Ruptured fungal mycotic internal carotid artery aneurysm successfully treated with stent-assisted coil embolization: A case report.

Background: Ruptured intracranial fungal mycotic aneurysms have a high mortality rate. It has been reported that the number of opportunistic infections has increased. Here, we report the first case of a patient in which a ruptured fungal carotid artery aneurysm was successfully treated by stent-assisted coil embolization. Case Description: A 76-year-old male receiving dual antiplatelet therapy due to a recent percutaneous transluminal angioplasty presented with blurred vision of the right eye and diplopia. Magnetic resonance imaging revealed a fungal mass in the sphenoid sinus, and the patient was pathologically diagnosed with invasive aspergillosis. After receiving oral voriconazole for 4 weeks, he was admitted to the hospital with hemorrhagic shock from epistaxis. The right internal carotid artery angiography revealed a de novo irregularly shaped aneurysm at the cavernous portion, projecting into the sphenoid sinus, which was considered to be the source of bleeding. Due to the lack of ischemic tolerance and urgent demand for hemostasis, we performed a stent-assisted coil embolization of the aneurysm without interrupting the blood flow. Postoperatively, the patient had no neurological deficit, and treatment with voriconazole was continued for 12 months without rebleeding. Conclusion: Stent-assisted coil embolization without parent artery occlusion might be a promising option for the urgent treatment of ruptured fungal mycotic aneurysms. Long-term administration of voriconazole might be continued for 12 months for such patients.

ORMDL3 overexpression facilitates FcεRI-mediated transcription of proinflammatory cytokines and thapsigargin-mediated PERK phosphorylation in RBL-2H3 cells.

INTRODUCTION: The chromosomal region 17q21 harbors the human orosomucoid-like 3 (ORMDL3) gene and has been linked to asthma and other inflammatory diseases. ORMDL3 is involved in the unfolded protein response (UPR), lipid metabolism, and inflammatory reactions. We investigated the effects of ORMDL3 overexpression in RBL-2H3 cells to determine the contribution of ORMDL3 to inflammatory disease development. METHODS: We generated ORMDL3 stably overexpressing RBL-2H3 cells to assess degranulation, transcriptional upregulation of interleukin-4 (IL-4), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and mitogen-activated protein kinase (MAPK) phosphorylation via FcεRI. In addition, we examined the effects of ORMDL3 overexpression on thapsigargin (TG)-mediated proinflammatory cytokine transcription and UPR by monitoring MAPK, protein kinase-like endoplasmic reticulum kinase (PERK), and inositol-requiring enzyme 1 (IRE1) phosphorylation. RESULTS: Overexpression of ORMDL3 enhanced IL-4, TNF-α, and MCP-1 expression after FcεRI cross-linking, whereas the sphingosine-1-phosphate (S1P) agonist FTY720 suppressed this enhancement. There was no significant difference in degranulation and MAPK phosphorylation via FcεRI-mediated activation between vector-transfected and ORMDL3-overexpressing cells. ORMDL3 overexpression accelerated TG-mediated PERK phosphorylation, while MAPK phosphorylation and proinflammatory cytokine expression showed no significant changes in ORMDL3-overexpressing cells. CONCLUSIONS: Our findings suggest that ORMDL3 plays an important role in regulating proinflammatory cytokine expression via the S1P pathway and selectively affects the UPR pathway in mast cells.

Involvement of Activation of Mast Cells via IgE Signaling and Epithelial Cell-Derived Cytokines in the Pathogenesis of Pollen Food Allergy Syndrome in a Murine Model.

Murine models to elucidate the pathogenesis of pollen food allergy syndrome (PFAS), characterized by oral hypersensitivity symptoms induced by specific foods in patients previously sensitized with a pollen, are lacking. The study aimed to examine PFAS pathogenesis in a novel murine model. Birch pollen-immunized mice were orally administered apple extract, and oral symptoms were evaluated based on oral rubbing frequency following the challenge. The birch pollen-immunized mice orally challenged with apple extract exhibited PFAS-like symptoms, including oral rubbing and positive reaction of swelling by the prick test. The apple extract administered with a protease inhibitor reduced the oral rubbing frequency, which was also significantly reduced in the immunized Fcer1a -/- and mast cell-deficient mice compared with the immunized control mice. The oral rubbing frequency, serum IgE levels, and Th2-cytokine production by the cervical lymph node cells were significantly reduced in the immunized Il-33 -/- and thymic stromal lymphopoietin receptor-deficient (Crlf2 -/-) mice as compared with the immunized wild-type mice. IL-33 and thymic stromal lymphopoietin involve the pathogenesis of PFAS. The apple-extract stimulation did not lead to increased Th2-cytokine production in the oral mucosa or number of group 2 innate lymphoid cells or eosinophils. PFAS involves an early-phase response by mast cell degranulation via IgE signaling after the cross-reactivity of Bet v 1-specific IgE and the food allergen, and exacerbation of allergic symptom via proteases in food; PFAS does not involve a late phase with local Th2/eosinophilic inflammation in the oral mucosa. This novel murine model might be used for elucidating the pathogenesis and assessing new therapeutic strategies for PFAS.

Elevated Serum Leptin Levels in Patients With Eosinophilic Chronic Rhinosinusitis.

Background: Eosinophilic chronic sinusitis (ECRS) is a subtype of CRS with nasal polyps (CRSwNP) that is frequently comorbid with asthma. Notably, ECRS patients often show a high recurrence of NPs after surgical resection. Leptin is a hormone produced by adipocytes that has been implicated in airway inflammatory diseases. However, to date, the role of leptin in ECRS has not been investigated. Objective: To determine whether the serum levels of leptin are altered in patients with ECRS. Methods: In total, 40 patients with ECRS, 15 patients with non-eosinophilic CRS (non-ECRS), and 12 individuals without CRS (control) were included in this study. Patient's serum leptin levels were assessed, and the number of eosinophils in their NPs were measured through a histological evaluation of the three densest areas with cellular infiltrate beneath the epithelial surface. Finally, nasal fibroblast cultures established from NPs were stimulated with varying concentrations of recombinant leptin in vitro to determine whether leptin affects eotaxin-3 (Chemokine (C-C motif) ligand 26 :26: CCL26) expression. Results: The serum leptin levels in both the ECRS and non-ECRS groups were significantly higher than those in the control subjects (p < 0.0001 vs. ECRS; p < 0.05 vs. non-ECRS). Furthermore, ECRS patients displayed significantly elevated serum leptin levels compared to non-ECRS patients (p < 0.001), although there was no difference in body mass index between the groups. Notably, serum leptin levels were correlated with the proportion of eosinophils in peripheral blood (r = 0.3575, p < 0.01) and the number of eosinophils in NPs (r = 0.5109, p < 0.0001). Serum leptin levels were also correlated with eotaxin-3 mRNA expression in NPs (r = 0.5374, p < 0.01). Finally, leptin significantly augmented eotaxin-3 expression in nasal fibroblasts established in vitro from NPs in a leptin receptor-dependent manner (p < 0.05). Conclusion: Leptin levels are elevated in ECRS patients and may both promote and indicate the severity of ECRS as well as systemic type 2-biased inflammatory responses. Combined, these data indicate that circulating leptin may play a significant role in the development of eosinophilic inflammation in NPs.

Epidemiological study of oral allergy syndrome in birch pollen dispersal-free regions.

BACKGROUND: Oral allergy syndrome (OAS) is an immediate allergy caused by a cross-reaction of highly homologous common antigens (pan-allergens) contained in fruits/vegetables and pollen. METHODS: A questionnaire was provided to 6824 outpatient visitors and serum levels of specific IgEs against crude antigens and pan-allergen components were measured to study the relationship between the prevalence of OAS and pollinosis in the Fukui Prefecture where there is almost no dispersal of birch pollen. RESULTS: The prevalence of OAS was 10.8%. The rate of pollinosis complication in the OAS group was 67.4%, and OAS was observed in 16.8% of pollinosis patients. Causative foods in order of frequency were melon, pineapple, kiwi fruit, peach, and apple. A significantly higher number of patients from the OAS group were positive for birch, alder, and timothy grass-specific IgE. The rate of positivity for anti-component IgE corresponding to pollen in OAS group was also significantly higher. Of 34 patients with OAS caused by eating apples, 28 (82.4%) were positive for Mal d1-specific IgE. Of the 52 patients with peach-induced OAS, 41 (78.8%) were positive for Pur p1-specific IgE. The concordance rates between crude antigen-specific IgE and anti-PR-10 component-specific IgE were 87.1% and 93.3% for apple and peach respectively. CONCLUSIONS: In regions where birch pollen is not dispersed, OAS patients have a significant association with the onset of Bet v1-associated allergy. Anti-PR-10 component IgE was useful in diagnosing OAS, and crude antigen-specific IgE was also associated with apple and peach allergies.

Human cystatin SN is an endogenous protease inhibitor that prevents allergic rhinitis.

BACKGROUND: Protease allergens disrupt epithelial barriers to exert their allergenicity. Cystatin SN (encoded by CST1) is an endogenous cysteine protease inhibitor upregulated in nasal epithelia in patients with allergic rhinitis (AR). OBJECTIVE: We sought to investigate the protective effect of human cystatin SN on AR symptoms using pollen-induced AR mouse models. METHODS: We performed an in vitro protease activity assay to evaluate the effect of recombinant human cystatin SN (rhCystatin SN) on Japanese cedar (JC) or ragweed proteases. A human nasal epithelial cell line, RPMI 2650, was used to examine tight junction (TJ) disruption in vitro. Mice were sensitized and nasally challenged with JC or ragweed pollens with or without rhCystatin SN to examine the effect of rhCystatin SN on AR symptoms and the epithelial barrier in vivo. Because mice lack CST1, we generated transgenic (Tg) mice expressing human CST1 under control of its genomic control region (hCST1-Tg mice) to examine the role of cystatin SN in physiologically expressed conditions. RESULTS: rhCystatin SN inhibited JC but not ragweed protease activities and prevented JC-induced but not ragweed-induced TJ disruption in vitro. Exogenous administration of rhCystatin SN ameliorated JC-induced but not ragweed-induced sneezing and nasal TJ disruption in vivo. Furthermore, hCST1-Tg mice showed decreased JC-induced but not ragweed-induced sneezing symptoms and nasal TJ disruption compared with wild-type mice. CONCLUSION: Human cystatin SN suppresses AR symptoms through inhibiting allergen protease activities and protecting the nasal TJ barrier in an allergen-specific manner. We propose that upregulation of nasal endogenous protease inhibitors, including cystatin SN, is a novel therapeutic strategy for protease allergen-induced AR.

DNA Methylation of Proximal PLAT Promoter in Chronic Rhinosinusitis With Nasal Polyps.

Background Nasal polyps (NP) are characterized by pseudocysts derived from stromal tissue edema and cause persistent infections in patients with chronic rhinosinusitis (CRS). A low level of tissue-type plasminogen activator (gene name PLAT) is considered a cause of stromal tissue edema because of insufficient plasmin activation in NP; however, the mechanism regulating PLAT gene expression levels is still unclear. The epigenetic mechanism regulating the PLAT gene expression has been studied in other tissues. Objective We aimed to investigate the methylation levels in the proximal PLAT promoter and their effects on gene expression in NP tissue. Methods We investigated the methylation levels at 3 CpG sites in the proximal PLAT promoter regions (-618, -121, and -105 with respect to the transcription initiation site) by bisulfite pyrosequencing and their effects on the gene expression by quantitative real-time polymerase chain reaction (qPCR) in 20 paired samples of NP and inferior turbinate tissue (IT) from patients with CRS. Results The DNA methylation levels at all CpG sites were higher ( P < .01), and the PLAT expression was lower ( P < .001) in NP compared with IT. The methylation changes at the -618 site showed a negative correlation with the gene expression changes between NP and IT ( r = -.65, P < .01). Conclusions Hypermethylation of PLAT promoter may downregulate the gene expression in NP, leading to excessive fibrin deposition by aberrant coagulation cascade. DNA methylation of proximal PLAT promoter may contribute to NP growth and have a potential as a new therapeutic target.

Expression and Functional Analysis of CST1 in Intractable Nasal Polyps.

In this study, we found Cystatin SN (CST1), a type 2 cystatin subfamily member, to be highly expressed in nasal polyps from patients with intractable chronic rhinosinusitis (CRS) with nasal polyps, using a whole-transcript analysis with next-generation sequencing. Eosinophilic CRS (ECRS) involves nasal polyps that are refractory and recur immediately after endoscopic sinus surgery. We hypothesized that CST1 may contribute to the pathogenesis of ECRS. We examined the expression of CST1 in nasal polyps from patients with ECRS by assessing mRNA expression levels using real-time PCR and immunohistochemistry. CST1 showed significantly greater expression in the epithelial cells of nasal polyps from patients with ECRS than in those from patients who did not have ECRS (non-ECRS). In particular, CST1 showed very strong expression in patients with severe ECRS. The expression of CST1 may be correlated with the recurrent and refractory nature of ECRS. We examined the function of CST1 using nasal epithelial cells and nasal fibroblasts. Stimulation by a combination of IL-4 plus double-stranded RNA plus CST1 significantly elevated mRNA expression levels and protein levels of TSLP in nasal epithelial cells. Stimulation by TSLP or IL-33 significantly elevated mRNA expression levels of CST1 in nasal epithelial cells. Stimulation of CST1 significantly elevated mRNA expression levels of CCL11 and POSTN in nasal fibroblasts. CST1 could amplify eosinophilic infiltration and T-helper cell type 2 inflammation by interacting with epithelial-derived cytokines and fibroblasts on nasal polyps. CST1 may be involved in the pathogenesis of ECRS, and may contribute to the severity and recurrence of CRS with nasal polyps after endoscopic sinus surgery.

Activation of group 2 innate lymphoid cells exacerbates and confers corticosteroid resistance to mouse nasal type 2 inflammation.

Both Th2 cells and group 2 innate lymphoid cells (ILC2s) contribute to allergic diseases. However, their exact role and relationship in nasal allergic disorders are unclear. In this study, we investigated the cooperation of Th2 cells and ILC2s in a mouse model of nasal allergic disorder. To differentially activate Th2 cells and/or ILC2s in nasal mucosa, mice were intra-nasally administered ovalbumin (OVA) antigen, papain, an ILC2-activator, or both for 2 weeks. Epithelial thickness and number of eosinophils in the nasal mucosa were evaluated at 24 h after the final challenge. Intra-nasal administration of OVA and papain preferentially activated Th2 cells and ILC2s, respectively, in the nose. Both OVA and papain increased the nasal epithelial thickness and number of eosinophils, and their coadministration significantly enhanced the symptoms. Although T-/B-cell-deficient mice showed severely decreased nasal symptoms induced by OVA or OVA-plus-papain, the mice still showed slight papain-induced nasal symptoms. In ILC2-deficient mice, OVA-plus-papain-induced nasal symptoms were suppressed to the same level as OVA-alone. Similarly, IL-33- and ST2-deficient mice showed decreased OVA-plus-papain-induced nasal symptoms. IL-5 induced eosinophilia only, but IL-13 contributed to both nasal epithelial thickening and eosinophilia induced by OVA-plus-papain. Dexamethasone ameliorated OVA-alone-induced nasal epithelial thickening. However, OVA-plus-papain-induced nasal epithelial thickening was only partially controlled by dexamethasone. These results demonstrate that IL-33/ST2-pathway-mediated ILC2 activation exacerbated Th2-cell-induced nasal inflammation by producing IL-13. Although Th2-cell-alone-induced nasal inflammation was controlled by corticosteroid treatment, the activation of ILC2s conferred treatment resistance. Therefore, ILC2s and their activators could be therapeutic targets for treatment-refractory nasal allergic disorders.