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For the first time, Bi-doped In2O3-indium tin oxide (ITO) nanocomposites were prepared on Si substrates with the assistance of a Au catalyst through the simple gas-phase transport of a mixture of Bi, In, and Sn powders. The square-shaped Bi-doped In2O3-ITO nanostructures were straight, a few hundreds of nanometres in width, and below a few tens of micrometres in length. Electron microscopy, x-ray diffraction, and energy-dispersive x-ray spectroscopy analyses indicated that the Bi-doped In2O3-ITO nanorods were single crystals with a basis of cubic In2O3 structures. The photoluminescence spectra revealed that the Bi-doped In2O3-ITO nanorods had a strong orange emission band centred at approximately 626 nm without any shoulder bands. The enhancement of orange emission might be due to the oxygen deficiencies of structural defects in the nanorods.

Increased oxidative stress has an important role in asthmatic airway inflammation and remodeling. A potent methyl donor, S-adenosylmethionine (SAMe), is known to protect against tissue injury and fibrosis through modulation of oxidative stress. The aim of this study was to evaluate the effect of SAMe on airway inflammation and remodeling in a murine model of chronic asthma. A mouse model was generated by repeated intranasal challenge with ovalbumin and Aspergillus fungal protease twice a week for 8 weeks. SAMe was orally administered every 24 h for 8 weeks. We performed bronchoalveolar lavage (BAL) fluid analysis and histopathological examination. The levels of various cytokines and 4-hydroxy-2-nonenal (HNE) were measured in the lung tissue. Cultured macrophages and fibroblasts were employed to evaluate the underlying anti-inflammatory and antifibrotic mechanisms of SAMe. The magnitude of airway inflammation and fibrosis, as well as the total BAL cell counts, were significantly suppressed in the SAMe-treated groups. A reduction in T helper type 2 pro-inflammatory cytokines and HNE levels was observed in mouse lung tissue after SAMe administration. Macrophages cultured with SAMe also showed reduced cellular oxidative stress and pro-inflammatory cytokine production. Moreover, SAMe treatment attenuated transforming growth factor-β (TGF-β)-induced fibronectin expression in cultured fibroblasts. SAMe had a suppressive effect on airway inflammation and fibrosis in a mouse model of chronic asthma, at least partially through the attenuation of oxidative stress and TGF-β-induced fibronectin expression. The results of this study suggest a potential role for SAMe as a novel therapeutic agent in chronic asthma. A molecule involved in many natural physiological processes, S-adenosylmethionine (SAMe), shows potential for treating chronic asthma. Asthma involves structural changes in the passages of the respiratory system, known as airway remodeling. There are no effective drugs to combat this process, which is believed to involve an imbalance between oxidant and anti-oxidant chemical activities in the affected cells. SAMe participates naturally in maintaining this balance and is already used as a drug to control it in several other diseases. You Sook Cho and co-workers at the University of Ulsan and other research centers in South Korea explored the effect of SAMe in a mouse model of chronic severe asthma. Oral administration of SAMe reduced airway inflammation and tissue thickening, indicating therapeutic possibilities. Studies on treated cells suggested plausible biochemical mechanisms for SAMe's effects.

On the phytochemical investigation of a 70% ethanol extract of the fruits of Opuntia ficus-indica, (Cacataceae), we could result in the isolation of thirteen phenolic compounds including seven flavonoids (1 - 9) and four simple phenolic glycosides (10 - 13) by column chromatographic methods. Among the isolated compounds, picein (11), androsin (12), and 1-O-feruloyl-β-D-glucopyranoside (13) were isolated for the first time from O. ficus-indica; additionally, this is the first report benzyl-O-β-D-glucopyranoside (10) from the genus Opuntia. The structures of the compounds were determined by spectral data analysis which included 1D, 2D NMR spectrum and ESIMS.

Toxocariasis is an important cause of secondary hypereosinophilia in Korea. Here, we describe a rare case of toxocariasis presenting as transient global amnesia due to secondary hypereosinophilia. A 44-year-old male visited the Emergency Department (ED) for transient global amnesia. He ate raw cow liver and omasum 2 weeks before the ED visit. The initial peripheral blood eosinophil count was 15,250/μL and serologic test for serum specific IgG antibodies to Toxocara canis larval antigen was positive. Radiologic studies revealed multiple small embolic infarctions of brainwithout cardioembolic sources or vascular abnormalities. He was treated with systemic corticosteroid, and neither neurologic deficit nor motor deficit was left. In our current case, the patient have a history of frequently eating raw cow liver and omasum, and his total IgE level was extremely high (> 5,000 IU/mL). Thus, the patient was diagnosed as having toxocariasis and secondary hypereosinophilia. Toxocariasis should be considered in the differential diagnosis in patients with eosinophilia and atypical neurologic symptoms, such as transient amnesia. (Allergy Asthma Respir Dis 2016;4:217-220)

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome—also known as drug-induced hypersensitivity syndrome—is an uncommon disease entity that manifests as fever, skin rash, blood cell abnormalities, lymphadenopathy, and often coagulopathy. Tigecycline is an antibiotic that is selectively used to treat complicated intra-abdominal and soft-tissue infections. Recently, a few cases of tigecycline-induced coagulopathy have been reported. Herein, we report a case of tigecycline-induced coagulopathy in a patient with DRESS syndrome. Both prothrombin time and activated partial thromboplastin time were abruptly exceeded beyond 180 seconds on day 6 of tigecycline treatment and normalized after discontinuation of tigecycline. (Allergy Asthma Respir Dis 2016;4:74-78)

Background The liver is the most commonly involved internal organ in drug-induced systemic hypersensitivity. However, data obtained from these patients have yet to be analyzed in depth with respect to liver injury. Methods The medical records of 136 patients who developed delayed-type drug hypersensitivity were reviewed at a tertiary referral hospital. Culprit drugs, the pattern and degree of liver injury, and the effect of systemic corticosteroids were evaluated in the group of patients with drug-induced systemic hypersensitivity and liver dysfunction (aspartate aminotransferase or alanine aminotransferase ≥80 IU/L). Clinical characteristics of patients with drug-induced systemic hypersensitivity and liver injury were analyzed. Results Among the 61 patients with drug-induced systemic hypersensitivity and liver dysfunction, the clinical phenotypes were drug reaction with eosinophilia and systemic symptoms (n = 29, 48%), Stevens-Johnson syndrome/toxic epidermal necrolysis (n = 11, 18%), and maculopapular rash (n = 17, 28%). Antibiotics (n = 27, 44%) were the most common cause of drug-induced systemic hypersensitivity with liver dysfunction. Whereas patients with Stevens-Johnson syndrome/toxic epidermal necrolysis had mild hepatocellular-type liver injury of relatively brief duration, those with drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome had more severe and prolonged hepatocellular injury in addition to moderate to severe cholestatic-type liver injury. The use of systemic corticosteroids did not significantly affect either recovery from liver injury or mortality. Limitations This study was retrospective and the number of subjects was small. Conclusion The results suggest that the severity, pattern, and duration of liver injury differ according to the drug-hypersensitivity phenotype. Further studies are needed to evaluate the role of systemic corticosteroids in drug-induced systemic hypersensitivity and liver injury.

Asthma is a heterogeneous airway disease with various clinical phenotypes. It is crucial to clearly identify clinical phenotypes to achieve better asthma management. We used cluster analysis to classify the clinical groups of 724 asthmatic patients from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA), and in 1843 subjects from another independent Korean asthma cohort of Soonchunhyang University Asthma Genome Research Centre (SCH) (Bucheon, Republic of Korea). Hierarchical cluster analysis was performed by Ward's method, followed by κ-means cluster analysis. Cluster analysis of the COREA cohort indicated four asthma subtypes: 1) smoking asthma; 2) severe obstructive asthma; 3) early-onset atopic asthma; and 4) late-onset mild asthma. An independent cluster analysis of the SCH cohort also indicated four clusters that were similar to the COREA clusters. Our results indicate that adult Korean asthma patients can be classified into four distinct clusters.

Recent reports have suggested that metformin has anti-inflammatory and anti-tissue remodeling properties. We investigated the potential effect of metformin on airway inflammation and remodeling in asthma. The effect of metformin treatment on airway inflammation and pivotal characteristics of airway remodeling were examined in a murine model of chronic asthma generated by repetitive challenges with ovalbumin and fungal-associated allergenic protease. To investigate the underlying mechanism of metformin, oxidative stress levels and AMP-activated protein kinase (AMPK) activation were assessed. To further elucidate the role of AMPK, we examined the effect of 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) as a specific activator of AMPK and employed AMPKα1-deficient mice as an asthma model. The role of metformin and AMPK in tissue fibrosis was evaluated using a bleomycin-induced acute lung injury model and in vitro experiments with cultured fibroblasts. Metformin suppressed eosinophilic inflammation and significantly reduced peribronchial fibrosis, smooth muscle layer thickness, and mucin secretion. Enhanced AMPK activation and decreased oxidative stress in lungs was found in metformin-treated asthmatic mice. Similar results were observed in the AICAR-treated group. In addition, the enhanced airway inflammation and fibrosis in heterozygous AMPKα1-deficient mice were induced by both allergen and bleomycin challenges. Fibronectin and collagen expression was diminished by metformin through AMPKα1 activation in cultured fibroblasts. Therefore metformin reduced both airway inflammation and remodeling at least partially through the induction of AMPK activation and decreased oxidative stress. These data provide insight into the beneficial role of metformin as a novel therapeutic drug for chronic asthma.

Refractory asthma, a subtype of asthma with uncontrolled symptoms despite antiasthma medications, is a heterogeneous syndrome with variable clinical features, presumably different etiologies, and pathophysiological mechanisms. The heterogeneity of refractory asthma, however, is poorly understood. We aimed to characterize refractory asthma and to improve our understanding of the heterogeneity of refractory asthma patients.We identified refractory asthma patients (n = 96) as defined by the American Thoracic Society's criteria from a cohort of Korean asthma patients (n = 2,187). Then, cluster analysis was conducted to classify subtypes of refractory asthma.Among the study group, 4.4 % (n = 96) of all asthma patients had refractory asthma. Cluster analysis identified four distinct groups of refractory asthma. Age at onset was younger in clusters 1 and 2 than in clusters 3 and 4. Patients in cluster 1 had the most well-preserved pulmonary function; patients in cluster 2 had a female predominance and the most severe airway obstruction; patients in cluster 3 were mostly female and had the most enhanced bronchial hyperresponsiveness; and patients in cluster 4 were most male and tended to be cigarette smokers.The current results suggest that refractory asthma is a heterogeneous syndrome and could be classified into four subtypes. Underlying pathogenesis and therapeutic approaches may differ for the different subtypes and further research is needed.

The use of raffinose family oligosaccharides (RFOs) to control several diseases and stimulate immune systems has been studied. Rehmannia glutinosa is reported to contain RFOs; however, there are no reports on their content level in R. glutinosa. Furthermore, it is difficult to analyse RFOs using common reverse-phase chromatographic techniques due to their high polarity.To develop a rapid and reliable chromatographic method for the simultaneous quantitation of multiple RFOs in R. glutinosa.Chromatographic separation was performed by using hydrophilic interaction liquid chromatography coupled with an evaporative light scattering detector. For efficient ultrasound-assisted extraction of oligosaccharides, a central composite design was used.Response surface analysis estimated the highest-obtained yields of raffinose, stachyose and verbascose to be 58.31, 408.75 and 26.59 mg, respectively, from 1 g of R. glutinosa, while under optimal conditions, experimental yields per gram were 56.79, 391.42 and 27.69 mg, respectively.A rapid and reliable chromatographic method to simultaneously quantitate multiple RFOs in R. glutinosa was developed. Three RFOs in R. glutinosa were separated within 10 min using isocratic conditions. Quantitative analysis of RFOs showed that R. glutinosa may be a rich source of α-galacto-oligosaccharides, especially stachyose.

Aims Oxidative stress is involved in the pathogenesis of asthma, and peroxiredoxins (PRDX) may be critical in controlling intracellular oxidative stress. The aim of this study was to evaluate expressions of PRDX and their hyperoxidized forms in asthmatic individuals. Main methods The levels of expression of PRDX1, PRDX2, PRDX3, and PRDX6 and their hyperoxidized forms (PRDX-SO3) were measured in PBMCs from asthma patients and control subjects. In addition, cells from these subjects were treated with hydrogen peroxide (H2O2) and their intracellular concentrations of reactive oxygen species (ROS) were measured. Key findings The ratios of hyperoxidized to total PRDX (PRDX-SO3/PRDX) in PBMCs were significantly higher in asthma patients than in normal subjects and were correlated with disease severity, with the highest ratio seen in patients with severe asthma. Furthermore, H2O2 treatment of PBMCs, particularly lymphocytes, increased intracellular ROS concentrations with greater and more persistent increases observed in cells from asthmatic than from control subjects. Significance Hyperoxidation of PRDX may serve as a biomarker of asthma severity and may predict enhanced susceptibility to oxidative stress load in PBMCs of asthmatics.

Background: Obesity is a risk factor for asthma in the general population, but the effect of obesity on airway hyperresponsiveness (AFHR) or airway inflammation in asthma is not clear. This study evaluated the relationship between obesity and asthma, assessing aspects of symptoms, AHR, and severity. Methods: In total, 852 patients with asthma diagnosed by asthma specialists based on AHR as confirmed by a methacholine bronchial provocation test, were enrolled from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) adult asthma cohort. The intensity of AHR was assessed by the concentration of methacholine needed to cause a 20% decrease in FEV1 (PC20). Patients were classified into four categories based on body mass index (BMI): underweight (Results: BMI was negatively correlated with FEV1 (l), FVC (l), and FEV1/FVC (%) in lung function tests. The prevalence of wheezing increased with higher BMI after adjustment for age, sex, smoking, medication history, and PC20 (p < 0.0001). logPC20 was lower in the normal weight group compared with the overweight group (p = 0.003). The risk of moderate or severe AHR (PC20 ≤ 4 mg/ml) decreased with increased BMI after adjustment for age, sex, smoking, and medication history (p = 0.035). Conclusions: Obesity is a risk factor for asthma in the general population, but obesity in asthmatic patients is negatively correlated with the intensity of AHR and is not related to asthma severity. Obesity is positively related with the prevalence of wheezing but negatively related to AHR in asthmatic patients.

The methanolic extract of the fruits of Cornus officinalis S et Z. (Cornaceae) showed the significant neuroprotective activity against glutamate-induced toxicity in HT22 hippocampal cells. Chemical profile of n-BuOH fraction of the methanolic extract of C. officinalis fruits, which showed the most potent activity, was established using HPLC-diode array detector-electrospray-MS (HPLC-DAD-ESI-MS). Through bioactivity-guided isolation, five iridoid glycosides including one new compound, 7-O-butylmorroniside (1), loganin (2), morroniside (3), 7R-O-methylmorroniside (4), 7S-O-methylmorroniside (5) were isolated from the n-BuOH fraction. The protective activities of the isolated compounds, themselves, were not statistically significant. However, the hydrolyzed products of compounds 1, 4 and 5 significantly protected glutamate-injured HT22 cells up to 78 ± 2.2%, 60 ± 3.2% and 59 ± 2.5% of non-treated control, respectively.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse cutaneous reactions to drugs. We report here the first case of severe pneumonia caused by an unusual combined infection with Pneumocystis carinii (jiroveci), parainfluenza virus type 3, cytomegalovirus and Aspergillus fumigatus in a 63-year-old female patient with allopurinol-induced SJS/TEN overlap syndrome. Following treatment with high-dose systemic corticosteroids and intravenous immunoglobulin for SJS/TEN, her mucocutaneous lesions improved and she was due to be discharged. However, 15 days after cessation of corticosteroids, she developed pneumonia. Broncho-alveolar lavage revealed that the cause of infection was Pneumocystis carinii (jiroveci), parainfluenza virus type 3, cytomegalovirus and Aspergillus. These findings indicate that patients with SJS/TEN, particularly those treated with systemic corticosteroids, may be susceptible to infection with combinations of pathological agents resulting from damage to the bronchial epithelia.

The methanolic extract of the bark of Betula platyphylla was found to suppress antigen mediated degranulation of RBL-2H3 cells. Four arylbutanoids ( 1 – 4 ) and eight diarylhepatonoids ( 5 – 12 ) were isolated from the methanolic extract using bioassay-guided fractionation. Among them, compounds 4 and 12 were isolated and assigned for the first time. Compounds 1 , 2 , 3 , 5 , 10 , and 12 showed remarkable inhibitory activity against the degranulation of RBL-2H3 by antigen stimulation in a dose dependent manner at the concentrations ranging from 10 μM to 100 μM.

Mucus hypersecretion is a clinically important manifestation of chronic inflammatory airway diseases, such as asthma and Chronic obstructive pulmonary disease (COPD). Mucin production in airway epithelia is increased under conditions of oxidative stress. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 suppression is related to the development of airway inflammation and increased ROS levels. In this study, we investigated the role of SHP-1 in mucin secretion triggered by oxidative stress. Human lung mucoepidermoid H292 carcinoma cells were transfected with specific siRNA to eliminate SHP-1 gene expression. Cultured cells were treated with hydrogen peroxide (H(2)O(2)), and Mucin 5AC(MUC5AC) gene expression and mucin production were determined. Activation of p38 mitogen activated protein kinase (MAPK) in association with MUC5AC production was evaluated. N-acetylcysteine (NAC) was employed to determine whether antioxidants could block MUC5AC production. To establish the precise role of p38, mucin expression was observed after pre-treatment of SHP-1-depleted H292 cells with the p38 chemical blocker. We investigated the in vivo effects of oxidative stress on airway mucus production in SHP-1-deficient heterozygous (mev/+) mice. MUC5AC expression was enhanced in SHP-1 knockdown H292 cells exposed to H(2)O(2), compared to that in control cells. The ratio between phosphorylated and total p38 was significantly increased in SHP-1-deficient cells under oxidative stress. Pre-treatment with NAC suppressed both MUC5AC production and p38 activation. Blockage of p38 MAPK led to suppression of MUC5AC mRNA expression. Notably, mucin production was enhanced in the airway epithelia of mev/+ mice exposed to oxidative stress. Our results clearly indicate that SHP-1 plays an important role in airway mucin production through regulating oxidative stress.

Background. While initial education and regular evaluation of inhaler technique in patients are emphasized in the management of asthma and chronic obstructive pulmonary disease, health care professionals are not experienced in using inhalers. This study assessed whether internal medicine residents used common inhalers correctly and whether a single teaching session successfully improved their performance. Methods. We evaluated 142 internal medicine residents from six university hospitals in Korea for their techniques with three different inhaler devices: a metered dose inhaler (MDI), Diskus, and Turbuhaler. We assessed whether participants completed each step in using the three inhalers and classified overall performance as good, adequate, or inadequate for each inhaler type. To estimate the effect of a single teaching session, reassessment was performed 2 months after education. Results. Performance grade was inadequate for 50.7% of participants with a MDI, 43.0% for Diskus, and 51.4% for Turbuhaler. An early year of residency was associated significantly with inappropriate technique for Diskus (p = 0.003), but not for MDI and Turbuhaler. After a single teaching session, overall skills improved significantly for all three inhalers. The proportion of subjects with good or adequate skill changed notably from 39.7% to 83.8% for MDI (p = 0.001), from 50.0% to 86.8% for Diskus (p = 0.001), and from 44.1% to 88.2% for Turbuhaler (p = 0.001). Conclusions. These findings demonstrate that a high proportion of internal medicine residents cannot use inhalers correctly and just a single teaching can effectively enhance their inhaler technique.

PURPOSE Chlamydophila pneumoniae infection in the airways is thought to be associated with the pathogenesis of asthma, especially in non-atopic severe asthma with irreversible airway obstruction that may be related to airway remodeling. Here, we investigated whether C. pneumoniae infection enhances the secretion of critical chemical mediators for airway remodeling, such as VEGF, TGF-beta, and TIMP-1, in human bronchial epithelial cells (BECs) in a Th2-dominant microenvironment. METHODS Human bronchial epithelial cells (BEAS-2B cells) were infected with C. pneumoniae strain TW183 and cultured in both a Th1-dominant microenvironment with INF-gamma and a Th2-dominant microenvironment with IL-4 or IL-13 added to the culture medium. The VEGF, TGF-beta, and TIMP-1 levels in the culture supernatants were measured using enzyme-linked immunosorbent assays (ELISA). The activation of NF-kappaB in each experimental condition was determined using an electrophoretic mobility shift assay. RESULTS Chlamydophila pneumoniae-infected BECs showed enhanced secretion of VEGF, TGF-beta, and TIMP-1 compared with non-infected BECs. The levels of cytokines secreted from BECs were increased more when IL-13 was added to the culture medium. C. pneumoniae-infected BECs also showed increased NF-kappaB activation. CONCLUSIONS These results suggest that C. pneumoniae plays a role in the pathogenesis of airway remodeling in asthma, revealing a Th2-dominant immune response. Further studies are required to clarify the precise mechanism of C. pneumoniae infection in airway remodeling.

Asthma presents with heterogeneous features, and patients show various phenotypes of differing severities. Therefore, it is necessary to define reliable predictable clinical factors that influence severity. To date, few large-scale studies have gathered clinical data on adult asthma patients in Asia.To establish an adult asthma cohort in Korea and to define significant factors associated with asthma severity and exacerbation.Researchers from 11 university hospitals have established an asthma cohort termed the COhort for Reality and Evolution of adult Asthma in Korea (COREA). We classified the severity of asthma into 3 groups: mild, moderate, and severe. In this article, the first analysis of our cohort, we evaluate various clinical factors associated with the severity and exacerbation of asthma using data from 1,260 asthma patients.Physician-evaluated severity of asthma was associated with a history of asthma exacerbation (P.001), a history of smoking (P.001), symptom duration (P = .007), and treatment duration (P.001). It was also significantly correlated with predicted forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) values and FEV1/FVC ratio (all P.001). Previous exacerbation was associated with smoking (P = .02), predicted FVC and FEV1 values (both P.001), FEV1/FVC ratio (P = .02), airway hyperresponsiveness (P = .002), and duration of disease (P.001).Previous exacerbation, duration of disease, and decrease in lung function were important clinical indices associated with asthma severity in the COREA study patients. Our long-term follow-up study is expected to soon yield more accurate and detailed outcomes.

Paragonimiasis typically results from the consumption of raw or improperly cooked crustacea, especially crabs and crayfish. Although previously endemic in Korea, the prevalence of this disease decreased in the early 1970s because of educational campaigns and fewer intermediate hosts as a result of ecological changes. Recently, we were presented with a family where all members were infected with Paragonimus after ingestion of Kejang (= drunken crab). The mother was hospitalized for general myalgia and weakness first, followed by the father, who was hospitalized for dyspnea 2 month later. After the parents were diagnosed with paragonimiasis, we recommended their daughter to visit our hospital for a checkup, because they all had eaten freshwater crabs soaked in soybean sauce. She complained of generalized myalgia, fever, and pleuritic pain, and was also diagnosed with paragonimiasis. Peripheral blood of the 3 patients revealed hypereosinophilia, and computed tomography (CT) scans of their chests showed pleural effusion. The results of antibody tests by ELISA were positive for paragonimiasis. We report here the case series of familial paragonimiasis in a modern urban city, rather than in a typical endemic area.

Background: Recent findings have raised new interests about the use of anticholinergics, especially tiotropium, for the treatment of asthma. This study was performed to determine whether an additional improvement in lung function is obtained when tiotropium is administrated in addition to conventional therapies in severe asthmatics, and to identify factors capable of predicting the response to tiotropium, using a pharmacogenetic approach. Methods: A total of 138 severe asthmatics on conventional medications and with decreased lung function were randomly recruited. Tiotropium 18 μg was added once a day and lung functions were measured every 4 weeks. Responders were defined as those with an improvement of ≥15% (or 200 ml) in the forced expiratory volume in 1 s (FEV1) that was maintained for at least 8 successive weeks. Eleven single nucleotide polymorphisms (SNPs) in CHRM1–3 (coding muscarinic receptors one to three) which were identified by re-sequencing, and Arg16Gly and Gln27Glu in ADRB2 (coding β2 adrenoreceptor) were scored in 80 of the 138 asthmatics. Results: Forty-six of the 138 asthmatics (33.3%) responded to tiotropium treatment. Logistic regression analyses (controlled for age, gender, and smoking status) showed that Arg16Gly in ADRB2 [P = 0.003, OR (95% CI) = 0.21 (0.07–0.59) in a minor allele–dominant model] was significantly associated with response to tiotropium. Conclusions: As many as 30% of severe asthmatics on conventional medications with reduced lung function were found to respond to adjuvant tiotropium. The presence of Arg16Gly in ADRB2 may predict response to tiotropium.

Reactive oxygen species (ROS) performs a pivotal function as a signaling mediator in receptor-mediated signaling. However, the sources of ROS in this signaling have yet to be determined, but may include lipoxygenases (LOXs) and NADPH oxidase. The stimulation of lymphoid cells with TNF-alpha, IL-1beta, and LPS resulted in significant ROS production and NF-kappaB activation. Intriguingly, these responses were markedly abolished via treatment with the LOXs inhibitor nordihydroguaiaretic acid (NDGA). We further examined in vivo anti-inflammatory effects of NDGA in allergic airway inflammation. Both intraperitoneal and intravenous NDGA administration attenuated ovalbumin (OVA)-induced influx into the lungs of total leukocytes, as well as IL-4, IL-5, IL-13, and TNF-alpha levels. NDGA also significantly reduced serum levels of OVA-specific IgE and suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. The results of our histological studies and flow cytometric analyses showed that NDGA inhibits OVA-induced lung inflammation and the infiltration of CD11b+ macrophages into the lung. Collectively, our findings indicate that LOXs performs an essential function in pro-inflammatory signaling via the regulation of ROS regulation, and also that the inhibition of LOXs activity may have therapeutic potential with regard to the treatment of allergic airway inflammation.

PURPOSE: This study was conducted to evaluate the effectiveness of a computerized surveillance system for adverse drug events (ADEs) reinforced with mandatory reporting of all past drug hypersensitivity reactions (DHSRs) and supervision of the processes by allergy specialists in a university hospital. METHODS: All information on both prior and newly developed DHSRs was collected via the surveillance system described above and compared with the data from previous system based on voluntary reporting of DHSRs by attending physicians. RESULTS: The report rate of past DHSRs was greatly increased and the estimated incidence of new events decreased under the new system. The occurrence rate of new DHSRs during hospitalization, which were caused by the repeated administration of the agents previously suspected as culprit drugs enormously, decreased from 15% of previous system to 1% of new system. CONCLUSION: The mandatory reporting system for past DHSRs and the supervision by allergy specialists appear to be important in improving the management of patients with drug hypersensitivity and in preventing the occurrence of DHSRs in a general hospital.

Although the recruitment of macrophages to the lung is a central feature of airway inflammation, its function in ongoing T(h)2 cell-mediated eosinophilic airway inflammation remains controversial. Here, we have demonstrated that the allergen-induced CD11b(+) CD11c(int) macrophage expressing CC chemokine receptor 3 (CCR3) in the lung performs a crucial function in the induction of eosinophilic asthma in a murine model. In the lungs of normal mice, residential cells evidencing high granularity phenotypically evidenced CD11b(int) CD11c(+) or CD11b(+) CD11c(int) cells, appearing at a 2:1 ratio. After allergen challenge, however, this reverses dramatically, up to a ratio of one to six. Approximately 91% of increased CD11b(+) CD11c(int) cells evidenced the expression of the CCR3 eotaxin receptor, but not other chemokine receptors, such as CCR5 and CXCR4. Interestingly, the CD11b(+) CD11c(int) cells purified from the lungs of OVA (ovalbumin)-sensitized and challenged mice evidenced higher antigen-presenting activity than was observed in CD11b(int) CD11c(+) cells. In order to investigate the in vivo function of CD11b(+) CD11c(int) cells, the cells were isolated from the lungs of OVA-sensitized and challenged mice and then adoptively transferred prior to the allergen challenge of normal mice. In the CD11b(+) CD11c(int)-transferred mice airway hyperresponsiveness, eosinophilic inflammation in the lung and T(h)2 cytokine secretion in the bronchoalveolar lavage fluids were significantly enhanced as the result of OVA challenge, as compared with the mice that received OVA-primed CD90(+) T cells or CD11b(int) CD11c(+) cells. These findings show that CD11b(+) CD11c(int) macrophages expressing CCR3 as key pro-inflammatory cells are both necessary and sufficient for allergen-specific T cell stimulation during ongoing eosinophilic airway inflammation.

Summary Background Asthma can frequently be induced or exacerbated by respiratory viral infections. Oxidative stress might also play an essential role in the pathogenesis of allergic airway diseases, indicating that antioxidant therapy may have a potential effect in controlling allergic airway diseases. Recent studies showed that 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) has the potential ability to modulate NADPH oxidase activity, indicating the antioxidant activity of AICAR. This study investigated the inhibitory effects of AICAR as an anti-inflammatory modulator on allergic airway inflammation in murine animal models. Methods The anti-inflammatory effects of AICAR were evaluated in two experimental asthma models: (1) an ovalbumin (OVA)-induced experimental asthma model and (2) an OVA plus polyinosinic-polycytidylic acid [poly (I:C)]-induced experimental asthma model to mimic respiratory viral infections. The inhibitory effects of AICAR in poly (I:C)-mediated signalling for NF-κB activation and production of TNF-α were analysed in vitro. Results AICAR was shown to have a marginal inhibitory effect in an OVA-induced asthma model. Interestingly, AICAR significantly attenuated poly (I:C)-induced airway hyperresponsiveness and airway inflammation, as shown by the attenuation of the influx of total inflammatory cells and soluble products into bronchoalveolar lavage fluid, such as macrophages, eosinophils, IL-5, IL-13, TNF-α and IFN-γ. AICAR also significantly reduced the serum levels of OVA-specific IgE and IgG2a antibodies. Histologic and flow cytometric studies showed that AICAR inhibited poly (I:C)-induced lung inflammation and the infiltration of CD11b+CD11c+ dendritic cells into the lung. Moreover, AICAR effectively inhibited poly (I:C)-mediated activation of NF-κB and the production of TNF-α. Conclusion These findings suggest that AICAR may be a novel immunomodulator with promising beneficial effects for the treatment of respiratory viral infection in airway allergic diseases.

Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is a rare systemic necrotizing vasculitis affecting smallto medium-sized vessels. EGPA is associated with severe asthma and eosinophilia. The most frequently involved organs are skin and peripheral nerves; however, EGPA may involve other organs, such as the gastrointestinal tract, kidney, and heart. Antineutrophil cytoplasm antibodies (ANCAs)-related abnormal immune reactions are known to be associated with EGPA, but only 30%–40% of patients have a positive marker of ANCA. ANCA-negative patients are at higher risk of cardiac involvement than ANCApositive patients. Cardiac involvement is one of the leading causes of mortality and could be resistant to conventional treatment. Early treatment with steroid plus cyclophosphamide is important because it could give chances of restoration of cardiac function. For patients undergoing heart transplantation, we should consider the severity of cardiac disease and the presence of systemic diseases, including vasculitis. Here, we report a case of a 25-year-old EGPA patient with cardiac involvement who eventually received heart transplantation for progressive heart failure, although treated with systemic corticosteroid with cyclophosphamide. EGPA patients undergoing heart transplantion are rarely reported worldwide, and this is the first case report in Korea. (Allergy Asthma Respir Dis 2015;3:159-163)

Purpose: To investigate whether causes of anaphylaxis vary according to regions and seasons in Korean adults. Methods: Based on previous retrospective studies of anaphylaxis between 2007 and 2011 at the 15 university hospitals. Regions were classified into 4 groups: region I, Seoul; region II, Gyeonggi; region III, Chungcheong; and region IV, Chonnam and Busan. The cases induced by 5 major allergens including drugs, food, bee sting, radiocontrast media, and exercise, were analyzed in the present study. Results: Among a total of 1,661 cases reported (53% male, 45.9±16.0 years), 367 (22.2%), 706 (42.5%), 319 (19.2%), and 269 cases (16.2%) were enrolled in regions I, II, III, and IV, respectively. Of the 5 major allergens, drugs (37.3%) were the most frequently reported, followed by food (25.7%), bee sting (17.9%), radiocontrast media (12.9%), and exercise (6.2%). There was no significant difference in the total occurrence of anaphylaxis in 4 seasons (374 in spring, 460 in summer, 460 in autumn, and 367 in winter). Multiple logistic regression analysis revealed that drug-induced anaphylaxis was significantly associated with the winter season (odds ratio [OR] 1.0 vs. OR 0.597, P

There has been growing concern regarding the effects of ambient air pollution on asthma. Particulate matter (PM) is one of the major air pollutants affecting both general population and the patients with asthma. This paper reviews the recent evidence of the adverse effects of PM on the inception and morbidity of asthma. Epidemiological studies confirmed that short-term exposure to PM aggravated respiratory symptoms and lung function in asthma patients. Furthermore, PM induces acute exacerbations of asthma with increased risk of hospitalization and death. Long-term exposure to PM is responsible for new onset of asthma and lung function decline in both children and adults. Various mechanisms are involved in the effects of PM on airway including oxidative stress, augmentation of inflammation, promotion of allergen sensitization, induction of airway hyperresponsiveness, aggravation of rhinitis and DNA methylation. Special attention and care is needed for the patients with asthma to prevent the detrimental effects of PM. (Allergy Asthma Respir Dis 2015;3:313-319)

Background : Several methods have been reported to induce asthmatic reactions in mice but few studies have compared their efficiency. We evaluated the efficiency of the protocols frequently used in the literature. Methods : BALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal injection; 1] Once a week for two weeks using OVA with alum (IPOA-2) or without (IPO-2), and provocation on days 28-30 by 1% OVA inhalation; 2] seven times for two weeks by OVA with alum (IPOA-7) or without (IPO-7) and provocation by 1% OVA inhalation on days 42-44. 3] Sensitization by 1% OVA inhalation for ten days (IHO-10) and provocation by 1% OVA inhalation on days 28-30. After the last challenge, airway hyperresponsiveness was measured with single chamber plethysmography 24 hours later and mice were sacrificed 48 hours later. Results : Airway hyperresponsiveness, BALF eosinophilia, airway inflammation, and OVA-specific IgE and IgG1 production were effectively induced in IPOA-2, IPOA-7, and IPO-7. However, these phenotypes were not induced in IPO-2 (except for increased BALF eosinophils) or IHO-10 (except for an increased OVA-specific IgG1 level). Conclusion : The intraperitoneal injections of OVA with alum once a week for two weeks proved to be the most efficient sensitization method of inducing an asthmatic reaction in mice.

Background Fractional exhaled nitric oxide (FeNO) is widely used as an inflammatory marker for asthma. However, reference values and influencing factors of FeNO using Niox Mino, which is the only device achieving US FDA approval, are not well described in healthy Asian adults. This study aimed to suggest the reference values and influencing factors of FeNO in healthy Korean adults. Methods Subjects who were over 19 years old and did not have any history of rhinitis, asthma or recent respiratory symptoms were enrolled. FeNO levels were measured using Niox Mino. Age, gender, body mass index (BMI), smoking status and lung function were also measured to analyze factors associated with FeNO levels. Results The mean value of FeNO was 16.14 ± 10.04 ppb. The reference value of FeNO, which was defined as the value of 95% in distribution curve, was same or less than 34 ppb. In a univariate analysis, FeNO levels were not associated with age, BMI and smoking history. However, atopy status (18.2 ± 11.8 for atopy and 15.1 ± 8.5 for nonatopy groups, P = 0.008) and gender (17.8 ± 10.2 for male and 14.8 ± 9.8 for female groups, P < 0.001) were positively associated with FeNO levels. In stratified analysis, the significance of both variables remained unchanged (P < 0.001). Conclusions Our data suggested that the reference value of FeNO in healthy Korean adults seemed to be same or less than 34 ppb. Reference values of FeNO in Korean adults are influenced by gender and atopy status.

Background Liver is the second most commonly involved organ in drug-induced systemic hypersensitivity reactions (DiSH). Although liver function is very important indicator in the course of DiSH, there have been few studies about the characteristics of the liver injury. In present study, we investigated clinical characteristics of DiSH associated with liver injury (liver-DiSH) Methods We retrospectively reviewed medical records of 38 hospitalized patients who developed liver-DiSH (AST or ALT ≥80 IU/L) from January 2008 to February 2011 in a tertiary referral hospital. We analyzed culprit drugs, the type and degree of liver injury, and the effect of systemic corticosteroids. Fisher's exact test and Chi-square test and Mann-Whitney test were used for statistical analysis. Results Thirty-eight patients of liver-DiSH were enrolled, whose clinical phenotypes were Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) (n = 9, 24%), drug reaction with eosinophilia and systemic symptoms (DRESS) (n = 23, 60%), maculopapular rash (MP rash) (n = 5, 13%) and acute generalized exanthematous pustulosis (AGEP) (n = 1, 3%). Antibiotics (n = 16/38, 41%) was the most common cause of liver-DiSH. Culprit agents of liver-DiSH were allopurinol (n = 3/9, 33%) in SJS/TEN and antibiotics (n = 13/23, 57%) in DRESS. Mortality tended to be higher in SJS/TEN than in DRESS (22% (2/9) vs 17% (4/23), P = 0.846). Degree of liver injury was statistically more severe in DRESS than in SJS/TEN (mean peak AST [423 IU/L vs 144 IU/L, P = 0.062], mean peak ALT [428 IU/L vs 156 IU/L, P = 0.013], mean peak ALP (alkaline phosphatase) [252 IU/L vs 85 IU/L, P = 0.002], mean total bilirubin [7.7 mg/dL vs 1.3 mg/dL, P = 0.064], and time required for AST/ALT to drop below 80 IU/L [15.8 days vs 4.1 days, P = 0.049]). Seventy-six percents (29/38) of patients were treated with systemic corticosteroid. The use of corticosteroid did not significantly affect both recovery of liver injury and mortality. Conclusions Our results suggest that liver-DiSH has distinguished clinical characteristics according to the disease phenotypes. Further studies are needed to evaluate the role of systemic corticosteroid in liver injury in DiSH.

PURPOSE: Cefaclor is widely prescribed for various infectious diseases. As its consumption increases, the number of hypersensitivity reactions to cefaclor has increased. This study aimed to evaluate the immunologic findings of immediate hypersensitivity to cefaclor. MATERIALS AND METHODS: We enrolled 47 patients with immediate hypersensitivity to cefaclor from Ajou University Hospital and Asan Medical Center. Serum specific IgE, IgG1, and IgG4 antibodies to cefaclor-human serum albumin (HSA) conjugate were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The most common phenotype was anaphylaxis (Group I, 78.7%), followed by urticaria (Group II, 21.3%). The detection of specific IgE, IgG1, and IgG4 to cefaclor-HSA conjugate by ELISA tended to be higher in Group I (40.5%, 41.7%, 21.6%) than in Group II (20.0%, 20.0%, 0%) with no statistical significance. Significant associations were found between specific IgE and IgG1 or IgG4 (p

Purpose Exhaled nitric oxide (NO) is a useful non-invasive biomarker for asthma diagnosis; however, the literature suggests that exhaled NO levels may be affected by demographic factors. The present analysis investigated determinant factors that present exhaled NO reference levels for Korean elderly adults. Methods For reference levels, we analyzed the baseline data of healthy adult participants in the Ansung cohort. The fraction of exhaled NO (FeNO) was measured by NIOX MINO®. The characterization of the subjects was performed through structured questionnaires, spirometry, and methacholine challenge tests. To validate the diagnostic utility of the determined reference levels, asthma patients were recruited from medical institutions for FeNO measurement. Results A total of 570 healthy subjects were analyzed (mean age, 59.9±12.3; male, 37.0%) for reference levels. FeNO levels significantly correlated with weight, height, body mass index, atopy, or forced expiratory volume in 1 second % predicted by simple linear regression analysis. Multiple linear regression analysis identified gender as an independent determinant for FeNO levels; subsequently, the reference values for FeNO were 18.2±10.6 ppb (5th to 95th percentile, 6.0 to 37.4 ppb) for males and 12.1±6.9 ppb (5th to 95th percentile, 2.5 to 27.0 ppb) for females. The diagnostic utility of FeNO reference levels was validated by receiver operating curve analysis (area under curve, 0.900 for males and 0.885 for females) for diagnosing asthma. The optimal cutoff values for the prediction of asthma were 30.5 ppb for males and 20.5 ppb for females. Conclusions The current analysis presented reference ranges and the diagnostic utility of FeNO levels for asthma in Korean elderly adults.

Cephalosporins are antibiotics widely used to treat infections in the skin, soft tissues, and respiratory and urinary tracts. Aplastic anemia (AA) has not previously been reported in patients treated with cephalosporins. We describe here a 50-year-old woman who experienced AA after treatment with cefroxadine. In November 2009, a 50-year-old woman was referred to our medical center for further treatment of AA. In October 2009, the patient had received a 3-day course of cefroxadine, non-steroidal anti-inflammatory drugs (NSAIDs), and antihistamines to treat symptoms of a common cold. The symptoms were relieved, but 1 week after treatment she developed a fever and sore throat. The patient visited a primary clinic, where a blood examination showed evidence of neutropenia. The patient had taken no other medications in the 6 months prior to the illness and had no underlying disease. Physical examination showed oropharyngeal injection and soft palate swelling. Her hemoglobin (Hb) level was 9.9 g/dL, WBC count was 300/mm3, with 3.1% neutrophils (absolute neutrophil count 10/mm3), and platelet count was 34,000/mm3. A marrow aspirate revealed severe hypoplasia, with almost complete disappearance of cells of the granulocytic and megakaryocytic lineages, and few cells of the erythroid lineage. A marrow biopsy showed severe AA (15% cellularity), affecting all hematopoietic lineages (Fig. 1). She was treated supportively with broad-spectrum antibiotics (meropenem) and granulocyte macrophage colony-stimulating factor (GM-CSF). Her fever subsided on day 6, and she showed clinical improvement. Her Hb and WBC and platelet counts gradually increased. She was discharged on day 29 with a Hb concentration of 11.4 g/dL, a WBC count of 4.3 × 103/μL (73% neutrophils), and a platelet count of 102 × 103/μL. One month later, her hemoglobin was 10.8 g/dL, WBC was 4,200/mm3 (52.4% neutrophils), and platelet count was 107,000/mm3. Fig. 1 Biopsy of bone marrow. Original magnification of a ×100 and b ×400, H&E staining. It shows low cellularity (15%) affecting all hematopoietic lineages It is noteworthy that this was the patient’s third incidence of drug-induced AA. She had a previous history of cefroxadine-induced recurrent AA, from which she had fully recovered after withdrawal of the medication. In December 2007, the patient had been referred to our medical center with laryngopharyngitis plus suppurative lymphadenitis and AA after taking an unknown drug 2 weeks previously. In April 2008, AA recurred after she took cefroxadine for URI medications. Initial bone marrow aspirations and biopsies taken after each incident revealed AA; 1 month after the incident, she had fully recovered from pancytopenia after conservative care. We guess that the drug in the first episode had probably been a cephalosporin. Cephalosporin was thus involved in at least 2 of the 3 episodes of AA. Because of its rarity, the mechanism underlying cephalosporin-induced AA has not been completely determined. In contrast to agranulocytosis, which is probably caused by a humoral immune reaction against mature circulating lymphocytes, acquired AA is most likely caused by a humoral autoimmune reaction against myeloid stem cells. A T cell attack on bone marrow leads to the apoptosis of CD34+ cells, resulting in pancytopenia and symptoms of bone marrow failure [1, 2]. A prospective cohort study of 102 patients with drug-induced agranulocytosis over 15 years (1985–2000) found that 21 patients had antibiotic-induced agranulocytosis, including 4 patients with agranulocytosis due to a cephalosporin, 2 due to cefotaxime and 1 each due to ceftriaxone and ceftazidime [3]. Similarly, of 108 patients with agranulocytosis over the period 1987–1990, 75 had drug-related agranulocytosis [4]. None of these patients with agranulocytosis, however, developed AA. Administration of high doses of cephalosporin to dogs induced AA, with evidence of immune-mediated destruction of peripheral blood cells and marrow colony-forming capacity [5]. The development of AA in association with cefroxadine, a second-generation cephalosporin, has not previously been reported. Both the occurrence of AA after administration of cefroxadine and its spontaneous resolution within 15 weeks of drug discontinuation indicate that AA in this patient was probably caused by cefroxadine. Prior to discharge, we performed an intradermal test with a gradual increase in concentration to determine whether this patient had an immediate type I hypersensitivity to cephalosporin. We found, however, that her recovered WBC decreased slightly for 1 week after the intradermal test and no immediate skin reaction occurred. The mechanism underlying this reaction is not certain, but it may be triggered weakly by intradermal injection of antigen (cephalosporin). The diagnostic relevance and the possible risks of the intradermal test in AA have not yet been established. Cephalosporins are among the safest antibiotics. Nevertheless, hematological abnormalities, ranging from monocytopenia to pancytopenia, do occur, albeit infrequently, following their therapeutic use. Cefroxadine has become more widely used for simple infectious conditions in primary clinics. This case illustrates that a severe complication of antibiotic treatment may occur. Therefore, physicians should use antibiotics more restrictively only when they are necessary, provide care to patients taking the drug, and be aware of this potentially life-threatening complication.

© 2010 The Authors. doi: 10.2340/00015555-0861 Journal Compilation © 2010 Acta Dermato-Venereologica. ISSN 0001-5555 Although angioedema, a condition characterized by swelling of the deeper layers of the skin, is common, its aetiology remains unknown in the majority of cases (80–90%) (1). We have described previously a 32-yearold woman with a variant of idiopathic angioedema presenting as facial swelling with a duration of more than one year (2). We now wish to report that after 7 months she was diagnosed with NK/T-cell lymphoma and died suddenly.

© 2010 The Authors. doi: 10.2340/00015555-0912 Journal Compilation © 2010 Acta Dermato-Venereologica. ISSN 0001-5555 Toxic epidermal necrolysis (TEN) is a severe episodic mucocutaneous reaction due largely to ingested drugs and/or occasionally to infections. TEN presents as sheets of erythema, necrosis and bullous detachment of the epidermis, with a mortality rate of 30–35% (1). The most commonly implicated drugs are sulphonamides, chlormezanone, non-steroidal anti-inflammatory drugs, imidazole antifungals, cephalosporins, anticonvulsants, and allopurinol (2). In contrast, fluoroquinolones, broad-spectrum bactericidal agents, rarely cause severe cutaneous adverse reactions (SCAR) such as TEN and Stevens-Johnson syndrome (SJS). To date, a total of 31 cases of SJS or TEN in which a fluoroquinolone was the offending agent have been reported. Of these, 26 were caused by ciprofloxacin (3), whereas only one was caused by ofloxacin (4). We describe here a patient with TEN induced by ingestion of oral ofloxacin.