Effect of pregnancy in asthma on health care use and perinatal outcomes

Kim, S.,Kim, J.,Park, S.Y.,Um, H.Y.,Kim, K.,Kim, Y.,Park, Y.,Baek, S.,Yoon, S.Y.,Kwon, H.S.,Cho, Y.S.,Moon, H.B.,Kim, T.B. Mosby 2015 The journal of allergy and clinical immunology Vol.136 No.5

Background: It is generally known that pregnancy in asthmatic patients increases the risk of asthma exacerbations and poor perinatal outcomes. However, the effect of pregnancy in asthmatic patients on health care use is not known well. In addition, its effect on perinatal outcomes is still controversial because of study limitations caused by ethical issues. National Health Insurance claim data are an ideal resource for studying real-world health care use patterns of asthma. Objective: We sought to evaluate the effect of pregnancy on asthma in terms of asthma-related health care use and prescription patterns in concert with the effect of asthma exacerbations on adverse pregnancy outcomes. Methods: Among all asthmatic patients in the Korean National Health Insurance claim database from January 2009 to December 2013, pregnant women who delivered in 2011 with pre-existing asthma were enrolled. Analyses included asthma-related health care use and prescription patterns compared between pregnant asthmatic women and nonpregnant female asthmatic control subjects, as well as within the pregnant subjects from before pregnancy throughout postpartum periods. In addition, the association between asthma exacerbation during pregnancy and adverse pregnancy outcomes was assessed. Results: A total of 3,357 pregnant asthmatic patients were compared with 50,355 nonpregnant asthmatic patients, and 10,311 pregnant patients were included to determine the effect of asthma exacerbations on adverse pregnancy outcome in the study. Pregnant asthmatic patients underwent more asthma-related hospitalizations (1.3% vs 0.8%, P = .005) but had significantly fewer outpatient visits and prescriptions for most asthma medications than nonpregnant asthmatic patients. The proportion of patients ever hospitalized gradually increased throughout pregnancy (first trimester, 0.2%; second trimester, 0.5%; and third trimester, 0.7%; P = .018). The prevalence of asthma exacerbation during pregnancy was 5.3%, and the patients who had acute exacerbation during pregnancy had significantly higher asthma-related health care use in terms of hospitalization, intensive care unit admission, and emergency department and outpatient visits within 1 year before delivery than those who had not. However, asthma exacerbation during pregnancy was not significantly related to adverse perinatal outcomes, except for cesarean section (27.1% vs 18.9%, P < .001). All exacerbations were managed with systemic corticosteroids, and the patients who ever experienced acute exacerbations maintained asthma medications, including inhaled corticosteroid-based inhalers, throughout the pregnancy period. Conclusion: Pregnancy profoundly affects asthma-related health care use but to a different degree depending on whether the patient experienced an exacerbation. Asthma exacerbation during pregnancy is not associated with adverse pregnancy outcomes while managed appropriately with systemic corticosteroids. However, further studies are needed to clarify the effect of asthma control on perinatal outcome and delivery method.

Intraoperative combined color and fluorescent images-based sentinel node mapping in the porcine lung: Comparison of indocyanine green with or without albumin premixing

Oh, Y.,Quan, Y.H.,Choi, Y.,Kim, C.K.,Kim, H.,Kim, H.K.,Kim, B.M. Mosby 2013 The Journal of thoracic and cardiovascular surgery Vol.146 No.6

Objectives: We developed a multimodal optical imaging system for intraoperative visualization of sentinel lymph nodes (SLNs). This study is to validate our system by showing SLNs in the lung through combined optical color and fluorescent image with indocyanine green (ICG) and ICG with human serum albumin (HSA). Methods: Identical ICG concentrations of ICG only or ICG:HSA was injected into the rat footpad and porcine lung. Absolute amounts of the fluorescents were scaled on the basis of animal weights. The entire procedures were recorded using color and near-infrared (NIR) charge-coupled device (CCD) cameras simultaneously, and the 2 images were merged by real-time image processing software. All fluorescence intensity signals to background ratio (SBR) and retention rates at SLN for both fluorescents were estimated and compared. Results: This newly developed intraoperative color and fluorescence optical imaging system successfully visualized the SLNs in animal experiments. The SLNs were identified 100% for both rat and pig under in vivo conditions. Real-time image processing software overcame the low signal of NIR fluorescence images. ICG and ICG:HSA provided no significantly different SBR in the SLN images for both rat thigh and pig lung. Conclusions: The intraoperative optical imaging system enabled real-time image-guided surgery during SLN mapping in lung in an animal model. The ICG retention rate was similar to ICG:HSA. ICG alone can be useful for SLN imaging during lung cancer surgery.

CCCTC-binding factor controls the homeostatic maintenance and migration of Langerhans cells

Kim, T.G.,Kim, M.,Lee, J.J.,Kim, S.H.,Je, J.H.,Lee, Y.,Song, M.J.,Choi, Y.,Chung, Y.W.,Park, C.G.,Cho, J.W.,Lee, M.G.,Lee, Y.S.,Kim, H.P. Mosby 2015 The journal of allergy and clinical immunology Vol.136 No.3

Background: Langerhans cells (LCs) are skin-resident dendritic cells (DCs) that orchestrate skin immunity. CCCTC-binding factor (CTCF) is a highly conserved DNA-binding protein that regulates higher-order chromatin organization and is involved in various gene regulation processes. Objective: We sought to clarify a possible role for CTCF in LC homeostasis and function in vivo. Methods: We used a conditional gene deletion mouse system to generate DC- and LC-specific CTCF-ablated mice. Short hairpin RNA-mediated RNA interference was used to silence CTCF expression in human monocyte-derived Langerhans cells. DC populations were assessed by using flow cytometry and immunofluorescence. Gene expression arrays were performed to identify genes regulated by CTCF in LCs. Contact hypersensitivity and epicutaneous sensitization responses were measured to examine the functional significance of CTCF ablation. Results: DC-specific CTCF deletion led to a reduced pool of systemic DCs, with LCs most severely affected. Decreases in epidermal LC numbers were specifically associated with self-turnover defects. Interestingly, CTCF-deficient LCs demonstrated impaired migration out of the epidermis. Whole-transcriptome analyses revealed that genes that promoted cell adhesion were highly expressed, but CCR7 was downregulated in CTCF-depleted LCs. Hapten-induced contact hypersensitivity responses were more sustained in LC-specific CTCF-deficient mice, whereas epicutaneous sensitization to protein antigen was attenuated, indicating that CTCF-dependent LC homeostasis is required for optimal immune function of LCs in a context-dependent manner. Conclusion: Our results show that CTCF positively regulates the homeostatic pool and the efficient emigration of LCs, which are required for modulating the functional immune network of the skin.

Lower vitamin D status is closely correlated with eczema of the head and neck

Noh, S.,Park, C.O.,Bae, J.M.,Lee, J.,Shin, J.U.,Hong, C.S.,Lee, K.H. Mosby 2014 The journal of allergy and clinical immunology Vol.133 No.6

Deficiency of vitamin D (VitD), which is known to affect both innate and adaptive immunity, has been reported to be associated with various allergic diseases. We compared the VitD status (serum 25-hydroxyvitamin D levels) between patients with atopic dermatitis (AD), asthma, and healthy controls. AD patients were found to have significantly lower VitD levels than asthma patients and healthy controls. In AD patients, a significant negative correlation was observed between VitD and the eczema area, especially head and neck while severity of AD was not significantly correlated with VitD levels. From these clinical observations, we suggest that the low VitD status of AD patients might be caused by impaired production of vitamin D3 in the skin due to the inflammatory skin condition.

Protease-activated receptor 2-dependent fluid secretion from airway submucosal glands by house dust mite extract

Cho, H.J.,Lee, H.J.,Kim, S.C.,Kim, K.,Kim, Y.S.,Kim, C.H.,Lee, J.G.,Yoon, J.H.,Choi, J.Y. Mosby 2012 The journal of allergy and clinical immunology Vol.129 No.2

Background: The submucosal gland (SMG) is important in the control of airway surface fluid. Protease-activated receptor (PAR) 2 contributes to the pathophysiology of allergies in response to nonspecific allergens bearing proteases and anion secretion. House dust mites (HDMs) have abundant proteases that can activate PAR2, but little is known about the direct effect of HDM on SMG secretion. Objective: The aim of this study was to investigate the effect of HDMs on glandular secretion and its mechanism in allergic patients, patients with chronic rhinosinusitis (CRS), or both. Methods: Inferior nasal turbinates were harvested from 55 patients and classified into 4 groups (the control, allergic rhinitis [AR], CRS, and AR+CRS groups). A microscope attached to a digital camera was used to quantify mucus bubbles from individual SMGs while stimulated with HDM extract, PAR2-activating peptide, and carbachol. PAR2 expression in the SMG was determined by means of immunostaining with anti-PAR2 mAb. Results: HDM induced a significantly higher secretion rate and number of responding glands in the AR and AR+CRS groups than in the control group. Interestingly, patients in the CRS group, who had no HDM-specific IgE antibody, showed a higher response than the control group, and its response was suppressed by a PAR2-selective antagonist. The responses to PAR2-activating peptide were similar to those to HDM, and their secretion rates positively correlated with HDM responses. PAR2 was highly expressed in all 3 disease groups with immunostaining. Conclusions: HDM allergens can induce glandular secretion in patients with AR, CRS, or both, and PAR2 represents a possible mechanism for nonspecific hyperreactivity in inflammatory airway diseases.

ERK½ antagonize AMPK-dependent regulation of FcεRI-mediated mast cell activation and anaphylaxis

Hwang, S.L.,Lu, Y.,Li, X.,Kim, Y.D.,Cho, Y.S.,Jahng, Y.,Son, J.K.,Lee, Y.J.,Kang, W.,Taketomi, Y.,Murakami, M.,Moon, T.C.,Chang, H.W. Mosby 2014 The journal of allergy and clinical immunology Vol.134 No.3

Background: Extracellular signal-regulated kinases ½ (ERK½) make important contributions to allergic responses via their regulation of degranulation, eicosanoid production, and cytokine expression by mast cells, yet the mechanisms underlying their positive effects on FcεRI-dependent signaling are not fully understood. Recently, we reported that mast cell activation and anaphylaxis are negatively regulated by AMP-activated protein kinase (AMPK). However, little is known about the relationship between ERK½-mediated positive and the AMPK-mediated negative regulation of FcεRI signaling in mast cells. Objective: We investigated possible interactions between ERK½ and AMPK in the modulation of mast cell signaling and anaphylaxis. Methods: Wild-type or AMPKα2<SUP>-/-</SUP> mice, or bone marrow-derived mast cells obtained from these mice, were treated with either chemical agents or small interfering RNAs that modulated the activity or expression of ERK½ or AMPK to evaluate the functional interplay between ERK½ and AMPK in FcεRI-dependent signaling. Results: The ERK½ pathway inhibitor U0126 and the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside similarly inhibited FcεRI-mediated mast cell signals in vitro and anaphylaxis in vivo. ERK½-specific small interfering RNA also mimicked this effect on FcεRI signals. Moreover, AMPKα2 knockdown or deficiency led to increased FcεRI-mediated mast cell activation and anaphylaxis that were insensitive to U0126 or activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside, suggesting that the suppression of FcεRI signals by the inhibition of the ERK½ pathway relies largely on AMPK activation. ERK½ controlled AMPK activity by regulating its subcellular translocation. Conclusions: ERK½ ablated the AMPK-dependent negative regulatory axis, thereby activating FcεRI signals in mast cells.

The role of air pollutants in atopic dermatitis

Mosby 2014 The journal of allergy and clinical immunology Vol.134 No.5

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease and a growing health concern, especially in children, because of its high prevalence and associated low quality of life. Genetic predisposition, environmental triggers, or interactions between them contribute to the pathophysiology of AD. Therefore, it is very important to identify and control risk factors from the environment in susceptible subjects for successful treatment and prevention. Both indoor and outdoor air pollution, which are of increasing concern with urbanization, are well-known environmental risk factors for asthma, whereas there is relatively little evidence in AD. This review highlights epidemiologic and experimental data on the role of air pollution in patients with AD. Recent evidence suggests that a variety of air pollutants, such as environmental tobacco smoke, volatile organic compounds, formaldehyde, toluene, nitrogen dioxide, and particulate matter, act as risk factors for the development or aggravation of AD. These air pollutants probably induce oxidative stress in the skin, leading to skin barrier dysfunction or immune dysregulation. However, these results are still controversial because of the low number of studies, limitations in study design, inaccurate assessment of exposure and absorption, and many other issues. Further research about the adverse effects of air pollution on AD will help to expand our understanding and to establish a better strategy for the prevention and management of AD.

IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis

Shin, H.W.,Kim, D.K.,Park, M.H.,Eun, K.M.,Lee, M.,So, D.,Kong, I.G.,Mo, J.H.,Yang, M.S.,Jin, H.R.,Park, J.W.,Kim, D.W. Mosby 2015 The journal of allergy and clinical immunology Vol.135 No.6

Background: Chronic rhinosinusitis (CRS) with nasal polyps (NPs) in Western populations is associated with T<SUB>H</SUB>2 cytokine polarization. IL-25, an IL-17 family cytokine, was recently reported to induce T<SUB>H</SUB>2-type immune responses and to contribute to several allergic diseases, such as atopic dermatitis and asthma. However, the role of IL-25 in Asian patients with nasal polyposis remains unclear. Objective: We sought to determine the role of IL-25 in Asian patients with nasal polyposis and CRS. Methods: We investigated IL-25 expression and its cellular origins in NPs of human subjects using immunohistochemistry (IHC), quantitative RT-PCR, and ELISA of NP tissues. Correlations between IL-25 expression and expression of other inflammatory markers in NP tissues were also explored. Anti-IL-25 neutralizing antibody was administered in an ovalbumin- and staphylococcal enterotoxin B-induced murine NP model to confirm the function of IL-25 during nasal polypogenesis. Results: IL-25 expression was upregulated in NP mucosa from patients with CRS with NPs compared with uncinate process tissue from control subjects and those with CRS without NPs. Overexpression of epithelial IL-25 was confirmed by using IHC, and double IHC staining showed that tryptase-positive cells were one of the main sources of IL-25 among immune cells. Furthermore, IL-17 receptor B levels were also increased in immune cells of patients with NPs compared with those in control subjects. In NPs IL-25 mRNA expression positively correlated with the expression of several inflammatory markers, including T-box transcription factor, RAR-related orphan receptor C, GATA3, eosinophil cationic protein, TGF-β1, and TGF-β2. IL-25 was more abundant in the murine NP model compared with control mice, and similar correlations between IL-25 and inflammatory markers were observed in murine models. Anti-IL-25 treatment reduced the number of polyps, mucosal edema thickness, collagen deposition, and infiltration of inflammatory cells, such as eosinophils and neutrophils. This treatment also inhibited expression of local inflammatory cytokines, such as IL-4 and IFN-γ. Furthermore, expression of CCL11, CXCL2, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in the nasal mucosa was suppressed in the anti-IL-25-treated group. Conclusion: Our results suggest that IL-25 secreted from the sinonasal epithelia and infiltrating mast cells plays a crucial role in the pathogenesis of CRS with NPs in Asian patients. In addition, our results suggest the novel possibility of treating nasal polyposis with anti-IL-25 therapy.

Intra-articular lesions and their relation to arthroscopic stabilization failure in young patients with first-time and recurrent shoulder dislocations

Shin, S.J.,Ko, Y.W.,Lee, J. Mosby Yearbook, Inc 2016 Journal of shoulder and elbow surgery Vol.25 No.11

Background: This study aimed to compare the frequency of intra-articular lesions between young patients with first-time shoulder dislocations and those with recurrent shoulder dislocations and to assess the correlation between intra-articular lesions and failure of arthroscopic stabilization. Methods: The study enrolled 33 patients who underwent arthroscopic Bankart repair after first-time shoulder dislocation before the age of 30 years. There were 89 age-matched patients who were treated arthroscopically for recurrent dislocation included as a control group. Results: Among intra-articular pathologic findings, anterior glenoid erosion (P@?=@?.043) and anterior labral periosteal sleeve avulsion lesions (P@?=@?.048) were found more frequently in the recurrent dislocation group. There was no statistically significant difference between the 2 groups in American Shoulder and Elbow Surgeons (P@?=@?.675) and Rowe (P@?=@?.132) scores at the last follow-up. However, there was a significant difference in the failure rate after operation between the 2 groups (P@?=@?.039). In the first-time dislocation group, 1 patient had redislocation and none showed positive apprehension. In the recurrent dislocation group, 6 patients had redislocation and 10 patients had positive apprehension. Eight of 10 patients who showed positive apprehension had either anterior labral periosteal sleeve avulsion lesions or anterior glenoid erosion. The patients' satisfaction with daily activities was significantly better in the first-time dislocation group (93.0@?+/-@?5.2) than in the recurrent dislocation group (82.7@?+/-@?7.2; P@?<@?.001). Conclusions: Primary surgical treatment for first-time traumatic anterior shoulder dislocation provided satisfactory functional outcomes and improved quality of life. Primary arthroscopic stabilization can be considered one of the treatment options in patients younger than 30 years with first-time shoulder dislocation to prevent further intra-articular injuries that may contribute to recurrence.

A synonymous variation in protease-activated receptor-2 is associated with atopy in Korean children

Lee, J.H.,Kim, K.W.,Gee, H.Y.,Lee, J.,Lee, K.H.,Park, H.S.,Kim, S.H.,Kim, S.W.,Kim, M.N.,Kim, K.E.,Kim, K.H.,Lee, M.G.,Sohn, M.H. Mosby 2011 The journal of allergy and clinical immunology Vol.128 No.6

Background: Atopic diseases are the most common chronic diseases of childhood, and the genetics of atopy are complex and heterogeneous. Protease-activated receptor-2 (PAR-2) is involved in various inflammatory diseases, but the association of PAR-2 with allergic diseases remains unclear. Objective: To examine the contribution of genetic variation of PAR-2 to atopic phenotypes in the Korean childhood cohort. Methods: We identified PAR-2 variations in a Korean population and conducted association analyses by using 316 unrelated atopic and 210 nonatopic subjects. We analyzed serum IgE and total eosinophil count levels and examined PAR-2 mRNA and protein expression levels. Results: In the case-control association analysis, atopy was significantly associated with a single c.621C>T (p.I207I, rs631465) polymorphism of PAR-2 (P = .001, odds ratio = 1.95). Subjects with the c.621T risk allele had significantly higher serum IgE (P = .004) and total eosinophil count (P = .03) levels. Moreover, the positive association of c.621T was reproduced in the replication study (P = .01, joint P value of the replication < .001). An in silico analysis of RNA secondary structure prediction revealed that the C to T conversion at c.621 greatly increased predicted PAR-2 mRNA stability. This was also confirmed by an in vitro assay for mRNA stability. Furthermore, following an in vivo approach on gene expression in PBMCs showed that the expression levels of PAR-2 mRNA and protein in subjects with the c.621CT or TT genotype were significantly higher than in those with the c.621CC genotype. Conclusions: These results indicate that the synonymous c.621C>T polymorphism in PAR-2 might be associated with the risk of atopy, potentially by altering PAR-2 gene expression.