, and outcomes remain unclear owing to its rarity. To describe the background, treatment, and outcomes of pemphigus, we identified 2598 patients with pemphigus vulgaris and 1186 patients with pemphigus foliaceus from a nationwide inpatient database in Japan. Patients with pemphigus vulgaris were younger (62 vs 72 years, P < 0.001), had fewer comorbidities, and were more likely to be admitted to high-volume hospitals (38% vs 30%, P < 0.001) than those with pemphigus foliaceus. Patients with pemphigus vulgaris had undergone more aggressive treatment, including steroid pulse therapy, intravenous immunoglobulin, or plasmapheresis, compared with those with pemphigus foliaceus (48% vs 42%, P = 0.001); specifically, in patients aged <70 years, the pemphigus vulgaris group was more likely to undergo aggressive treatment than the pemphigus foliaceus group (52% vs 45%), whereas there was no significant difference in patients aged ≥70 years (40% vs 40%). Immunosuppressive agents (30% vs 26%, P = 0.015) and analgesics, including opioids (45% vs 36%, P < 0.001), were used more frequently, whereas topical corticosteroids were used less frequently (32% vs 48%, P < 0.001) in patients with pemphigus vulgaris compared with those with pemphigus foliaceus. In-hospital mortality was lower in patients with pemphigus vulgaris than in those with pemphigus foliaceus (2.2% vs 4.0%, P = 0.002); in the comparison stratified by age, the mortality was equivalent among the two groups (0.6% in patients aged <70 years and 6.1% in those aged ≥70 years). Overall, patients with pemphigus vulgaris had a 10-day longer hospitalization period and higher hospitalization costs than those with pemphigus foliaceus. Our findings provide useful information for understanding the current trends in the management of pemphigus in Japan.

Simultaneous development of generalized pustular psoriasis and pemphigoid with multiple autoantibodies in a complete responder of pembrolizumab for lung cancer.

Patients with psoriasis vulgaris have a higher incidence of pemphigoid than the general population. However, there are only a few concise reports on the coexistence of generalized pustular psoriasis (GPP) and pemphigoid. The authors describe a rare case of the simultaneous development of GPP and pemphigoid with multiple autoantibodies (i.e., BP180-C-terminal, 200-kDa protein, and laminin 332 proteins) in a complete responder of immune checkpoint inhibitor (ICI) treatment for lung cancer. Anti-interleukin 17 inhibitors for the GPP and oral corticosteroids at 10 mg/day for the pemphigoid effectively achieved remission in both diseases. It may not be uncommon to detect multiple autoantibodies in patients with pemphigoid; however, the detection of autoantibodies to more than three antigens in a single patient is relatively rare. In the current patient, the severe inflammation of GPP might have generated multiple autoantibodies. In addition, although pembrolizumab achieved a complete response and was discontinued 9 months before the onset of GPP and pemphigoid, the ICI might have affected the development of the two diseases. This case report adds useful information to the limited knowledge regarding the coexistence of GPP and pemphigoid, and aids in a better understanding of the pathological mechanisms and treatment options for such patients. Furthermore, the possibility that more patients may develop multiple autoimmune and autoinflammatory diseases in the era of ICIs should be recognized.

Association between psoriasis and short-term outcomes of acute myocardial infarction: A matched-pair cohort study using a nationwide inpatient database in Japan.

Background: Psoriasis is a known risk factor for acute myocardial infarction (AMI). However, the associations between psoriasis and short-term outcomes of AMI remain controversial. Objective: To compare the short-term outcomes of AMI patients with and without psoriasis accounting for patient background characteristics and site-specific effects. Methods: We identified patients with AMI between July 2010 and March 2020, using a Japanese national inpatient database. We matched patients with and without psoriasis to generate a 1:10 matched-pair cohort matched for sex, hospital, and fiscal year at admission. Multivariable regression analyses with adjustment for background characteristics including age and Killip class at admission were conducted to compare short-term outcomes of AMI. Results: In this study of AMI patients with psoriasis (n = 455) and without psoriasis (n = 438,534), 30-day in-hospital mortality was 5.6%. Patients with psoriasis had higher proportions of comorbidities than patients without psoriasis. Multivariable regression analyses in the matched-pair cohort revealed that psoriasis was significantly associated with decreased 30-day in-hospital mortality (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.08-0.85). Limitations: Retrospective study design without data on psoriasis severity. Conclusion: The matched-pair cohort analyses with adjustment for patient background characteristics and site-specific effects revealed decreased in-hospital mortality in AMI patients with psoriasis.

Theoretical study on reaction scheme of silver(I) containing 5-substituted uracils bridge formation.

We present a reaction scheme of silver containing 5-substituted uracils (N) bridge formation with two silver ions to a silver-mediated base pair [N-Ag(2)-N] by using the conductor-like polarizable continuum model (CPCM)-B3LYP/aug-cc-pVDZ level of theory. The whole reaction scheme is divided into the following three steps: (1) silver ion binding and deprotonation, (2) silver ion transfer, and (3) dimer formation and structural fluctuation. With a new pK(a) computing scheme proposed in our previous studies, it is found that a silver coordination decreases the pK(a) of N by 2.5-3.0 pK(a) units, which is an important clue for silver-ion selectivity by N. Judging from the calculation, we revealed that the silver ion transfer reaction and the dimerization reaction occur spontaneously. Moreover, both reactions are independent of the C5 ligand in N so that the deprotonation reaction, which is the first step of this scheme, plays a key role in forming the [N-Ag(2)-N] pairing.

Effects of mercury(II) on structural properties, electronic structure and UV absorption spectra of a duplex containing thymine-mercury(II)-thymine nucleobase pairs.

Structural properties, electronic structure and UV absorption spectra of mercury(ii) mediated metal-DNA complex, thymine-mercury(ii)-thymine base pair (T-Hg(II)-T), were theoretically and computationally investigated along with experimental data [Ono et al., J. Am. Chem. Soc., 2006, 128(7), 2172-2173]. The results were obtained by density functional theory (DFT) calculations for ground state and time-dependent DFT (TD-DFT) calculations for excited states associated with the polarized continuum model (PCM) in order to account for the bulk solvent effect. The LUMO of T-Hg(II)-T was stabilized due to the presence of Hg(II) since an unoccupied 6p orbital interacted with the 2p orbitals of thymine N3 atoms in the same way as in a pi-conjugated system. Thus, excitations in T-Hg(II)-T involve transitions qualitatively different from those of the thymine-thymine mismatch base pair (T-T). Since conventional DFT functionals lack correct description of dispersion forces, a method previously developed in our research group which combines DFT and a van der Waals correction functional was introduced to study multiple stacking nucleobase pairs. Based on the evaluated distance and the interaction energy between two stacking nucleobase pairs, the selective capturing of Hg(II) ion by T-T compared to other metal ions is explained. The calculated UV absorption spectra of multiple stacking nucleobase pairs reproduced the decrease of absorption around 260 nm and the red-shift of the main peak experimentally observed in the presence of Hg(II) ion. Detailed analysis of the electronic structure revealed that the metal-metal interaction between two Hg(II) in multiple stacking T-Hg(II)-T is the origin of the significant changes in UV absorption spectra.

Post-vaccination subcutaneous aluminum granuloma.

Vaccination is a successful and cost-effective public health intervention. Aluminum-containing adjuvants are used worldwide to improve the immune response of vaccines. Side effects of aluminum-containing adjuvants in skin and subcutis are usually accompanied by persistent itch, and it may be challenging to diagnose asymptomatic cases. Here we present a case of a 1-year-old girl with asymptomatic subcutaneous nodules. Magnetic resonance imaging (MRI) revealed subcutaneous lesions: 16 mm on the upper right and 4 mm on the upper left arms. Histological examination revealed a granulomatous reaction with lymphoid follicle-like structures in the subcutis, accompanied by a considerable number of macrophages with PAS-positive granular cytoplasm. Moreover, the granules stained positive with aluminon staining, which revealed the existence of aluminum. These findings indicate post-vaccination aluminum granuloma. Due to the benign nature of aluminum granuloma and the benefit of routine vaccination, we decided to recommend that the patient continue taking the routine vaccination.

Theoretical studies on sulfur and metal cation (Cu(II), Ni(II), Pd(II), and Pt(II))-containing artificial DNA.

We evaluated the stability, UV-vis spectra, and possibility of stacking of [S-M(II)-S] (M=Ni, Pd, Pt, S: hydroxypyridinethione) using density functional theory (DFT). We calculated the formation energies of modified bases with possible combinations of chalcogen atoms and metal cations. The results confirmed that [H-Ni(II)-H] (H: hydroxypyridone), [H-Cu(II)-H], and [S-Cu(II)-S] would form stable metal-base pairing; on the other hand, [H-Zn(II)-H], [S-Zn(II)-S], and [H-Pt(II)-H] would not. We predicted UV-vis excitations at 400-410 nm, mainly dominated by a d-pi* transition accompanied by a pi-pi* transition in [S-M(II)-S], where a metal-to-ligand charge transfer shifts the peak of S (without metal cations) by performing time-dependent density functional theory (TDDFT) calculations. By adding the Andersson-Langreth-Lundqvist van der Waals correction to the hybrid DFT results, we estimated the interaction energy between base pairs of [S-M(II)-S]. According to the results, the interaction between [S-M(II)-S] monomers for all cases is attractive, so that the selectivity of formation of the metal-containing DNA is governed mainly by the formation of the base pair in the aqueous phase and only slightly by the pi-pi stacking interaction between the modified bases.

Case of fertility treatment-induced Stevens-Johnson syndrome with a severe ocular complication.

Pharmacological regimens with multiple medications are being used in fertility treatments. Herein, we report a case of a 40-year-old Japanese woman who developed Stevens-Johnson syndrome (SJS) with a severe ocular complication during fertility treatment. Despite early multimodal interventions, including methylprednisolone pulse therapy and plasma exchange, her ocular complications persisted for more than a year. The four drugs administered in this case (cabergoline, medroxyprogesterone acetate, clomiphene, and intravenous human chorionic gonadotropin) have never been reported to induce SJS. Based on this case, we suggest that obstetricians, gynecologists, and dermatologists should be aware of fertility treatment-induced severe drug eruptions.

Structural origin of copper ion containing artificial DNA: a density functional study.

In order to investigate an origin of structural stability of a copper ion containing artificial DNA, we evaluated the stacking energy between [H-Cu(2+)-H] (H: hydroxypyridone) dimer by means of density functional theory (DFT) with an Anderson-Langreth-Lindqvist van der Waals (vdW) functional. The calculated distance between the copper ions is about 3.6 angstroms, which agrees well with the experimental data. Evaluated stacking energy is about 8-10 kcal/mol, which is slightly smaller than that of two base pairs in a natural B-DNA. This tendency does not change in [H-2H(+)-H], which does not contain copper ions. These results indicate that the vdW interaction dominates the inter-base-pair interaction over spin-spin interaction, in contrast to a conjecture by an experimental group. According to the results by the open-shell DFT, antiferromagnetic (singlet) and ferromagnetic (triplet) states are almost degenerated when the two bases are vertically located and both bases have a planar structure as found in the B-DNA.