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Kyoung-Hee Sohn,1 Myung-Nam Lee,2 Da Woon Sim,3 Sujeong Kim,4 You Sook Cho,5 Hyouk-Soo Kwon,5 Sang-Heon Kim6 1Division of Pulmonology and Allergy, Department of Internal Medicine, Kyung Hee University Hospital, Seoul, South Korea; 2Department of Nursing, College of Health Science, Kangwon National University Samcheok, Samcheok-si, Gangwon-do, South Korea; 3Department of Allergy and Clinical Immunology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, South Korea; 4Division of Allergy and Clinical Immunology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea; 5Department of Allergy and Clinical Immunology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 6Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South KoreaCorrespondence: Hyouk-Soo Kwon, Department of Allergy and Clinical Immunology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea, Email kwonhs21@naver.com Sang-Heon Kim, Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea, Email sangheonkim@hanyang.ac.kr

Background: Patients with severe asthma are susceptible to lung function decline (LFD), but biomarkers that reliably predict an accelerated LFD have not been fully recognized., Objective: To identify variables associated with previous LFD occurrences in patients with severe asthma by exploring the computed tomography (CT) imaging features within predefined LFD groups., Methods: We obtained inspiratory and expiratory CT images of 102 patients with severe asthma and derived 2 airway structural parameters (wall thickness [WT] and hydraulic diameter) and 2 parenchymal variables (functional small airway disease and emphysema). We retrospectively calculated the annual changes in forced expiratory volume in 1 second and grouped participants by their values determined. The 4-imaging metrics, along with levels of several biomarkers, were compared among the LFD groups., Results: Patients with severe asthma with enhanced LFD exhibited significantly lower WT and smaller hydraulic diameter compared with those with minimal change or slight decline in lung function, after an adjustment of smoking status. Conversely, CT-based percentages of emphysema and functional small airway disease did not significantly differ according to LFD. Furthermore, fractional exhaled nitric oxide (FeNO) level and the blood matrix metalloproteinase-9/TIMP metallopeptidase inhibitor 1 ratio were significantly higher in patients with severe asthma with enhanced LFD compared with those in the others., Conclusion: Lower WT on CT scans with increased FeNO that may represent increased airway inflammation significantly correlated with enhanced LFD in patients with severe asthma. Consequently, active management plans may help to attenuate LFD for patients with severe asthma with lower WT and high FeNO., Competing Interests: Disclosures All authors declare that they have no conflicts of interest related to this article., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

This study aimed to determine the effects of indoor environment (IE) and outdoor air pollutants (OAPs) in residential areas on acute exacerbation (AE) in patients with severe asthma. A total of 115 participants were recruited. To characterize IE, we used structured questionnaires and estimated OAP concentrations using a land-use regression model. Participants who were exposed to passive smoking and lived in houses where the kitchen and living room were not separated showed a significantly higher rate of AE ( p  = 0.014 and 0.0016, respectively). The mean concentration of PM 2.5 in residential areas during the last 3 years was significantly higher in participants with AE than that in those without AE (19.8 ± 3.1 vs . 21.0 ± 2.5 µg/m 3 , p  = 0.033). Moreover, the serum level of 8-hydroxy-2'-deoxyguanosine significantly increased in participants with AE compared to those without AE (56.9 ± 30.0 vs . 94.7 ± 44.5 ng/mL, p  = 0.0047) suggesting enhanced oxidative stress in those with AE.

Purpose: Symptoms are important components in determining asthma control and in the adjustment of treatment levels. However, clinical relevance of cough in severe asthma is not well-understood. This study aimed to evaluate the severity and association of cough with patient-reported outcomes (PROs) in patients with severe asthma., Methods: This study analyzed cross-sectional data from the Korean Severe Asthma Registry. The severity of coughing and wheezing symptoms was assessed using a Visual Analog Scale (VAS) ranging from 0 to 100 for each symptom. Additionally, PROs included the Asthma Control Test (ACT), the Severe Asthma Questionnaire (SAQ), and the EuroQoL 5-Dimension (EQ-5D) index. Multivariate linear regression analysis was employed to explore the relationship between cough severity and other PRO scores., Results: A total of 498 patients with severe asthma (age: 57.9 ± 13.1 years, females: 60.2%) were analyzed. The cough VAS score was higher than the wheeze score (median 30, [interquartile range 10-50] vs. 20 [0-50]; P < 0.001). Additionally, 22.5% of patients ranked in a higher tertile for cough severity compared to wheezing, while 18.5% ranked higher for wheezing severity than cough. Significant correlations were observed between cough and wheeze VAS scores (r = 0.61, P < 0.05) and between each symptom's VAS score and the SAQ (cough: r = -0.41, P < 0.001; wheeze: r = -0.52, P < 0.001), ACT scores (cough: r = -0.50, P < 0.001; wheeze: r = -0.63, P < 0.001) and EQ-5D index (cough: r = -0.40, P < 0.001; wheeze: r = -0.45, P < 0.001). In univariate regression analysis, the cough VAS score had weaker descriptive power (R 2 ) values than the wheeze VAS score in relation to the PRO measures. Nevertheless, cough severity remained significantly associated with ACT, SAQ scores and EQ-5D index in multivariate analyses adjusted for wheeze severity and other confounders., Conclusion: Cough frequently presents as a severe symptom in patients with severe asthma and could have distinct impact on asthma control and quality of life., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Angiotensin receptor blockers are widely used antihypertensive drugs in South Korea. In 2021, the Korea Ministry of Food and Drug Safety acknowledged the need for national compensation for a drug-induced liver injury (DILI) after azilsartan use. However, little is known regarding the association between angiotensin receptor blockers and DILI., Objective: We conducted a retrospective cohort study in incident users of angiotensin receptor blockers from a common data model database (1 January, 2017-31 December, 2021) to compare the risk of DILI among specific angiotensin receptor blockers against valsartan., Methods: Patients were assigned to treatment groups at cohort entry based on prescribed angiotensin receptor blockers. Drug-induced liver injury was operationally defined using the International DILI Expert Working Group criteria. Cox regression analyses were conducted to derive hazard ratios and the inverse probability of treatment weighting method was applied. All analyses were performed using R., Results: In total, 229,881 angiotensin receptor blocker users from 20 university hospitals were included. Crude DILI incidence ranged from 15.6 to 82.8 per 1000 person-years in treatment groups, most were cholestatic and of mild severity. Overall, the risk of DILI was significantly lower in olmesartan users than in valsartan users (hazard ratio: 0.73 [95% confidence interval 0.55-0.96]). In monotherapy patients, the risk was significantly higher in azilsartan users than in valsartan users (hazard ratio: 6.55 [95% confidence interval 5.28-8.12])., Conclusions: We found a significantly higher risk of suspected DILI in patients receiving azilsartan monotherapy compared with valsartan monotherapy. Our findings emphasize the utility of real-world evidence in advancing our understanding of adverse drug reactions in clinical practice., (© 2024. The Author(s).)

The diagnosis of anaphylaxis is based on the clinical history. The utility of tryptase measurements in clinical setting is limited. Mas-related G protein-coupled receptor-X2 (MRGPRX2) is expressed in mast cells and is involved in the degranulation of these cells. We evaluated the potential of MRGPRX2 as a diagnostic biomarker in patients with iodinated contrast media (ICM)-induced immediate hypersensitivity reactions (IHRs). A total of 173 patients with documented ICM-induced IHR within 4 months from registration were enrolled and skin tests for the culprit ICM were performed. The time interval was evaluated as the duration between the onset of ICM-induced IHR and the measurement of serum MRGPRX2 levels. Serum MRGPRX2 concentration was determined using an enzyme-linked immunosorbent assay kit. Of the 173 patients, 33 and 140 were included in the anaphylaxis and non-anaphylaxis groups, respectively. Serum MRGPRX2 levels were significantly higher in the anaphylaxis than in the non-anaphylaxis group (29.9 ± 24.1 vs. 20.7±17.5, P = 0.044). Serum MRGPRX2 showed a moderate predictive ability for anaphylaxis, with an area under the curve of 0.61 ( P = 0.058). When groups were classified based on the time interval, T1(0-2months) and T2 (2-4months), patients with anaphylaxis had higher MRGPRX2 levels compared to the non-anaphylaxis group in the T2 group (36.5±19.2 vs. 20.5±19.0, P = 0.035). This pilot study shows that serum MRGPRX2 is a potential long-term biomarker for predicting anaphylaxis, particularly ICM-induced anaphylaxis. Further studies are needed to determine the role of MRGPRX2 in anaphylaxis in a larger population of patients with various drug-induced IHRs., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Purpose: Few studies have compared the clinical characteristics of severe asthma (SA) in elderly patients compared to that in nonelderly patients., Methods: We analyzed data from the Korean SA Registry, a nationwide, real-world observational study of SA in Korea. The baseline clinical characteristics, disease control status, and medication use of the patients were compared between elderly (≥ 65 years) and nonelderly groups., Results: Of the 864 patients with SA, 260 (30.1%) were in the elderly group. The elderly group had lower atopy rate, but had higher prevalence of chronic obstructive pulmonary disease (COPD), hypertension, and osteoporosis than did the nonelderly group. The elderly group had a lower rate of type 2 inflammation and lower levels of forced expiratory volume in 1 second (FEV1) (% predicted) and FEV1/forced vital capacity ratio than did the nonelderly group ( P < 0.05 for all). However, asthma symptom scores and the frequency of asthma exacerbation were not significantly different between the 2 groups. Of controller medications, biologics were less frequently used in the elderly group ( P < 0.05 for all)., Conclusions: SA in the elderly is characterized by lower lung function, less type 2-low airway inflammation, and comorbidity with COPD. These findings are being taken into consideration in the management of elderly patients with SA in real-world clinical practice., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Background: Symptom perception and quality of life (QOL) are important domains for properly managing severe asthma. This study aimed to assess the relationship between airway structural and parenchymal variables measured using chest computed tomography (CT) and subjective symptom perception and QOL in patients with severe asthma enrolled in the Korean Severe Asthma Registry., Methods: This study used CT-based objective measurements, including airway wall thickness (WT), hydraulic diameter, functional small airway disease (fSAD), and emphysematous lung (Emph), to assess their association with subjective symptom (cough, dyspnea, wheezing, and sputum) perception measured using the visual analog scale, and QOL measured by the Severe Asthma Questionnaire (SAQ)., Results: A total of 94 patients with severe asthma were enrolled in this study. The WT and fSAD% were significantly positively associated with cough and dyspnea, respectively. For QOL, WT and Emph% showed significant negative associations with the SAQ. However, there was no significant association between lung function and symptom perception or between lung function and QOL., Conclusion: Overall, WT, fSAD%, and Emph% measured using chest CT were associated with subjective symptom perception and QOL in patients with severe asthma. This study provides a basis for clarifying the clinical correlates of imaging-derived metrics and for understanding the mechanisms of respiratory symptom perception., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: With the availability of retrospective pharmacovigilance data, the common data model (CDM) has been identified as an efficient approach towards anonymized multicenter analysis; however, the establishment of a suitable model for individual medical systems and applications supporting their analysis is a challenge., Objective: The aim of this study was to construct a specialized Korean CDM (K-CDM) for pharmacovigilance systems based on a clinical scenario to detect adverse drug reactions (ADRs)., Methods: De-identified patient records (n = 5,402,129) from 13 institutions were converted to the K-CDM. From 2005 to 2017, 37,698,535 visits, 39,910,849 conditions, 259,594,727 drug exposures, and 30,176,929 procedures were recorded. The K-CDM, which comprises three layers, is compatible with existing models and is potentially adaptable to extended clinical research. Local codes for electronic medical records (EMRs), including diagnosis, drug prescriptions, and procedures, were mapped using standard vocabulary. Distributed queries based on clinical scenarios were developed and applied to K-CDM through decentralized or distributed networks., Results: Meta-analysis of drug relative risk ratios from ten institutions revealed that non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of gastrointestinal hemorrhage by twofold compared with aspirin, and non-vitamin K anticoagulants decreased cerebrovascular bleeding risk by 0.18-fold compared with warfarin., Conclusion: These results are similar to those from previous studies and are conducive for new research, thereby demonstrating the feasibility of K-CDM for pharmacovigilance. However, the low quality of original EMR data, incomplete mapping, and heterogeneity between institutions reduced the validity of the analysis, thus necessitating continuous calibration among researchers, clinicians, and the government., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Although beta-lactams are 1 of the major causative agents of severe cutaneous adverse reactions (SCAR), their epidemiology and clinical aspects have been poorly studied. This study aimed to investigate the characteristics of SCAR caused by beta-lactams in the Korean SCAR registry., Methods: We retrospectively analyzed beta-lactam-induced SCAR cases collected from 28 tertiary university hospitals in Korea between 2010 and 2015. The SCAR phenotypes included Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN overlap, and drug reaction with eosinophilia and systemic symptoms (DRESS). Beta-lactams were classified according to their chemical structures: penicillins, cephalosporins, and carbapenems. The causative beta-lactams, clinical and laboratory features, treatments, and outcomes were evaluated., Results: Among the 275 antibiotic-induced SCAR cases, 170 patients developed SCAR induced by beta-lactams. Beta-lactam antibiotic-induced SCAR showed more frequent SJS/TEN compared to SCAR induced by non-beta-lactam antibiotics (SJS/TEN/SJS-TEN overlap/DRESS: 36.5/11.2/5.9/46.5% vs. 23.8/10.5/2.9/62.9%, P  = 0.049). Cephalosporin was the most common culprit drug. Particularly, 91 and 79 patients presented with SJS/TEN and DRESS, respectively. The odds ratio (OR) for poor prognosis, such as sequelae and death, was significantly increased in subjects with SJS-TEN overlap and TEN and carbapenem as culprit drug in the multivariate analysis (OR, 35.61; P  = 0.016, OR, 28.07; P  = 0.006, OR 30.46; P  = 0.027)., Conclusion: Among antibiotic-induced SCAR, clinical features were different depending on whether the culprit drug was a beta-lactam antibiotic or SCAR type. The poor prognosis was related to SJS-TEN overlap, TEN type, and carbapenem as the culprit drug., (© 2022 The Author(s).)

Purpose: Oral corticosteroids (OCSs) are frequently prescribed for asthma management despite their adverse effects. An understanding of the pattern of OCS treatment is required to optimize asthma treatment and reduce OCS usage. This study evaluated the prescription patterns of OCSs in patients with asthma., Methods: This is a retrospective multicenter observational study. We enrolled adult (≥18 years) patients with asthma who had been followed up by asthma specialists in 13 university hospitals for ≥3 years. Lung function tests, the number of asthma exacerbations, and prescription data, including the days of supply and OCS dosage, were collected. The clinical characteristics of OCS-dependent and exacerbation-prone asthmatic patients were evaluated., Results: Of the 2,386 enrolled patients with asthma, 27.7% (n = 660) were OCS users (the median daily dose of OCS was 20 mg/day prednisolone equivalent to a median of 14 days/year). OCS users were more likely to be female, to be treated at higher asthma treatment steps, and to show poorer lung function and more frequent exacerbations in the previous year than non-OCS users. A total of 88.0% of OCS users were treated with OCS burst with a mean dose of 21.6 ± 10.2 mg per day prednisolone equivalent to 7.8 ± 3.2 days per event and 2.4 times per year. There were 2.1% (51/2,386) of patients with OCS-dependent asthma and 9.5% (227/2,386) with exacerbation-prone asthma. These asthma phenotypes were consistent over the 3 consecutive years in 47.1% of OCS-dependent asthmatic patients and 34.4% of exacerbation-prone asthmatic patients when assessed annually over the 3-year study period., Conclusions: We used real-world data from university hospitals in Korea to describe the OCS prescription patterns and relievers in asthma. Novel strategies are required to reduce the burden of OCS use in patients with asthma., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2022 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, potentially life-threatening, delayed, drug-induced hypersensitivity reaction. Immediate withdrawal of the culprit drug and administration of systemic corticosteroids is the most widely accepted treatment. However, it is difficult to manage patients with DRESS syndrome who are not responsive to systemic steroids. We studied the efficacy of intravenous immunoglobulins (IVIGs) in patients with DRESS syndrome unresponsive to systemic steroids. We retrospectively reviewed patients with DRESS syndrome who received IVIG in addition to systemic steroids during 2012-2017 and compared the clinical features and course of DRESS syndrome, before and after IVIG treatment. Eighteen DRESS patients (9 men) were included. The most frequent offending drugs were dapsone in five patients, followed by vancomycin in three patients, and carbamazepine in three patients. Rash, fever, lymphadenopathy, atypical lymphocytes, and hepatic involvement were common clinical findings. IVIG treatment was added within a median time of 7 days from the commencement of systemic steroid therapy. After IVIG treatment (total dosage: 1-2 g/kg), the fever resolved within a median time of 1 day (range, 0-3) and liver enzymes improved substantially within a median time of 13 days (range, 0-27). No severe adverse reactions related to IVIG therapy were observed in this study; however, there was one case of mortality. The addition of IVIG in DRESS syndrome in cases refractory to systemic steroid treatment may be helpful in hastening recovery. However, comparative studies using a placebo group are needed., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Competing Interests: There are no financial or other issues that might lead to conflict of interest.

Background: Multiple drug hypersensitivity syndrome (MDHS) results in treatment delay or failure and often results in severe drug hypersensitivity reactions. There are few reports of MDHS in response to anti-tuberculosis drugs; however, clinical information is scarce. Understanding the frequency and clinical characteristics of simultaneous MDHS against first-line anti-tuberculosis drugs in patients with non-severe drug hypersensitivity reactions is necessary., Methods: We reviewed 27 patients with drug fever or maculopapular exanthem in response to first-line anti-tuberculosis drugs between January 2010 and June 2019. Drug fever or maculopapular exanthem occurred when isoniazid, rifampin, ethambutol, and pyrazinamide were administered simultaneously. Drug provocation tests for the 4 drugs were performed to identify the culprit drugs., Results: All patients showed positive reactions to 1 or more drugs. MDHS was diagnosed in 13 (48%) patients, of whom 11 and 2 patients reacted to 2 and 3 drugs, respectively. In comparison to the patients with single-drug hypersensitivity, the patients with MDHS did not exhibit any differences in characteristics. Ethambutol and rifampin were the common drugs that induced a reaction, and the combination of these 2 drugs induced MDHS most frequently. Among the patients with MDHS, there were no differences between the drugs that caused drug fever and maculopapular exanthem. All patients with MDHS were successfully treated with alternative drugs., Conclusions: Simultaneous MDHS may occur frequently in patients with drug fever or maculopapular exanthem caused by first-line anti-tuberculosis drugs, indicating the need to evaluate the allergy responses for all 4 drugs, even in patients without severe drug hypersensitivity. The combination of ethambutol and rifampin was the most common trigger that induced MDHS., Competing Interests: The authors have declared that they have no conflicts of interest in this work., (© 2021 The Authors.)

Background: Erdosteine is used as a mucolytic agent and has a low incidence of adverse drug reactions, most of which are gastrointestinal and mild. Moreover, drug antigens rarely induce multiple simultaneous immunologic reactions. Only one previous case report has demonstrated hypersensitivity reaction induced by erdosteine. Here, we report a case of fixed drug eruption and anaphylaxis, which were concurrently induced by erdosteine. The association between the symptoms and erdosteine was proven by a drug provocation test., Case Presentation: A 35-year-old woman presented with recurrent angioedema and pruritic rash on the hands, which developed within 2 h following the administration of drugs, including erdosteine, for acute upper respiratory infection. Her rash was characterized by well-defined erythematous plaques, which recurred at the same site following the administration of the medications. She also experienced angioedema of the lips. Fixed drug eruption was considered after excluding other possible causes for the presented skin lesions. A drug provocation test confirmed that fixed drug eruption on both hands had occurred after administration of erdosteine, suggesting that erdosteine was the cause of the allergic reaction. However, she also experienced angioedema, isolated wheal, and laryngeal edema; thus, IgE-mediated type I hypersensitivity could also be concurrently occurring with the fixed drug eruption., Conclusions: We report about a patient who was diagnosed with two different hypersensitivity reactions concurrently induced by erdosteine. We also demonstrate that patients may exhibit multiple simultaneous symptoms that usually arise from overlapping of different hypersensitivity mechanisms. Physicians should be aware of the possibility that some patients who are allergic to certain drugs could exhibit several symptoms caused by different mechanisms of hypersensitivity reactions simultaneously.

Background: Because severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) rarely occur, clinical data based on large-scale studies are still lacking., Objective: To provide information on culprit drugs and clinical characteristics, including morbidity and mortality of SCARs based on a nationwide registry., Methods: SCAR cases that occurred from 2010 to 2015 were recruited to the Korean SCAR registry from 34 tertiary referral hospitals. Demographics, causative drugs, causality, and clinical outcomes were collected by reviewing the medical record., Results: A total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs were registered. The main causative drugs were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and antituberculous agents (6.3%). A strong preference for SJS/TEN was observed in carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%), whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were more likely to cause DRESS. The mortality rate was 6.6% (SJS/TEN 8.9% and DRESS 4.2%). The median time to death was 19 days and 29 days in SJS/TEN and DRESS respectively, and 89.8% of deaths occurred within 60 days after the onset of the skin symptoms., Conclusion: Allopurinol, carbamazepine, vancomycin, and antituberculous agents were the leading causes of SCARs in Korea. Some drugs preferentially caused a specific phenotype. The mortality rate of SCARs was 6.6%, and most of the deaths occurred within 2 months., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: Exposure to particulate matter (PM) is a well-known risk factor in the triggering and exacerbation of allergic airway disease. Indoor environments, where people spend most of their time, are of utmost importance. To assess the effects of air purifiers [equipped with high-efficiency particulate air (HEPA) filters] on allergic rhinitis (AR) in adult patients, we performed a multicenter, randomized, double-blind, and placebo-controlled study., Materials and Methods: Patients with house dust mite (HDM)-induced AR were randomly assigned to either active or mockup (placebo) air-purification groups. Two air purifiers (placed in living room and bedroom) were operated for 6 weeks in each home environment. The primary study endpoint was to achieve improvement in AR symptoms and medication scores. Secondary endpoints were to achieve improvement in the quality of life (QoL) and visual analog scale (VAS) scores, as well as in the indoor (bedroom and living room) concentrations of PM 2.5 and PM 10 ., Results: After 6 weeks of air purifier use, medication scores improved significantly in the active (vs. placebo) group, although subjective measures (symptoms, VAS, and QoL scores) did not differ. Bedroom PM 2.5 concentrations initially exceeded living room or outdoor levels, but declined (by up to 51.8%) following active purifier operation. Concentrations of PM 2.5 in living room and PM 10 in bedroom and living room were also significantly reduced through active purification., Conclusion: The use of air purifiers with HEPA filters significantly reduced medication requirements for patients with HDM-induced AR and significantly lowered indoor PM 2.5 concentrations, regardless of room placement. Active intervention to reduce household air pollutants may help improve allergic airway disease (clinicaltrials.gov NCT03313453)., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Background: The incidence of severe reaction induced by iodinated contrast media (ICM) has increased over the years with an increasing use of imaging modalities. Although ICM anaphylaxis is rare, it can be life-threatening, but currently, there is no biomarker that can identify individuals at risk of ICM anaphylaxis., Objective: The aim of this study is to investigate the genetic susceptibility of ICM anaphylaxis., Methods: Patients who had ICM anaphylaxis were enrolled in the study, and their blood samples were collected for genotyping of human leukocyte antigen (HLA)-A, -B, -C, and -DR. The results were compared with those of healthy Korean general population. MRGPRX2 gene in ICM anaphylaxis group was also sequenced and compared with the Korean standard database of genetic polymorphism., Results: The frequencies of 3 HLA alleles (B*52:01, C*12:02, and DRB1*15:02) were significantly higher in 47 patients with ICM anaphylaxis. In particular, HLA-DRB1*15:02 was 5 times more frequent in the ICM anaphylaxis group than the Korean general population (34.0% vs 6.6%; odds ratio, 7.306; 95% confidence interval, 3.622-14.740), and this difference was most pronounced in subjects with iohexol-induced anaphylaxis (odds ratio, 16.516; 95% CI, 5.241-52.047; P < 0.0001). Eight single nucleotide polymorphisms were identified in MRGPRX2 gene, but their frequencies were not different in those with ICM anaphylaxis compared with the general Korean population., Conclusions: HLA-DRB1*15:02 is associated with ICM anaphylaxis in the Korean population.

Purpose: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but serious condition that systematically damages various internal organs through T-cell-mediated immunological drug reactions. We aimed to investigate whether clinical manifestations of DRESS syndrome differ according to culprit drugs., Methods: We retrospectively analyzed data from 123 patients with probable/definite DRESS syndrome based on the RegiSCAR criteria (January 2011 to July 2016). The data were obtained from the Korean Severe Cutaneous Adverse Reaction Registry. Causality was assessed using the World Health Organization-Uppsala Monitoring Centre criteria. The culprit drugs were categorized as allopurinol, carbamazepine, anti-tuberculosis drug, vancomycin, cephalosporins, dapsone, and nonsteroidal anti-inflammatory drugs., Results: Differences were observed among culprit drugs regarding the frequencies of hepatitis (P < 0.01), renal dysfunction (P < 0.0001), lymphadenopathy (P < 0.01), and atypical lymphocyte (P < 0.01). Latency period differed among culprit drugs (P < 0.0001), being shorter in vancomycin and cephalosporin. In terms of clinical severity, admission duration (P < 0.01) and treatment duration (P < 0.05) differed among culprit drugs, being longer in vancomycin and anti-tuberculosis drugs, respectively., Conclusions: Based on the findings, clinical manifestations, including latency period and clinical severity, may differ according to culprit drugs in DRESS syndrome., (© 2019 John Wiley & Sons, Ltd.)

Background/aims: Although eosinophilic liver infiltration (ELI) is not rare, few data exist regarding its clinical characteristics and etiology. Therefore, we evaluated these aspects to better understand the clinical implications of this lesion type, which is reasonably common in Korea., Methods: Patients suspected of having ELI, based on abdominal computed tomography results obtained between January 2010 and September 2017, were enrolled in this retrospective study. The presumptive etiologies of ELI were categorized as parasite infections, hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), malignancies, and unidentified. Clinical courses and treatment responses were also evaluated., Results: The mean age of the enrolled patients (male, 237/328) was 62 years. Most patients (63%) were diagnosed incidentally and had peripheral eosinophilia (90%). Only 38% of the enrolled patients (n=126) underwent further evaluations to elucidate the etiology of the suspected ELI; 82 (25%) had parasite infections, 31 (9%) had HES, five (2%) had EGPA, and five (2%) had drug reactions in conjunction with eosinophilia and systemic symptoms. Almost half of the other enrolled patients had cancer. Radiologic resolution was achieved in 191 patients (61%; median time to radiologic resolution, 185 days). Resolution of peripheral eosinophilia was achieved in 220 patients (79%). In most cases, the course of ELI was benign., Conclusions: This large ELI study is unique in that the incidence rate, underlying diseases, and clinical courses were comprehensively evaluated. Clinicians should investigate the etiology of ELI, as several of the underlying diseases require intervention rather than observation.

Rationale: Hepatocellular carcinomas (HCCs) with metastases to the right atrium (RA) and lungs are rare, with a poor prognosis. Furthermore, the treatment outcomes in patients with advanced HCCs remain unsatisfactory., Patient Concerns: A 46-year-old man presented to our hospital for dyspnea on exertion and abdominal pain., Diagnoses: HCC and extra-hepatic metastases to the lung and RA., Interventions: Multidisciplinary treatment including radiotherapy (RT), transarterial chemoembolization (TACE), and sorafenib. During a follow-up evaluation computed tomography, he experienced a radio-contrast-induced anaphylaxis. After the event, treatment such as RT, TACE, and sorafenib were continued., Outcomes: His tumor burden decreased, finally leading to a complete response as per the modified Response Evaluation Criteria in Solid Tumors. The patient is still alive, 30 months after the episode. Subsequent blood tests showed increased natural killer (NK) cell activity, which was significantly higher than that seen in other age-matched HCC patients with an identical stage of the tumor, receiving sorafenib. This suggests that the increase in NK cells induced by anaphylaxis influenced the tumor burden., Lessons: We report here a rare case of long-term survival of an HCC patient with multiple metastases treated with multidisciplinary modalities, in which high NK cell activity was observed after a radio-contrast-induced anaphylactic reaction during follow-up investigations.

Background: Various allergenic proteins are produced by house dust mites (HDM). However, the allergenicity and clinical implications of these allergens are unknown., Objective: The purpose of this study was to identify allergens in Dermatophagoides farinae and elucidate the sensitization profiles to these in Korean patients suffering from respiratory (allergic rhinitis and/or asthma) and atopic dermatitis symptoms., Methods: IgE reactivities in sera from 160 HDM allergy patients were analysed by one- and two-dimensional gel electrophoresis and immunoblotting. IgE-reactive components were identified by liquid chromatography-coupled electrospray ionization-tandem mass spectrometry. Nine recombinant mite allergens (Der f 1, Der f 2, Der f 10, Der f 11, Der f 13, Der f 14, Der f 30, Der f 32 and Der f Alt a 10) were produced, and the IgE reactivity in sera to each was determined by ELISAs., Results: Der f 1 and Der f 2 were recognized by IgE in serum samples from 88.1% and 78.1% of all patients, respectively. Patients with respiratory allergies were mainly sensitized to these major allergens, whereas patients with atopic dermatitis symptoms showed polysensitization to major and minor allergen components (including Der f 11, Der f 13, Der f 14, Der f 32 and Der f Alt a 10)., Conclusions: Patients with respiratory allergic disease sensitize to major allergen components of HDM. Those with atopic dermatitis were sensitized to a broader range of minor allergen components of HDM (Der f 11, Der f 13, Der f 14, Der f 32 and Der f Alt a 10)., (© 2018 John Wiley & Sons Ltd.)

Background: We developed skin prick test (SPT) reagents for common inhalant allergens that reflected the real exposure in Korea. The study aim was to evaluate diagnostic usefulness and allergen potency of our inhalant SPT reagents in comparison with commercial products., Methods: We produced eight common inhalant allergen SPT reagents using total extract (Prolagen): Dermatophagoides farinae, Dermatophagoides pteronyssinus, oak, ragweed, mugwort, Humulus japonicus pollens, as well as cat and dog allergens. We compared the newly developed reagents with three commercially available SPT reagents (Allergopharma, Hollister-Stier, Lofarma). We measured total protein concentrations, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), major allergen concentration, and biological allergen potencies measured by immunoglobulin E (IgE) immunoblotting and ImmunoCAP inhibition test., Results: Diagnostic values of these SPT reagents were expressed as positivity rate and concordance rate of the results from ImmunoCAP allergen-specific IgE test in 94 allergic patients. In vitro analysis showed marked differences in protein concentrations, SDS-PAGE features, major allergen concentrations, and biological allergen potencies of four different SPT reagents. In vivo analysis showed that positive rates and concordance rates of Prolagen® SPT reagents were similar compared to the three commercial SPT reagents., Conclusion: The newly developed Prolagen® inhalant SPT reagents are not inferior to the commercially available SPT reagents in allergy diagnosis., Competing Interests: Dr. Park JW reports serving as an unpaid chief technology officer for Prolagen; Dr. Kim JD, serving as chief executive officer for Prolagen. Dr. Park JW, Dr. Kim JD, Dr. Park KH, having an equity interest in Prolagen. These authors' interests did not influence academic fairness in conducting this study, analyzing results, and writing a paper. Other authors have no potential conflicts of interest to disclose., (© 2018 The Korean Academy of Medical Sciences.)

Background: The identification of clinically meaningful specific immunoglobulin E (sIgE) is important for the diagnosis and management of allergic diseases. Various in vitro sIgE detection methods are available worldwide. Depending on the number of antigens that can be tested simultaneously, there are two representative methods: singleplex and multiplex. Singleplex sIgE detection is mainly provided by Thermo Fisher (ImmunoCAP) and Siemens (Immulite). This study aimed to compare the diagnostic agreement of two singleplex sIgE detection assays., Methods: Sera from 209 Korean patients with allergic disease were used to compare the ImmunoCAP and Immulite assays with respect to the following allergens: inhalant allergens (Dermatophagoides farinae, cat and dog dander, oak, rye grass, mugwort, Alternaria, German cockroach) and food allergens (hen's egg white, cow's milk, wheat, peanut, soybean, and shrimp). Data from 902 paired comparison tests were included for comparisons. Qualitative, semi-quantitative, and quantitative comparisons were performed using statistical analyses., Results: In qualitative comparisons, the positivity and negativity agreements ranged from 75% (wheat, shrimp) to 96% (Alternaria). Class consistency (classes 0-6) was well matched. Spearman's rank correlation coefficients for all allergens except shrimp were over 0.7. In quantitative comparisons, all allergens excluding shrimp showed >0.7 intra-class correlation coefficients., Conclusions: The ImmunoCAP and Immulite systems showed similar performances. However, clinicians should consider fundamental methodological differences between the assays., Competing Interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication., (© The Korean Society for Laboratory Medicine)

Scope: IgE against galactose-α-1,3-galactose (α-Gal) causes alpha-gal syndrome. Bovine thyroglobulin (BTG) and cetuximab share this epitope. We aimed to determine the utility of specific IgE (sIgE) against cetuximab as compared to BTG for diagnosing alpha-gal syndrome., Methods and Results: Twelve patients with alpha-gal syndrome, 11 patients with immediate beef or pork allergy, 18 asymptomatic individuals with meat sensitization, and 10 non-atopic subjects were enrolled. We checked the levels of sIgE against BTG and cetuximab using the streptavidin CAP assay. Additionally, IgE reactivity to BTG and cetuximab was assessed by immunoblotting. All alpha-gal syndrome patients had a high concentration of sIgE against BTG, and cetuximab. In contrast to alpha-gal syndrome, patients with immediate allergic reactions to meat consumption and those with asymptomatic sensitization had significantly lower concentration of BTG and cetuximab sIgE, and a high prevalence of sIgE against bovine or porcine serum albumin. Although the concentration of sIgE against alpha-gal was lower in individuals with asymptomatic sensitization, IgE immunoblotting showed the presence of sIgE against α-Gal in this group., Conclusion: Differentiation of alpha-gal syndrome from patients with immediate allergy to meat consumption or asymptomatic sensitization requires quantification of cetuximab- or BTG-induced sIgE via detection of IgE for α-gal., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A large portion of proteins in living organisms are membrane proteins which play critical roles in the biology of the cell, from maintenance of the biological membrane integrity to communication of cells with their surroundings. To understand their mechanism of action, structural information is essential. Nevertheless, structure determination of transmembrane proteins is still a challenging area, even though recently the number of deposited structures of membrane proteins in the PDB has rapidly increased thanks to the efforts using X-ray crystallography, electron microscopy, and solid and solution nuclear magnetic resonance (NMR) technology. Among these technologies, solution NMR is a powerful tool for studying protein-protein, protein-ligand interactions and protein dynamics at a wide range of time scales as well as structure determination of membrane proteins. This review provides general and useful guideline for membrane protein sample preparation and the choice of membrane-mimetic media, which are the key step for successful structural analysis. Furthermore, this review provides an opportunity to look at recent applications of solution NMR to structural studies on α-helical membrane proteins through some success stories., Competing Interests: The authors declare no conflict of interest.

Purpose: The AdvanSure™ AlloScreen assay is an advanced multiplex test that allows for simultaneous detection of specific IgE (sIgE) against multiple allergens. For precise identification of causative allergens in allergic patients, we compared this new multiplex sIgE assay with the ImmunoCAP assay, which is currently the gold-standard method for sIgE detection., Materials and Methods: Serum samples from 218 Korean allergic disease patients were used to compare the ImmunoCAP and AlloScreen assays with respect to the following 13 allergens: Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat and dog dander, Alternaria, birch, oak, ragweed, mugwort, rye grass, and food allergens (egg white, cow's milk, peanuts)., Results: A total of 957 paired tests using the 13 allergens were compared. The total agreement ratio ranged from 0.74 (oak) to 0.97 (Alternaria). With respect to class association analyses, the gamma index ranged from 0.819 (rye grass) to 0.990 (Alternaria). The intra-class correlation coefficients for house dust mites, cat and dog dander, Alternaria, birch, ragweed, egg white, cow's milk, and peanut sIgE titers were >0.8., Conclusion: The AlloScreen and ImmunoCAP assays exhibited similar diagnostic performance. However, due to methodological differences between the two systems, careful interpretation of their results is needed in clinical applications., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2017)

Competing Interests: We have read and understood BMJ policy on declaration of interests and declare that we have no competing interests.

Purpose: CD93 is receiving renewed attention as a biomarker of inflammation. We aimed to evaluate the potential for serum sCD93 to serve as a novel biomarker for allergic inflammation., Materials and Methods: We enrolled 348 subjects with an allergic disease [allergic rhinitis (AR), chronic spontaneous urticaria (CSU), or bronchial asthma (BA)], including 14 steroid-naïve BA patients who were serially followed-up., Results: The serum sCD93 levels (ng/mL) in patients with exacerbated AR (mean±standard deviation, 153.1±58.4) were significantly higher than in patients without AR (132.2±49.0) or with stable AR (122.3±42.1). Serum sCD93 levels in exacerbated CSU (169.5±42.8) were also significantly higher than those in non-CSU (132.4±51.6) and stable CSU (122.8±36.2). This trend was also seen in BA. Serum levels in patients with ICS-naïve BA (161.4±53.1) were significantly higher than those in healthy controls without BA (112.2±30.8), low- and medium-dose ICS users. Serum sCD93 levels in high-dose ICS users (72.2±20.6) were significantly lower than those in low- and medium-dose users. The serum sCD93 levels in steroid-naïve patients with BA (195.1±72.7) decreased after ICS use for 4 weeks (134.4±42.8) and 8 weeks (100.7±13.4), serially., Conclusion: Elevated serum sCD93 levels reflected exacerbated status of allergic diseases, including CSU, AR, and asthma. ICS use significantly diminished serum sCD93 levels in steroid-naïve patients with BA. This result may suggest sCD93 in serum as a therapeutic marker for allergic inflammation., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2017)

Although cyclic AMP receptor protein (CRP) has long served as a typical example of effector-mediated protein allostery, mechanistic details into its regulation have been controversial due to discrepancy between the known crystal structure and NMR structure of apo-CRP. Here, we report that the recombinant protein corresponding to its C-terminal DNA-binding domain (CDD) forms a dimer. This result, together with structural information obtained in the present NMR study, is consistent with the previous crystal structure and validates its relevance also in solution. Therefore, our findings suggest that dissociation of the CDD may be critically involved in cAMP-induced allosteric activation of CRP., (© 2017 Federation of European Biochemical Societies.)

Background: Oaks are the most common trees in Korean forests, and Mongolian oak, Quercus mongolica, is the dominant species. However, no allergen has been characterized from Mongolian oak. In this study, we tried to characterize a major allergen from Mongolian oak., Methods: A molecule homologous to pathogenesis-related 10 (PR-10)-like protein, Que m 1, was cloned by RT-PCR. Its recombinant protein, along with Que a 1, an allergen from white oak (Q. alba), was produced. The allergenicity and diagnostic value of recombinant Que m 1, Que a 1, and Bet v 1 proteins were compared by ELISA using sera from oak-sensitized subjects. A basophil activation test was also performed using CD63 expression as an activation marker., Results: Que m 1 sequence shares 57.5-96.2% amino acid sequence identity with PR-10-like allergens from various plants. Specific IgE to recombinant Que m 1, Que a 1, and Bet v 1 were detected in 92.0, 74.0, and 38.0% of 50 serum samples from Korean tree pollinosis patients. Recombinant Que m 1 was able to inhibit IgE reactivity to Que a 1 and Bet v 1, indicating its strong cross-reactivity. The activation patterns of basophils from 5 patients were similar in terms of the CD63 expression and protein concentration of challenged Bet v 1 and Que m 1., Conclusions: A major allergen, Que m 1, was cloned, and its recombinant protein was produced from Mongolian oak, a dominant species in Korea. Recombinant Que m 1 is potentially useful for the diagnosis and treatment of tree pollinosis in Korea., (© 2017 S. Karger AG, Basel.)

Background: We previously reported that as many as one third of hospitalized patients with asthma treated with a low to medium daily dose of inhaled steroids (ICSs) for an average of 4.5 years showed adrenal insufficiency (AI)., Objective: To re-examine this issue in consecutive outpatients with asthma because of possible subject selection bias., Methods: One hundred twenty-one consecutive adult patients with asthma under ICS treatment for at least 6 months underwent a rapid adrenocorticotrophic hormone stimulation test. AI was defined as a morning serum cortisol level no higher than 3 μg/dL or lower than 18 μg/dL before and after administration of 250 μg of adrenocorticotrophic hormone., Results: The mean durations of ICS use in the short-term (less than the median) and long-term (at least the median) users were 3.8 and 11.5 years, respectively. The proportion of subjects affected by AI tended to increase with the increasing cumulative dose of ICS (short-term users at a low to medium daily dose: mean cumulative dose 502 mg [15 of 34, 44.1%]; short-term users at a high dose of 941 mg [16 of 26, 61.5%]; long-term users at a low to medium dose of 1,077 mg [25 of 41, 61.0%]; long-term users at a high dose of 2,805 mg [13 of 20, 65.0%]), although not significantly. In short-term users, daily and cumulative ICS doses were significantly related to serum cortisol levels 60 minutes after taking adrenocorticotrophic hormone (r = -0.300 and -0.287, respectively; P < .05)., Conclusion: A large number of patients with asthma might have AI even with low- to medium-dose ICS treatment when ICSs are administered over a long period. Thus, it is essential that patients with asthma under ICS treatment be checked for AI much more frequently., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Fragment engineering of monoclonal antibodies (mAbs) has emerged as an excellent paradigm to develop highly efficient therapeutic and/or diagnostic agents. Engineered mAb fragments can be economically produced in bacterial systems using recombinant DNA technologies. In this work, we established recombinant production in Escherichia coli for monovalent antigen-binding fragment (Fab) adopted from a clinically used anticancer mAB drug cetuximab targeting epidermal growth factor receptor (EGFR). Recombinant DNA constructs were designed to express both polypeptide chains comprising Fab in a single vector and to secrete them to bacterial periplasmic space for efficient folding. Particularly, a C-terminal engineering to confer an interchain disulfide bond appeared to be able to enhance its heterodimeric integrity and EGFR-binding activity. Conformational relevance of the purified final product was validated by mass spectrometry and crystal structure at 1.9 Å resolution. Finally, our recombinant cetuximab-Fab was found to have strong binding affinity to EGFR overexpressed in human squamous carcinoma model (A431) cells. Its binding ability was comparable to that of cetuximab. Its EGFR-binding affinity was estimated at approximately 0.7 nM of Kd in vitro, which was quite stronger than the binding affinity of natural ligand EGF. Hence, the results validate that our construction could serve as an efficient platform to produce a recombinant cetuximab-Fab with a retained antigen-binding functionality.

Purpose: The use of monoclonal antibodies (mAbs) is increasing in various clinical fields. Although mAb safety must be demonstrated prior to approval, targeted pharmacovigilance is essential for the recognition and assessment of adverse reactions. The purpose of this study was to identify the major clinical features of adverse reactions to mAbs in Korea., Methods: Spontaneous reports of adverse reactions attributed to 18 mAbs from January 2005 to December 2014 were extracted from the Korea Adverse Event Reporting System. We analyzed these reports for information relating to patient characteristics and the types of adverse reactions., Results: In total, 11 492 adverse reactions were reported in 7569 patients. Almost 19% of total study population showed suspected hypersensitivity reactions. Leukocyte abnormalities were reported frequently (10.0%), as well as infections (9.5%), drug eruptions (7.5%), and pruritus (5.0%). Furthermore, 3716 of the adverse reactions in 2538 patients were classified as serious; these included severe infections (18.2%), neutropenia (12.1%), visual dysfunctions (6.6%), and anaphylaxis (4.8%). The mAbs with the highest number of adverse reaction reports were rituximab (27.6%), adalimumab (17.5%), cetuximab (11.9%), and infliximab (10.7%)., Conclusions: Hypersensitivity reactions were observed more frequently than expected, although no previously unrecognized reactions were observed. Adverse reactions occurred more frequently in children and in elderly patients. Close monitoring of adverse reactions to therapeutic mAbs is therefore warranted because these can potentially cause serious medical conditions or death. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Histamine H2 receptor antagonists are commonly prescribed medications and are known to be well tolerated. However, 99 cases of ranitidine-induced anaphylaxis occurred in Korea from 2007 to 2014., Objective: The purpose of this study was to determine the incidence, clinical features, and diagnostic methods for ranitidine-induced anaphylaxis., Methods: Ranitidine-related pharmacovigilance data from 2007 to 2014 were reviewed. Adverse drug reactions with causal relationships were selected, and clinical manifestations, outcomes, and drug-related information were assessed. For further investigation, 8 years of pharmacovigilance data were collected at a single centre. Twenty-three patients participated in in vivo and in vitro studies. Skin tests, oral provocation tests, and laboratory tests were performed, including tests using other kinds of histamine H2 receptor antagonists., Results: Over 7 years, 584 patients suffered adverse reactions to ranitidine. The most common manifestation was cutaneous symptoms. Among them, 99 patients (17.0%) experienced anaphylaxis. In a single-centre study, skin prick tests were positive in 91.7% of ranitidine-induced anaphylaxis patients (11/12); the optimal concentration was 20 mg/mL. Detection of ranitidine-specific immunoglobulin E failed. Cimetidine and proton pump inhibitors showed no cross-reactivity with ranitidine based on the skin prick test, oral provocation test, or clinical determination. Surprisingly, 82.6% of patients reintroduced ranitidine and re-experienced the same adverse reactions because ranitidine was not considered the culprit drug., Conclusions and Clinical Relevance: Although ranitidine is known as a safe drug, it can also cause diverse adverse reactions, including anaphylaxis. This study demonstrates the need to pay attention to adverse reactions to ranitidine and consider ranitidine as a cause of anaphylaxis., (© 2016 John Wiley & Sons Ltd.)

The activation process of the redox-regulated chaperone heat shock protein 33 (Hsp33) is constituted by the oxidation-induced unfolding of the C-terminal zinc-binding domain and concomitant oligomerization of the N-terminal core domain. Herein, the semi-empirical solution structure of Escherichia coli Hsp33 in the reduced, inactive form was generated through conformational space annealing calculations, utilizing minimalistic NMR data and multiple homology restraints. The various conformations of oxidized Hsp33 and some mutant forms were also investigated in solution. Interestingly, a specific region concentrated around the interdomain linker stretch and its interacting counterparts, the N-terminal β-strand 1 and α-helix 1, hardly showed up as signals in the NMR measurements. The NMR spectra of an Hsp33 derivative with a six-residue deletion in the disordered N-terminus implied a plausible conformational exchange associated with the identified region, and the corresponding exchange rate appeared slower than that of the wild type. Subsequent mutations that destroyed the structure of the β1 or α1 elements resulted in the formation of a reduced but active monomer, without the unfolding of the zinc-binding domain. Collectively, structural insights into the inactive and active conformations, including wild-type and mutant proteins, suggest that the dynamic interactions of the N-terminal segments with their contacting counterpart, the interdomain linker stretch, in the reduced, inactive state are the structural determinants regulating the activation process of the post-translationally regulated chaperone, Hsp33., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Antimicrobial peptides (AMPs), also called host defense peptides, particularly those with amphipathic helical structures, are emerging as target molecules for therapeutic development due to their immunomodulatory properties. Although the antimicrobial activity of AMPs is known to be exerted primarily by permeation of the bacterial membrane, the mechanism underlying its anti-inflammatory activity remains to be elucidated. We report potent anti-inflammatory activity of WALK11.3, an antimicrobial model peptide with an amphipathic helical conformation, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. This peptide inhibited the expression of inflammatory mediators, including nitric oxide, COX-2, IL-1β, IL-6, INF-β, and TNF-α. Although WALK11.3 did not exert a major effect on all downstream signaling in the MyD88-dependent pathway, toll-like receptor 4 (TLR4)- mediated pro-inflammatory signals were markedly attenuated in the TRIF-dependent pathway due to inhibition of the phosphorylation of STAT1 by attenuation of IRF3 phosphorylation. WALK11.3 specifically inhibited the endocytosis of TLR4, which is essential for triggering TRIF-mediated signaling in macrophage cells. Hence, we suggest that specific interference with TLR4 endocytosis could be one of the major modes of the anti-inflammatory action of AMPs. Our designed WALK11 peptides, which possess both antimicrobial and anti-inflammatory activities, may be promising molecules for the development of therapies for infectious inflammation.

HP0268 is a conserved, uncharacterized protein from Helicobacter pylori. Here, we determined the solution structure of HP0268 using three-dimensional nuclear magnetic resonance (NMR) spectroscopy, revealing that this protein is structurally most similar to a small MutS-related (SMR) domain that exhibits nicking endonuclease activity. We also demonstrated for the first time that HP0268 is a nicking endonuclease and a purine-specific ribonuclease through gel electrophoresis and fluorescence spectroscopy. The nuclease activities for DNA and RNA were maximally increased by Mn(2+) and Mg(2+) ions, respectively, and decreased by Cu(2+) ions. Using NMR chemical shift perturbations, the metal and nucleotide binding sites of HP0268 were determined to be spatially divided but close to each other. The lysine residues (Lys7, Lys11 and Lys43) are clustered and form the nucleotide binding site. Moreover, site-directed mutagenesis was used to define the catalytic active site of HP0268, revealing that this site contains two acidic residues, Asp50 and Glu54, in the metal binding site. The nucleotide binding and active sites are not conserved in the structural homologues of HP0268. This study will contribute to improving our understanding of the structure and functionality of a wide spectrum of nucleases., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)