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Background Cefaclor, a second-generation oral cephalosporin, is widely prescribed to treat infectious diseases. Immediate hypersensitivity (HS) reactions to cefaclor have continuously been reported and are expected to increase with its greater use. This study aimed to investigate the clinical characteristics and risk factors of immediate HS to cefaclor over the most recent 5 years. Methods This retrospective study investigated 521 adverse drug reactions (ADRs) to cefaclor at pharmacovigilance centers at two tertiary hospitals from January 2014 to December 2018. In total, 459 patients with immediate HS to cefaclor were reviewed. Results A total of 459 cases of cefaclor immediate HS were included among 521 cefaclor ADRs, and anaphylaxis was recorded in 61.2%. Female sex (odds ratio 2.917, 95% confidence interval 2.397–3.550, P P P P = 0.010), asthma (8.075, 5.301–12.302, P P Conclusions Cefaclor was found to elicit high proportions of immediate HS and anaphylaxis. Physicians ought to be cautious with prescribing cefaclor to females, individuals with hypertension, liver diseases, or asthma, and patients taking nonsteroidal anti-inflammatory drugs. Trial registration This study was retrospectively registered.

The skin is the largest organ in the human body, providing a barrier to the external environment. It is composed of three layers: epidermis, dermis and hypodermis. The most external epidermis is exposed to stress factors that may lead to skin conditions such as photo-aging and skin cancer. Some treatments for skin disease utilize the incorporation of drugs or bioactive compounds into nanocarriers known as liposomes. Liposomes are membranes whose sizes range from nano to micrometers and are composed mostly of phospholipids and cholesterol, forming similar structures to cell membranes. Thus, skin treatments with liposomes have lower toxicity in comparison to traditional treatment routes such as parenteral and oral. Furthermore, addition of edge activators to the liposomes decreases the rigidity of the bilayer structure making it deformable, thereby improving skin permeability. Liposomes are composed of an aqueous core and a lipidic bilayer, which confers their amphiphilic property. Thus, they can carry hydrophobic and hydrophilic compounds, even simultaneously. Current applications of these nanocarriers are mainly in the cosmetic and pharmaceutic industries. Nevertheless, new research has revealed promising results regarding the effectiveness of liposomes for transporting bioactive compounds through the skin. Liposomes have been well studied; however, additional research is needed on the efficacy of liposomes loaded with bioactive peptides for skin delivery. The objective of this review is to provide an up-to-date description of existing techniques for the development of liposomes and their use as transporters of bioactive compounds in skin conditions such as melanoma and skin inflammation. Furthermore, to gain an understanding of the behavior of liposomes during the process of skin delivery of bioactive compounds into skin cells.

Although younger patients with allergic rhinitis (AR) have been successfully treated with pharmacotherapy, there are no definitive data on treatment outcomes in older patients with AR. We performed a prospective study of 51 older adults with AR (aged over 65 years) and 101 younger AR patients (aged from 19 to 40 years) to compare clinical outcomes between the 2 groups and to evaluate the impact of depressed mood on treatment outcomes in older AR patients. Changes in total symptom scores (TSS), rhinitis-specific quality of life questionnaire (RQLQ) results, rhinitis control assessment test (RCAT) results and visual analog scale (VAS) scores were evaluated after 4-week treatment according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline, and the severity of depressed mood was assessed by using the geriatric depression scale. After 4-week treatment, younger AR patients had greater improvements in clinical scores compared with older adults; differences in least squares mean changes from baseline in older patients vs. younger patients were 1.71 (P = 0.004) for TSS, 10.84 (P < 0.001) for RQLQ, 0.80 (P = 0.275) for RCAT, and 8.60 for VAS score (P = 0.061). Multiple logistic regression analysis showed that the severity of depressed mood was independently associated with severe chronic upper airway disease (adjusted odds ratio, 1.385; P = 0.004). Our results suggest that older AR patients are less responsive to standard treatment compared with younger AR patients and that depressed mood is strongly associated with the increased risk of uncontrolled AR in older AR patients.

Genomic instability resulting from defective DNA damage responses or repair causes several abnormalities, including progressive cerebellar ataxia, for which the molecular mechanisms are not well understood. Here, we report a new murine model of cerebellar ataxia resulting from concomitant inactivation of POLB and ATM. POLB is one of key enzymes for the repair of damaged or chemically modified bases, including methylated cytosine, but selective inactivation of Polb during neurogenesis affects only a subpopulation of cortical interneurons despite the accumulation of DNA damage throughout the brain. However, dual inactivation of Polb and Atm resulted in ataxia without significant neuropathological defects in the cerebellum. ATM is a protein kinase that responds to DNA strand breaks, and mutations in ATM are responsible for Ataxia Telangiectasia, which is characterized by progressive cerebellar ataxia. In the cerebella of mice deficient for both Polb and Atm, the most downregulated gene was Itpr1, likely because of misregulated DNA methylation cycle. ITPR1 is known to mediate calcium homeostasis, and ITPR1 mutations result in genetic diseases with cerebellar ataxia. Our data suggest that dysregulation of ITPR1 in the cerebellum could be one of contributing factors to progressive ataxia observed in human genomic instability syndromes.

PURPOSE Asthma control in older asthmatics is often less effective, which may be attributed to small airway dysfunction and poor inhalation technique. We compared the efficacy of 2 inhalers (fluticasone propionate/formoterol treatment using a pressurized metered-dose inhaler [p-MDI group] vs. fluticasone propionate/salmeterol treatment using a dry powder inhaler [DPI group]) in older asthmatics. METHODS We conducted a 12-week, randomized, open-label, parallel-designed trial in older patients (over 55 years old) with moderate-to-severe asthma, and compared the efficacy and safety for asthma control between the 2 groups. Subgroup analyses on disease duration and air trapping were performed. Clinical parameters, including changes in lung function parameters, inhaler technique and adherence, were compared with monitoring adverse reactions between the 2 groups. RESULTS A total of 68 patients underwent randomization, and 63 (30 in the p-MDI group and 33 in the DPI group) completed this study. The p-MDI group was non-inferior to the DPI group with regard to the rate of well-controlled asthma (53.3% vs. 45.5%, p < 0.001; a predefined non-inferiority limit of 17%). In subgroup analyses, the proportion of patients who did not reach well-controlled asthma in the p-MDI group was non-inferior to that in the DPI group; the difference was 12.7% among those with a longer disease duration (≥ 15 years) and 17.5% among those with higher air-trapping (RV/TLC ≥ 45%), respectively (a predefined non-inferiority limit of 17%, p < 0.001). No significant differences were observed in lung function parameters, inhalation techniques, adherence and adverse reactions between the 2 groups. CONCLUSION These results suggest that the p-MDI group may be comparable to the DPI group in the management of older asthmatics in aspects of efficacy and safety.

Background Evaluation of interstitial lung disease (ILD) at CT is a challenging task that requires experience and is subject to substantial interreader variability. Purpose To investigate whether a proposed content-based image retrieval (CBIR) of similar chest CT images by using deep learning can aid in the diagnosis of ILD by readers with different levels of experience. Materials and Methods This retrospective study included patients with confirmed ILD after multidisciplinary discussion and available CT images identified between January 2000 and December 2015. Database was composed of four disease classes: usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia, and chronic hypersensitivity pneumonitis. Eighty patients were selected as queries from the database. The proposed CBIR retrieved the top three similar CT images with diagnosis from the database by comparing the extent and distribution of different regional disease patterns quantified by a deep learning algorithm. Eight readers with varying experience interpreted the query CT images and provided their most probable diagnosis in two reading sessions 2 weeks apart, before and after applying CBIR. Diagnostic accuracy was analyzed by using McNemar test and generalized estimating equation, and interreader agreement was analyzed by using Fleiss κ. Results A total of 288 patients were included (mean age, 58 years ± 11 [standard deviation]; 145 women). After applying CBIR, the overall diagnostic accuracy improved in all readers (before CBIR, 46.1% [95% CI: 37.1, 55.3]; after CBIR, 60.9% [95% CI: 51.8, 69.3]

PURPOSE OF REVIEW The aim of this review is to emphasize the role of neutrophils in patients with occupational asthma. This review facilitates a better understanding, accurate diagnosis, and proper management of asthmatic reactions provoked at the workplace. RECENT FINDINGS Increased recruitment and infiltration of neutrophils are found in patients with occupational asthma. Activated neutrophils release several mediators including pro-inflammatory cytokines and extracellular traps, leading to stimulation of airway epithelium and other inflammatory cells. SUMMARY New insights into neutrophils in the pathogenesis of occupational asthma may provide a novel approach to the individual patient with occupational asthma.

PURPOSE Dupilumab is recommended to be administered biweekly to treat adult patients with moderate-to-severe atopic dermatitis (AD). Real clinical practice data on the clinical efficacy of monthly dupilumab therapy are limited. We analyzed real clinical practice data on the clinical efficacy of monthly dupilumab therapy and predictive markers for favorable clinical responses to the therapy. METHODS Medical records of 57 adult patients with moderate-to-severe AD who received dupilumab therapy every 4 weeks for 16 weeks were analyzed retrospectively. Eczema Area and Severity Index (EASI) were recorded at baseline and week 16. Clinical responses to monthly dupilumab therapy were defined as the proportion of patients with decreased EASI scores of at least 50% or 75% from baseline at week 16 (EASI-50 or EASI-75). Blood eosinophil counts and serum lactate dehydrogenase (LDH) levels were measured at baseline and week 16. RESULTS Monthly dupilumab therapy showed EASI-50 and EASI-75 clinical responses in 48 (84.2%) and 27 (47.4%) of 57 patients at week 16, respectively. The percentage decrease in EASI scores from baseline at week 16 was significantly inversely correlated with baseline blood eosinophil count (correlation coefficient [r] = -0.405, P = 0.002) and baseline serum LDH level (r = -0.466, P < 0.001). The EASI-75 response rate was higher in patients with low (< 500/µL, 73.3%) than in those with high (≥ 500/µL, 37.5%) baseline blood eosinophil counts (P = 0.032), and was higher in patients with low (< 400 U/L, 55.6%) than those with high (≥ 400 U/L, 10.0%) baseline serum LDH levels (P = 0.013). CONCLUSIONS Monthly dupilumab therapy was clinically effective in adult patients with moderate-to-severe AD in real clinical practice. Baseline blood eosinophil count and serum LDH level could be predictive markers for clinical response to dupilumab therapy.

Background Aging populations are often accompanied by comorbidity and polypharmacy, leading to increases in adverse drug reactions (ADRs). We sought to evaluate the causes and characteristics of ADRs in older Korean adults (≥65 years) in comparison to younger individuals ( Methods Of 37,523 cases reported at a Korean pharmacovigilance center from 2011 to 2018, we reviewed 18,842 ADRs of certain or probable causality on the basis of WHO-UMC criteria. We estimated the number of ADRs per 1000 patients exposed to the major culprit drugs, and incidence rate ratios were obtained to assess high- and low-risk medications in older adults. Results In total, 4152 (22.0%) ADRs were reported for 3437 older adults (mean age, 74.6 years and 57.3% female). Tramadol (rate ratio, 1.32; 95% confidence interval [CI], 1.21–1.44; P P = 0.002) posed higher risks of ADRs in the older adults, whereas nonsteroidal anti-inflammatory drugs (NSAIDs) (0.35, 0.30–0.40, P P P P = 0.001) were higher in the older adults than in the younger patients. Analgesics primarily elicited cutaneous ADRs in the younger patients and gastrointestinal reactions in the older adults. ICM more commonly led to anaphylaxis in the older adults than the younger patients (3.0% vs. 1.6%, P = 0.019). Conclusion For early detection of ADRs in older adults, better understanding of differences in the causes and characteristics thereof in comparison to the general population is needed.

There have been few studies assessing long-term outcomes of asthma based on regular follow-up data.We aimed to demonstrate clinical outcomes of asthma by multidimensional analyses of a long-term real-world database and a prediction model of severe asthma using machine learning.The database included 567 severe and 1337 nonsevere adult asthmatics, who had been monitored during a follow-up of up to 10 years. We evaluated longitudinal changes in eosinophilic inflammation, lung function, and the annual number of asthma exacerbations (AEs) using a linear mixed effects model. Least absolute shrinkage and selection operator logistic regression was used to develop a prediction model for severe asthma. Model performance was evaluated and validated.Severe asthmatics had higher blood eosinophil (P = .02) and neutrophil (P.001) counts at baseline than nonsevere asthmatics; blood eosinophil counts showed significantly slower declines in severe asthmatics than nonsevere asthmatics throughout the follow-up (P = .009). Severe asthmatics had a lower level of forced expiratory volume in 1 second (P.001), which declined faster than nonsevere asthmatics (P = .033). Severe asthmatics showed a higher annual number of severe AEs than nonsevere asthmatics. The prediction model for severe asthma consisted of 17 variables, including novel biomarkers.Severe asthma is a distinct phenotype of asthma with persistent eosinophilia, progressive lung function decline, and frequent severe AEs even on regular asthma medication. We suggest a useful prediction model of severe asthma for research and clinical purposes.

Cefaclor, a second-generation oral cephalosporin, is the most frequently prescribed cephalosporin in Korea. Studies, however, have yet to analyze the incidence of cefaclor-associated adverse drug reactions (ADRs), including hypersensitivity (HS), according to total national usage rates. This study aimed to investigate the incidence rates and clinical features of cefaclor ADRs reported to the Korean Adverse Event Reporting System (KAERS) and Health Insurance Review and Assessment Service (HIRA) database for the most recent 5 years. Reviewing the HIRA database, which contains information on all insurance claims, including prescribed medications and patient demographics, we identified the total number of individuals who had been prescribed cefaclor and other cephalosporins including 2nd generation without cefaclor and 3rd generation antibiotics from January 2014 to December 2018. Additionally, we retrospectively analyzed all ADRs reported to the KAERS for these drugs over the same study period. Incidence rates for ADRs, HS, and anaphylaxis to cefaclor were 1.92/10,000 persons, 1.17/10,000 persons, and 0.38/10,000 persons, respectively, lower than those to other 2nd and 3rd cephalosporins. Among all ADRs, HS (60.9% vs. 43.6% vs. 44.8%, P P nd and 3rd cephalosporins. Females, individuals under 65 years of age, concomitant use of drugs, and serious ADRs were more strongly associated with HS to cefaclor than with HS to other 2nd and 3rd cephalosporins. In a nationwide database for the Korean population, the incidence of cefaclor-induced ADRs, particularly HS and anaphylaxis, was high. Female sex, age younger than 65 years, and concomitant use of drugs may be associated with HS to cefaclor.

Background It has been known that a high serum total immunoglobulin E (IgE) level is a predisposing factor of allergic asthma; however, there are considerable limitations to apply it in clinical practice. Objective To determine the clinical significance of the serum-free IgE level in patients with adult asthma. Methods We measured free IgE levels using our homemade enzyme-linked immunosorbent assay by applying a novel IgE TRAP protein (GI innovation, Seoul, Republic of Korea) in sera of adults with asthma (n = 116) compared with healthy controls (n = 32); enzyme-linked immunosorbent assay inhibition test was performed to validate its binding specificity. Associations between asthma-related clinical and laboratory parameters were analyzed. The diagnostic value and cutoff point for detecting atopy and type 2 asthma were determined using receiver operating characteristic curve analysis. Results The serum-free IgE levels were significantly higher in adults with asthma than in healthy controls and were significantly associated with atopic status and type 2 asthma (all P Conclusion It is suggested that a higher serum-free IgE level may be a useful biomarker of atopy and type 2 asthma in adults with asthma.

Butyrate possesses negative sensory qualities and is most effectively utilized in the intestine to provide energy to the colonocyte for the maintenance of intestinal health. Butyrate has also shown promise in the treatment of intestinal disorders and diseases such as short bowel syndrome, inflammatory bowel disease, and colon cancer. To modify sensory properties, intestinal release, and butyrate production capabilities, tributyrin (TB) was microencapsulated in whey protein isolate (WPI)-based and gamma-cyclodextrin (GC)-based materials. Using an in vitro digestion and fermentation model, microcapsules containing TB were monitored for their release and production of butyrate in vitro. All samples containing TB showed limited butyrate release ( 0.05) across formulations. During the fermentation phase, GC-based microcapsules produced significantly more butyrate (P < 0.001) on a molar basis than all WPI-based microcapsules. Butyrate production increased significantly (P < 0.001) over each time interval with GC-based microcapsules having the highest during the 12 h of fermentation. The GC-based TB encapsulation systems were able to effectively deliver butyrate to the small intestine and generate butyrate in the large intestine. These microcapsules may, therefore, be beneficial for the maintenance of intestinal health and improvement of disease states across all areas of the gastrointestinal tract.

Nonsteroidal anti-inflammatory drug (NSAID) is one of the most frequently prescribed medications in the medical field, and hypersensitivity to NSAID is a common adverse drug reaction encountered. However, NSAID hypersensitivity presents a variety of symptoms caused by diverse pharmacological and immunological mechanisms.Owing to the heterogeneity of the disease, a new concept for the classification of NSAID hypersensitivity has recently been proposed to diagnose and manage NSAID hypersensitivity for personalized treatment. Acute and delayed reactions were distinguished in this classification, and identification of symptoms and speculation of putative mechanisms help physicians make the right diagnosis. NSAID-exacerbated respiratory disease is a noticeable phenotype of NSAID hypersensitivity that involves upper airway comorbidities (chronic rhinosinusitis with nasal polyps) as well as asthmatic features. The cutaneous phenotypes of NSAID hypersensitivity occur, and cross-reactivity with other types of NSAID should be considered in establishing a proper diagnosis. Hypersensitivity to a single NSAID can present urticaria/angioedema and anaphylaxis, in which an IgE-mediated immune response is suggested to be a prime mechanism. Management of NSAID hypersensitivity reactions includes avoidance, pharmacological treatment following standard guidelines, and aspirin desensitization.The classification, diagnosis, and management of NSAID hypersensitivity should be individually reached by identifying its phenotype.

PURPOSE Eosinophilic inflammation is a key component of severe asthma (SA). However, there has been no reliable serum biomarker for the eosinophilic inflammation of SA. We hypothesized that serum eosinophil-derived neurotoxin (EDN) could predict the eosinophilic inflammation of SA in adult asthmatics. METHODS Severe asthmatics (n = 235), nonsevere asthmatics (n = 898), and healthy controls (n = 125) were enrolled from Ajou University Hospital, South Korea. The serum levels of EDN and periostin were measured by enzyme-linked immunosorbent assay and compared between severe and nonsevere asthmatics. Their associations with total eosinophil count (TEC) and clinical parameters were evaluated; clinical validation of the K-EDN kit for the measurement of serum EDN was evaluated. RESULTS Severe asthmatics were older and had longer disease duration with significantly lower levels of forced expiratory volume in 1 second and methacholine PC20 than nonsevere asthmatics. Significant differences were found in TEC or sputum eosinophil count (%) between the groups. The serum levels of EDN and periostin were significantly higher in severe asthmatics than in nonsevere asthmatics and in healthy controls (all P < 0.05). Although significant correlations were found between serum EDN levels measured by the 2 kits (ρ = 0.545, P < 0.0001), higher correlation coefficients between serum EDN levels measured by the K-EDN kit and TEC were higher (ρ = 0.358, P < 0.0001) than those between serum EDN levels measured by the MBL kit and TEC (ρ = 0.319, P < 0.0001) or serum periostin level (ρ = 0.222, P < 0.0001). Multivariate regression analysis demonstrated that serum EDN levels measured by the K-EDN kit predicted the phenotype of SA (P = 0.003), while 2 other biomarkers did not. CONCLUSIONS The serum EDN level may be a useful biomarker for assessing asthma severity in adult asthmatics.

Patients with severe eosinophilic asthma (SEA) suffer from frequent asthma exacerbations, where eosinophils are major effector cells in airway inflammation, and anti-interleukin (IL)-5 becomes an effective treatment modality to control eosinophilic inflammation of SEA. Fifteen patients with SEA who had been treated with anti-IL5 (reslizumab, 100 mg monthly intravenously) for 6 months at Ajou University Hospital (Suwon, Korea) were enrolled in this study. Clinical parameters, including total blood eosinophil count (TEC), FEV1%, fractional exhaled nitric oxide (FeNO) levels, and serum biomarkers such as eosinophil-derived neurotoxin (EDN), periostin (PON), and transforming growth factor-β1 (TGF-β1), were analyzed. EDN levels and TEC decreased significantly after 1 month of treatment (P < 0.05 for both), while no changes were noted in FeNO/PON/TGF-β1 levels. FEV1% increased after 2 months of treatment (P < 0.05). A positive correlation was observed between TEC and EDN levels (r = 0.60, P = 0.02). Significant negative correlations were noted between age and TEC/EDN levels (r = −0.57, P = 0.02 and r = −0.56, P = 0.03, respectively). Baseline TEC was higher in the EDN-responder group (≥75% decrease) than in the non-responder group (P = 0.06) with a positive correlation between %reduction in EDN and TEC (r = 0.67, P = 0.01). The onset age was younger and asthma duration was longer in the FEV1%-non-responder group (

A novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 in China. The mutated coronavirus spread worldwide, and some patients infected with SARS-CoV-2 developed coronavirus disease 2019 (CO VID-19) manifested with upper respiratory infection, pneumonia, or respiratory distress. Since the SARS-CoV-2 pandemic was de clared with surging confirmed cases and mortality of COVID-19 worldwide, it has reshaped our way of living and how to manage patients with allergic diseases. The medical staff, including allergy specialists, has been at the forefront of fighting against the SARS-CoV-2 pandemic and is struggling to guarantee safety to themselves and their patients. Thanks to vigorous research into the rela tionship between SARS-CoV-2 and allergic diseases, we have become able to treat allergic patients with the best of evidence to date. The clinician should make a careful decision on each clinical situation with regard to patient characteristics, local and national circumstances as well as the knowledge we have, since it is still limited. We hope further efforts to identify the nature of SARS-CoV-2 and COVID-19 clearer and effective SARS-CoV-2 vaccination will soon remove the grim picture of the worldwide pandemic and bring us back to normal. (Allergy Asthma Respir Dis 2021;9:115-123)

Severe asthma (SA) is a heterogeneous disease characterized by uncontrolled symptoms, frequent exacerbations, and lung function decline. The discovery of phenotypes and endotypes of SA significantly improves our understanding of its pathophysiology and allows the advent of biologics blocking multiple molecular targets. The advances have mainly been made in type 2-high asthma associated with elevated type 2 inflammatory biomarkers such as immunoglobulin E (IgE), interleukins (IL)-4, IL-5, and IL-13. Previous clinical trials have demonstrated that type 2 biomarkers, including blood/sputum eosinophils and the fraction of exhaled nitric oxide (FeNO), were correlated to severe airway inflammation, persistent symptoms, frequent exacerbations, and the clinical efficacy of these biomarkers in predicting treatment outcomes of type 2-targeting biologics. However, it is well known that type 2 inflammation is partially attributable to the pathogenesis of SA. Although some recent studies have suggested that type 2-low and mixed phenotypes of asthma are important contributors to the heterogeneity of SA, many questions about these non-type 2 asthma phenotypes remain to be solved. Consequently, many efforts to investigate and find novel biomarkers for SA have also made in their methods. Many cross-sectional experimental studies in large-scale cohorts and randomized clinical trials have proved their value in understanding SA. More recently, real-world cohort studies have been in the limelight for SA research, which is unbiased and expected to give us an answer to the unmet needs of the heterogeneity of SA.

Although some mutations are beneficial and are the driving force behind evolution, it is important to maintain DNA integrity and stability because it contains genetic information. However, in the oxygen-rich environment we live in, the DNA molecule is under constant threat from endogenous or exogenous insults. DNA damage could trigger the DNA damage response (DDR), which involves DNA repair, the regulation of cell cycle checkpoints, and the induction of programmed cell death or senescence. Dysregulation of these physiological responses to DNA damage causes developmental defects, neurological defects, premature aging, infertility, immune system defects, and tumors in humans. Some human syndromes are characterized by unique neurological phenotypes including microcephaly, mental retardation, ataxia, neurodegeneration, and neuropathy, suggesting a direct link between genomic instability resulting from defective DDR and neuropathology. In this review, rare human genetic disorders related to abnormal DDR and damage repair with neural defects will be discussed.

Severe asthma (SA) presents in about 3%-5% of adult asthmatics and is responsible for over 60% of asthma-related medical expenses, posing a heavy socioeconomic burden. However, to date, a precise definition of or clear diagnostic criteria for SA have not been established, and therefore, it has been challenging for clinicians to diagnose and treat this disease. Currently, novel biologics targeting several molecules, such as immunoglobulin E, interleukin (IL)5, and IL4/IL13, have emerged, and many new drugs are under development. These have brought a paradigm shift in understanding the mechanism of SA and have also provided new treatment options. However, we need to agree on a precise definition of and its diagnostic criteria for SA. Additionally, it is necessary to explain the diagnostic criteria and to summarize current standard and additional treatment options. This review is an experts' opinion on SA from the Korean Academy of Asthma, Allergy, and Clinical Immunology, the Working Group on Severe Asthma, and aims to provide a definition of and diagnostic criteria for SA, and propose future direction for SA diagnosis and management in Korea.

Purpose Anaphylaxis is an immediate allergic reaction characterized by potentially life-threatening, severe, systemic manifestations. While studies have evaluated links between serious illness and posttraumatic stress disorder (PTSD), few have investigated PTSD after anaphylaxis in adults. We sought to investigate the psychosocial burden of recent anaphylaxis in Korean adults. Methods A total of 203 (mean age of 44 years, 120 females) patients with anaphylaxis were recruited from 15 university hospitals in Korea. Questionnaires, including the Impact of Event Scale-Revised-Korean version (IES-R-K), the Korean version of the Beck Anxiety Inventory (K-BAI), and the Korean version of the Beck Depression Inventory (K-BDI), were administered. Demographic characteristics, causes and clinical features of anaphylaxis, and serum inflammatory markers, including tryptase, platelet-activating factor, interleukin-6, tumor necrosis factor-α, and C-reactive protein, were evaluated. Results PTSD (IES-R-K ≥ 25) was noted in 84 (41.4%) patients with anaphylaxis. Of them, 56.0% had severe PTSD (IES-R-K ≥ 40). Additionally, 23.2% and 28.1% of the patients had anxiety (K-BAI ≥ 22) and depression (K-BDI ≥ 17), respectively. IES-R-K was significantly correlated with both K-BAI (r = 0.609, P < 0.0001) and K-BDI (r = 0.550, P < 0.0001). Among the inflammatory mediators, tryptase levels were lower in patients exhibiting PTSD; meanwhile, platelet-activating factor levels were lower in patients exhibiting anxiety and depression while recovering from anaphylaxis. In multivariate analysis, K-BAI and K-BDI were identified as major predictive variables of PTSD in patients with anaphylaxis. Conclusions In patients with anaphylaxis, we found a remarkably high prevalence of PTSD and associated psychological distresses, including anxiety and depression. Physicians ought to be aware of the potential for psychological distress in anaphylactic patients and to consider psychological evaluation.

Although a viral infection is a major triggering factor of asthma and allergic diseases, asthma is suggested to be not a predisposing condition for coronavirus disease 2019 (COVID-19) infection. However, patients with severe asthma/allergic disease requiring systemic corticosteroids or immunosuppressive agents may be at higher risk of more severe clinical course of this infectious disease. For allergic patients who have been followed up at an allergy clinic in our region, it is recommended that they (patients with asthma, rhinitis, atopic dermatitis or chronic urticaria) continue to receive maintenance therapy and be in a well-controlled status. Patients who have used biologics (currently available for targeting type 2 inflammation) and allergen immunotherapy should continue the treatment while minimizing hospital and face-to-face visits. It is essential to wear protective equipment for the protection of health care workers as well as patients. We report this consensus to support allergists and clinical immunologists to make optimal decisions under the urgent situation in Asia.

Defects in DNA damage response or repair mechanisms during neurogenesis result in genomic instability, which is causative for several neural defects. These include brain tumors, particularly medulloblastoma, which occurs in the cerebellum with a high incidence in children. We generated an animal model with defective base excision repair during brain development through selective inactivation of DNA polymerase β (Polb) in neuroprogenitor cells. All of Polb conditional knockout mice developed medulloblastoma in a p53 null background, similar to the Xrcc1 and p53 double deficient animal model. XRCC1 is a scaffolding protein which is involved in DNA damage repair and binds to POLB. In both animal models, the histopathological characteristics of the medulloblastoma were similar to those of human classic medulloblastoma. Brain tumor development was slower in the Polb and p53 double null animals than in the Xrcc1 and p53 double knockout animals. Molecular marker analysis suggested that Polb- and Xrcc1-deficient medulloblastomas belonged to the SHHα subtype, underscoring the important role of genomic stability in preventing this devastating pediatric cerebellar tumor.

Rationale Anaphylaxis is a serious allergic reaction which could be life-threatening. To date, it could be diagnosed by causality between clinical manifestations and triggers. But it is not always easy to find out the clue. Chlorpheniramine maleate (peniramin) is known to safe and it is an antihistamine commonly used to treat almost the whole allergic disease, including urticaria and allergic rhinitis. We recently experienced 2 cases of chlorpheniramine induced anaphylaxis. To document suspected cases of chlorpheniramine-induced adverse reactions, we analyzed a database spontaneously reported adverse drug reactions in the Ajou Regional Pharmacovigilance Center from 2011 to 2017. Patient concerns Two female patients presented urticaria and abdominal pain right after chlorpheniramine injection. Diagnoses Both patients were diagnosed with symptoms. One patient confirmed by assistance with tryptase level and another one confirmed cross-reactivity by skin tests. Interventions One patient was instructed to avoid future administration of chlorpheniramine. The other patient was advised not to take chlorpheniramine, and piperazine derivatives including cetirizine/levocetirizine, but piperidine derivatives such as fexofenadine, loratadine, and ebastine can be available. Outcomes The patients fully recovered after prompt treatment for anaphylaxis. After that, no recurrences were observed at the following. Among 54 patients with chlorpheniramine-induced adverse drug reactions from the Pharmacovigilance Center database, 17 (31.5%) were reported as anaphylaxis. Lessons Physicians should be aware chlorpheniramine could be a cause for allergic reaction. In addition, we suggest that serum tryptase level, skin prick test, and intradermal test could be considered as a supplementary test for diagnosing chlorpheniramine anaphylaxis and cross-reactivity should also be considered.

The miR-17∼92 cluster family is composed of three members encoding microRNAs that share seed sequences. To assess their role in cerebellar and medulloblastoma (MB) development, we deleted the miR-17∼92 cluster family in Nestin-positive neural progenitors and in mice heterozygous for the Sonic Hedgehog (SHH) receptor Patched 1 (Ptch1+/−). We show that mice in which we conditionally deleted the miR-17∼92 cluster (miR-17∼92floxed/floxed; Nestin-Cre+) alone or together with the complete loss of the miR-106b∼25 cluster (miR-106b∼25−/−) were born alive but with small brains and reduced cerebellar foliation. Remarkably, deletion of the miR-17∼92 cluster abolished the development of SHH-MB in Ptch1+/− mice. Using an orthotopic transplant approach, we showed that granule neuron precursors (GNPs) purified from the cerebella of postnatal day 7 (P7) Ptch1+/−; miR-106b∼25−/− mice and overexpressing Mycn induced MBs in the cortices of naïve recipient mice. In contrast, GNPs purified from the cerebella of P7 Ptch1+/−; miR-17∼92floxed/floxed; Nestin-Cre+ animals and overexpressing Mycn failed to induce tumors in recipient animals. Taken together, our findings demonstrate that the miR-17∼92 cluster is dispensable for cerebellar development, but required for SHH-MB development.

DNA damage is considered a prime factor in multiple spinocerebellar neurodegenerative diseases; however, the DNA lesions underpinning disease etiology are unknown. Here we identify the endogenous accumulation of pathogenic topoisomerase-1-DNA cleavage complexes (Top1cc) in murine models of ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy 1. We also show that the defective DNA damage response factors in these two diseases cooperatively modulate Top1cc turnover in a non-epistatic and ATM kinase-independent manner. Furthermore, coincident neural inactivation of ATM and DNA single strand break repair factors including tyrosyl-DNA phosphodiesterase-1 or XRCC1 result in increased Top1cc formation and excessive DNA damage and neurodevelopmental defects. Importantly, direct topoisomerase-1 poisoning to elevate Top1cc levels phenocopies the neuropathology of the mouse models above. Our study identifies a critical endogenous pathogenic lesion associated with neurodegenerative syndromes arising from DNA repair deficiency, indicating the essential role that genome integrity plays in preventing disease in the nervous system.

Eosinophils have long been recognized as a central effector cell in the lungs of asthmatic patients. They contribute to airway inflammation and remodeling through releasing several molecules such as cytokines, granule proteins, lipid mediators and extracellular traps/vesicles. Repeated evidence reveals that intense eosinophil infiltration in upper and lower airway mucosae contributes to the pathogenesis of aspirin-exacerbated respiratory disease (AERD). Persistent eosinophilia is found to be associated with type 2 immune responses, cysteinyl leukotriene overproduction and eosinophil-epithelium interactions. This review highlights recent findings about key mechanisms of eosinophil activation in the airway inflammation of AERD. In addition, current biologics (targeting type 2 immune responses) were suggested to control eosinophilic inflammation for AERD patients.

As the technical medium evolves, the method of accepting information is changing. The technical medium also appears in various ways through the combination with art. This study aims to conduct research on how hypermedia, appearing from this, will reveal itself in the urban public design in terms of its expression mode. First, this study looks at the characteristics for expression representation of hypermedia art through theoretical considerations on the hypermedia. Second, this study identifies how hypermedia art is introduced in the urban public design through art cases. Third, this study reveals the characteristics depending on the expression mode of hypermedia art shown in the urban public design based on the analyzed cases. As a result, first, hypermedia appeared in various image lighting expression modes that use `light` in the urban public design and interacted with the public. Second, hypermedia reacted to `motion` and was the expression mode of using bodies in the urban public design and using peripheral devices and external environment and characterized by having complex patterns of multi-layered structure through multi-media. It also applied sight, hearing, and touch partially or integratedly to attract synesthesia from the public and checked mutual interaction rapidly in an improvised way. Third, such a complex digital technology was the network expression mode beyond space and time by medium of urban public design and characterized by the new experience of virtual space expansion through the world wide network and the communication mode of participation. With such a role change of media and combination with art, hypermedia has been achieving varied extended representations. It is considered to change our monotonous urban environment, restore our relationship with the public, and open a new field of communication. Accordingly, the significance of this study can be identified through how it aimed to display the expression method of hypermedia which caused its extension in the field of urban public design as well as through the derivation of relevant characteristics.

Inactivation of homologous recombination (HR) or nonhomologous end-joining (NHEJ) predisposes to a spectrum of tumor types. Here, we inactivated DNA double-strand break repair (DSBR) proteins, DNA Ligase IV (Lig4), Xrcc2, and Brca2, or combined Lig4/Xrcc2 during neural development using Nestin-cre. In all cases, inactivation of these repair factors, together with p53 loss, led to rapid medulloblastoma formation. Genomic analysis of these tumors showed recurring chromosome 13 alterations via chromosomal loss or translocations involving regions containing Ptch1 . Sequence analysis of the remaining Ptch1 allele showed a variety of inactivating mutations in all tumors analyzed, highlighting the critical tumor suppressor function of this hedgehog-signaling regulator. We also observed genomic amplification or up-regulation of either N-Myc or cyclin D2 in all medulloblastomas. Additionally, chromosome 19, which contains Pten, was also selectively deleted in medulloblastoma arising after disruption of HR. Thus, our data highlight the preeminence of Ptch1 as a tumor suppressor in cerebellar granule cells and reveal other genomic events central to the genesis of medulloblastoma.

Defective DNA damage responses in the nervous system can result in neurodegeneration or tumorigenesis. Despite the importance of DNA damage signalling, the neural function of many critical DNA repair factors is unclear. BRCA2 is necessary for homologous recombination repair of DNA and the prevention of diseases including Fanconi Anemia and cancer. We determined the role of BRCA2 during brain development by inactivating murine Brca2 throughout neural tissues. In striking contrast to early embryonic lethality after germ-line inactivation, Brca2(LoxP/LoxP);Nestin-cre mice were viable. However, Brca2 loss profoundly affected neurogenesis, particularly during embryonic and postnatal neural development. These neurological defects arose from DNA damage as Brca2(LoxP/LoxP);Nestin-cre mice showed extensive gammaH2AX in neural tissue and p53 deficiency restored brain histology but lead to rapid formation of medulloblastoma brain tumors. In contrast, loss of the Atm kinase did not markedly attenuate apoptosis after Brca2 loss, but did partially restore cerebellar morphology, supporting a genomic surveillance function for ATM during neurogenesis. These data illustrate the importance of Brca2 during nervous system development and underscore the tissue-specific requirements for DNA repair factors.

Dicer, a ribonuclease III enzyme, is required for the maturation of microRNAs. To assess its role in cerebellar and medulloblastoma development, we genetically deleted Dicer in Nestin-positive neural progenitors and in mice lacking one copy for the Sonic Hedgehog receptor, Patched 1. We found that conditional loss of Dicer in mouse neural progenitors induced massive Trp53-independent apoptosis in all proliferative zones of the brain and decreased proliferation of cerebellar granule progenitors at embryonic day 15.5 leading to abnormal cerebellar development and perinatal lethality. Loss of one copy of Dicer significantly accelerated the formation of mouse medulloblastoma of the Sonic Hedgehog subgroup in Patched1-heterozygous mice. We conclude that Dicer is required for proper cerebellar development, and to restrain medulloblastoma formation.

The sonic hedgehog (SHH) receptor Patched 1 (Ptch1) is critical for embryonic development, and its loss is linked to tumorigenesis. Germ line inactivation of one copy of Ptch1 predisposes to basal cell carcinoma and medulloblastoma in mouse and man. In many cases, medulloblastoma arising from perturbations of Ptch1 function leads to a concomitant up-regulation of a highly similar gene, Patched2 (Ptch2). As increased expression of Ptch2 is associated with medulloblastoma and other tumors, we investigated the role of Ptch2 in tumor suppression by generating Ptch2-deficient mice. In striking contrast to Ptch1−/− mice, Ptch2−/− animals were born alive and showed no obvious defects and were not cancer prone. However, loss of Ptch2 markedly affected tumor formation in combination with Ptch1 haploinsufficiency. Ptch1+/−Ptch2−/− and Ptch1+/−Ptch2+/− animals showed a higher incidence of tumors and a broader spectrum of tumor types compared with Ptch1+/− animals. Therefore, Ptch2 modulates tumorigenesis associated with Ptch1 haploinsufficiency. (Cancer Res 2006; 66(14): 6964-71)

The aim of this study is to report the pharmacokinetics of omeprazole after intravenous (20 mg/kg) and oral (40 mg/kg) administration to rats with liver cirrhosis induced by dimethylnitrosamine (cirrhotic rats) with respect to CYP isozyme changes. The expressions of CYP1A2 and 3A1 decreased in cirrhotic rats and omeprazole is reported to be mainly metabolized via CYP1A1/2, 2D1, and 3A1/2 in male Sprague-Dawley rats. Hence, the pharmacokinetics of omeprazole could be changed in cirrhotic rats. After intravenous administration to cirrhotic rats, the AUC (1180 microg min/ml versus 474 microg min/ml) and CL(NR) (17.4 ml/min/kg versus 42.3 ml/min/kg) of omeprazole were significantly greater and slower, respectively, than the controls. This could be due to decrease in the expressions of CYP1A2 and 3A1 in cirrhotic rats. The significantly slower CL(NR) could be supported by significantly slower in vitro CL(int) for the disappearance of omeprazole from hepatic microsomal study (0.102 ml/min/mg protein versus 0.144 ml/min/mg protein) and slower hepatic blood flow rate in cirrhotic rats. After oral administration to cirrhotic rats, the AUC difference was considerably greater (451% versus 149%) than that after intravenous administration, possibly due to decrease in intestinal first-pass effect of omeprazole in addition to decrease in hepatic metabolism of omeprazole in cirrhotic rats.

Purpose To assess the feasibility of performing central molecular analyses of fresh medulloblastomas obtained from multiple institutions and using these data to identify prognostic markers for contemporaneously treated patients. Materials and Methods Ninety-seven samples of medulloblastoma were collected. Tumor content in samples was judged by frozen section review. Tumor ERBB2 protein and MYCC, MYCN, and TRKC mRNA levels were measured blind to clinical details using Western blotting and real-time polymerase chain reaction, respectively. Histopathologic and clinical review of each case was also performed. All data were subjected to independent statistical analysis. Results Sample acquisition and analysis times ranged from 3 to 6 days. Eighty-six samples contained sufficient tumor for analysis, including 38 classic, 30 nodular desmoplastic, and 18 large-cell anaplastic (LCA) medulloblastomas. Protein and mRNA were extracted from 81 and 49 tumors, respectively. ERBB2 was detected in 40% (n = 32 of 81) of tumors, most frequently in LCA disease (P = .005), and was independently associated with a poor prognosis (P = .031). A combination of clinical characteristics and ERBB2 expression provided a highly accurate means of discriminating disease risk. One hundred percent (n = 26) of children with clinical average-risk, ERBB2-negative disease were alive at 5 years, with a median follow-up of 5.6 years, compared with only 54% for children with average-risk, ERBB2-positive tumors (n = 13; P = .0001). TRKC, MYCC, and MYCN expression and histopathologic subtype were not associated with prognosis in this study. Conclusion Central and rapid molecular analysis of frozen medulloblastomas collected from multiple institutions is feasible. ERBB2 expression and clinical risk factors together constitute a highly accurate disease risk stratification tool.

Ataxia telangiectasia results from mutations of ATM and is characterized by severe neurodegeneration and defective responses to DNA damage. Inactivation of certain DNA repair genes such as DNA ligase IV results in massive neuronal apoptosis and embryonic lethality in the mouse, indicating the occurrence of endogenously formed DNA double-strand breaks during nervous system development. Here we report that Atm is required for apoptosis in all areas of the DNA ligase IV-deficient developing nervous system. However, Atm deficiency failed to rescue deficits in immune differentiation in DNA ligase IV-null mice. These data indicate that ATM responds to endogenous DNA lesions and functions during development to eliminate neural cells that have incurred genomic damage. Therefore, ATM could be important for preventing accumulation of DNA-damaged cells in the nervous system that might eventually lead to the neurodegeneration observed in ataxia telangiectasia.

Prolactin (PRL) serves an important luteotrophic function in the rat during early pregnancy, expressed as a nocturnal surge in the early morning and a diurnal surge in the late afternoon. Several areas of the hypothalamus, including the preoptic area (POA), the suprachiasmatic nucleus (SCN) and the ventromedial and dorsomedial nuclei (VM-DM) have been implicated in PRL surges. We investigated the temporal relationship between neuronal activity as measured by c-Fos immunocytochemistry in these areas and PRL secretion during early and late pregnancy. Brains were collected at nine time points (24:00, 02:00, 04:00, 06:00, 10:00, 14:00, 16:00, 18:00 and 20:00 h) on days 6–7 and three time points (02:00, 14:00 and 18:00 h) on days 14–15 of pregnancy. Plasma PRL levels determined by radioimmunoassay revealed two surges with peaks at 02:00 and 18:00 h and a trough at 14:00 h on days 6–7, which were absent on days 14–15 of pregnancy. The number of neurons expressing c-Fos in the anterior medial preoptic nucleus, the medial preoptic area and the medial preoptic nucleus, but not the anteroventral preoptic nucleus of the POA, and the VM-DM, showed a semicircadian rhythm which was maximal at 02:00 h or/and 04:00 and 18:00 h and reached the lowest value at 14:00 h, in parallel with the PRL surges in early pregnancy. However, the temporal pattern of c-Fos in these areas was reversed during late pregnancy, with a peak at 14:00 h and low levels at 02:00 and 18:00 h. PRL surges were absent and levels were uniformly low during these times. Neuronal activity in the SCN did not show any correlation with PRL surges. The dorsomedial subdivision of the SCN showed high neuronal activity during the daytime in both stages of pregnancy. Neuronal activity in the ventrolateral subdivision of the SCN was high during the nighttime in early pregnancy, however it exhibited high levels during the daytime in late pregnancy. These results suggest that the two daily surges of PRL secretion during the first half of pregnancy might be related to the temporal rhythm of neuronal activity in the POA and the VM-DM, and a major change in the pattern of neuronal activity in these hypothalamic areas might result in termination of the PRL surges at midpregnancy.

As a major food ingredient, soybean provides numerous health benefits, for example, individuals who consume soybean-rich diets exhibit lower incidence of high plasma cholesterol, cancer (including bowel and kidney), diabetes mellitus, and obesity (Carroll and Kurowska, 1995; Friedman and Brandon, 2001; Duranti et al., 2004; Ali et al., 2004; Omini and Aluko, 2005; Kim et al., 2006). However, soybean is also among the “big 8” most allergenic foods, and the only possible solution currently to prevent allergenic reactions is total avoidance of the allergen-containing foods. Because soybean is ubiquitous in vegetarian and many meat based food products, avoidance has become increasingly difficult, and its prevalence will inevitably continue to rise. Due to the innumerable health benefits and economic importance of soy commercial products, there is a mounting need to remove the allergenic components contained in soybean proteins to a threshold deemed to be safe. The estimated threshold level for common food allergy is usually low and a small amount of the allergen may be enough to trigger an allergenic reaction (Poms et al., 2004). The threshold for soybean allergen is estimated to range from 88 mg to several grams of soy protein (Bindslev-Jensen et al., 2002; Fiocchi et al., 2003). Soybean allergy is of particular importance because soybean is widely used in processed foods and represents a particularly insidious source of hidden allergens. Since finding foods that do not contain soy is difficult and total elimination of food allergens is practically impossible to attain, investigations on the hypoallergenization of soy ingredients and products are imperative. Current requirements by the labeling regulations also make it imperative to identify a processing technology that is capable of reducing or eliminating the allergens from soy containing products. Elimination or reduction of allergens in allergenic foods has been attempted for years by various investigators, which has included, among various strategies, the use of genetic engineering, thermal processing, enzyme treatment, ultrafiltration, chemical agents, microwave, irradiation, high pressure processing, pulsed ultraviolet light, power ultrasound and pulsed electric field. The reduction or elimination of allergens from soybean proteins by different processing technologies offers unique insight to the structure and biological interaction of the antigenic proteins. With allergens reduced, the industry can further profit from the economical attributes of soybean and promote the

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1(+) precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

The progressive accumulation of DNA damage is thought to be one of the driving forces that initiates ageing. However, the nature of the damage that arises endogenously is still ill-defined. A known source of endogenous damage is replicative stress (RS), which is intrinsically associated to DNA replication and prevented mainly by the ATR kinase. Here, we have developed a murine model of the human Seckel Syndrome characterized by a severe deficiency in ATR. Seckel mice suffer high levels of RS during embryogenesis when proliferation is widespread, but which decrease to marginal levels in postnatal life. In spite of this decrease, adult Seckel mice present accelerated ageing, which is further aggravated in the absence of p53 due to a further increase of RS. Together, these results support the concept that endogenous RS, particularly in utero, contributes to the onset of ageing in postnatal life and this is counterbalanced by the RS-limiting role of the checkpoint proteins ATR and p53.

The MRN complex (Mre11/RAD50/NBS1) and ATM (ataxia telangiectasia, mutated) are critical for the cellular response to DNA damage. ATM disruption causes ataxia telangiectasia (A-T), while MRN dysfunction can lead to A-T-like disease (ATLD) or Nijmegen breakage syndrome (NBS). Neuropathology is a hallmark of these diseases, whereby neurodegeneration occurs in A-T and ATLD while microcephaly characterizes NBS. To understand the contrasting neuropathology resulting from Mre11 or Nbs1 hypomorphic mutations, we analyzed neural tissue from Mre11ATLD1/ATLD1 and Nbs1ΔB/ΔB mice after genotoxic stress. We found a pronounced resistance to DNA damage-induced apoptosis after ionizing radiation or DNA ligase IV (Lig4) loss in the Mre11ATLD1/ATLD1 nervous system that was associated with defective Atm activation and phosphorylation of its substrates Chk2 and p53. Conversely, DNA damage-induced Atm phosphorylation was defective in Nbs1ΔB/ΔB neural tissue, although apoptosis occurred normally. We also conditionally disrupted Lig4 throughout the nervous system using Nestin-cre (Lig4Nes-Cre), and while viable, these mice showed pronounced microcephaly and a prominent age-related accumulation of DNA damage throughout the brain. Either Atm−/− or Mre11ATLD1/ATLD1 genetic backgrounds, but not Nbs1ΔB/ΔB, rescued Lig4Nes-Cre microcephaly. Thus, DNA damage signaling in the nervous system is different between ATLD and NBS and likely explains their respective neuropathology.

Various foods can induce anaphylaxis. However, mushrooms-induced anaphylaxis has not been reported in Korea. We report a patient with past anaphylactic episode caused by mushroom ingestion, confirmed by the skin test and specific IgE antibody to mushrooms. A 17-year-old girl with asthma was referred to our department due to itchy throat, dyspnea, and urticaria within 10 minutes after ingestion of a soup containing Oyster mushrooms. She presented an itching throat after ingestion of cooked mushrooms 3 years before the visit. She had an elevated serum IgE level (205 kU/L) and was sensitized to house dust mites. Skin prick tests with mushroom extracts showed a strong positive on Oyster and King Oyster mushrooms as well as Pyogo mushroom. The specific IgE antibody to each mushroom measured by enzyme-linked immunosorbent assay showed significant positive results to Oyster and Pyogo mushroom extracts, but was negative on King Oyster mushroom. We educated her to avoid eating Oyster and Pyogo mushrooms for preventing recurrence, whereas we couldn’t perform oral challenge tests (Allergy Asthma Respir Dis 2015;3:82-85)

Gene expression profiling indicates that the Sonic Hedgehog (Shh) pathway is active in ∼30% of human medulloblastomas, suggesting that it could provide a useful therapeutic target. Previously, we showed that spontaneous medulloblastomas in Ptc1+/−p53−/− mice could be eradicated by treatment with a small-molecule inhibitor (HhAntag) of Smoothened (Smo). Here, we compared the responses of mouse medulloblastoma cells propagated in flank allografts, either directly or after culture in vitro, to HhAntag. We found that Shh pathway activity was suppressed in medulloblastoma cells cultured in vitro and it was not restored when these cells were transplanted into the flank of nude mice. The growth of these transplanted tumor cells was not inhibited by treatment of mice with doses of HhAntag that completely suppressed Smo activity. Interestingly, tumor cells transplanted directly into the flank maintained Smo activity and were sensitive to treatment with HhAntag. These findings indicate that propagation of tumor cells in culture inhibits Smo activity in a way that cannot be reversed by transplantation in vivo, and they raise concerns about the use of cultured tumor cells to test the efficacy of Shh pathway inhibitors as anticancer therapies. (Cancer Res 2006; 66(8): 4215-22)

Recurrent genetic alterations in human medulloblastoma (MB) include mutations in the sonic hedgehog (SHH) signaling pathway andTP53inactivation (∼25% and 10% of cases, respectively). However, mouse models of MB, regardless of their initiating lesions, generally depend uponp53inactivation for rapid onset and high penetrance. The gene encoding the cyclin-dependent kinase inhibitor p18Ink4cis transiently expressed in mouse cerebellar granule neuronal precursor cells (GNPs) as they exit the cell division cycle and differentiate. Coinactivation ofInk4candp53provided cultured GNPs with an additive proliferative advantage, either in the presence or absence of Shh, and induced MB with low penetrance but with greatly increased incidence following postnatal irradiation. In contrast, mice lacking one or two functionalInk4calleles and one copy ofPatched(Ptc1) encoding the Shh receptor rapidly developed MBs that retained wild-typep53. In tumor cells purified from double heterozygotes, the wild-typePtc1allele, but notInk4c, was inactivated. Therefore, when combined withPtc1mutation,Ink4cis haploinsufficient for tumor suppression. Methylation ofINK4C(CDKN2C) was observed in four of 23 human MBs, and p18INK4Cprotein expression was extinguished in 14 of 73 cases. Hence, p18INK4Closs may contribute to MB formation in children.

IgG4-related disease (IgG4-RD) is characterized by a systemic involvement of tumor-like lesions with IgG4-positive plasmacytes. We experienced a case of IgG4-RD developed in a patient with bronchial asthma (BA) and chronic rhinosinusitis (CRS). A 55-yr-old female patient with BA and CRS complained of both eyes and neck swelling as well as a recurrent upper respiratory infection in recent 1 yr. The serum levels of IgG4, creatinine, and pancreatic enzymes were elevated. A biopsy of the submandibular gland showed an abundant infiltration of IgG4-positive plasmacytes. Her symptoms remarkably improved after the treatment of a systemic steroid that has been maintained without recurrence. We report a rare case of IgG4-RD developed in a patient with BA and CRS. Graphical Abstract

Prolactin plays major roles in maintaining the corpora lutea of pregnancy and in the synthesis of milk during lactation. The hypothalamic mechanisms involved in these functions have been investigated. Mating leads to a surge of prolactin and programs daily surges during early pregnancy. The expression of Fos-immunoreactivity shows that mating activates several hypothalamic nuclei, particularly the arcuate nucleus and medial preoptic area. In the arcuate nucleus, mating is associated with Fos expression in β-endorphin neurons, and infusion of naloxone blocks both mating-induced and diurnal prolactin surges. Tyrosine hydroxylase-immunoreactive dopamine neurons appear not to participate in surge generation. However, after day 10 of gestation the secretion of placental lactogens suppresses prolactin secretion via activation of dopamine neurons without involvement of β-endorphin neurons. Intracerebroventricular implantation of placental lactogen-secreting cells will block pregnancy prolactin surges, increase Fos expression in dopamine neurons, and increase tyrosine hydroxylase activity. During lactation the mechanisms regulating dopamine and β-endorphin neurons are further modified. In early lactation a prolactin-induced increase in tyrosine hydroxylase activity leads to negative feedback, but this effect is lost by mid-lactation. Overriding this negative feedback is the inhibitory effect that suckling has on dopaminergic activity. This may involve β-endorphin-mediated inhibition of dopamine neurons, as naloxone causes a marked increase in tyrosine hydroxylase activity and suppression of circulating prolactin. However, removal of tonic dopamine inhibition is not sufficient to account for the high levels of prolactin attained during lactation, and additional releasing factors are probably involved. In situ hybrization histochemistry for the most recent candidate, prolactin-releasing peptide, suggests that this may involve brain stem neurons that co-localize noradrenaline. Thus, prolactin secretion during pregnancy and lactation involve complex interactions of regulatory factors and plasticity of neuronal responsiveness.

Sanyak has been used as a food and herbal material for various symptoms in oriental medicine. There have been few reports of occupational asthma induced by herb materials (1–6). Until now there has been no account of occupational asthma caused by Korean ginseng. We describe a case of occupational asthma and rhinitis caused by Sanyak (Dioscorea batatas) and Korean ginseng (Panax ginseng), as confirmed by specific inhalation challenge tests. A 29-year-old female patient was presented to the emergency department (ED) of Eulji University Hospital in Daejeon, Korea, for the treatment of dyspnea, wheezing, and cough. The patient had been incidentally exposed to airborne Sanyak dust, during the process of grinding dried Sanyak into powder, 5 min before the onset of symptoms. She had been a merchant of herbal materials for the previous 26 months. Twelve months before her visit, she had been admitted to another hospital and diagnosed with bronchial asthma after the sudden onset of dyspnea following an exposure to airborne ginseng dust. The patient had been suffering from nasal itching, sneezing, rhinorrhea, and nasal obstruction during the spring season for 6 years and had also experienced itching and swelling of the lips, tongue, and throat after ingesting fresh chestnut, sweet potato, and ginseng. The patient was a non-smoker and had no family history of allergic diseases. The patient appeared acutely ill and had tachypnea. Diffuse expiratory wheezes were noted over both lung fields. Arterial blood gas measurements at the ED indicated a pH of 7.414, PaCO2 of 30.8 mmHg, PaO2 of 70.4 mmHg and SaO2 94.6%. The total IgE level was 663.0 IU/ml. After pharmacological treatment, her symptoms resolved in a day. Proteins were extracted from Ginseng and Sanyak, and used for skin-prick tests, inhalation challenge tests, and laboratory studies. The skin-prick testing was expressed as mean wheal diameter/ mean erythema diameter (in millimeters): Dermatophagoides pteronyssinus 6.5/23.5 (Allergopharma, Reinbek, Germany); alder tree pollen 5.5/33.5 (Allergopharma); birch tree pollen 3.5/17 (Allergopharma); ginseng (1 : 100 w/v) 3/12; Sanyak (1 : 100 w/v) 3.75/19; histamine 4/17.5; and saline 0/0. Nonspecific and specific challenge tests were performed during her stable state. The methacholine bronchial challenge test revealed a 20% decline of forced expiratory volume in 1 s[FEV1] at the concentration of 0.75 mg/ml. The bronchoprovocation tests showed early asthmatic responses to both Sanyak and ginseng extracts (1 : 1000 and 1 : 100 w/ v, respectively). Serum-specific IgE and IgG4 antibodies to Sanyak were detected by enzyme linked immunosorbent assay[ELISA], but there was no specific antibody binding to ginseng. The sodium dodecyl sulphate-polyacrylamide gel electrophoresis[SDS-PAGE] and an IgEimmunoblot, a 35-kDa IgE-binding component was detected in the Sanyak extracts (Fig. 1), but no IgE-binding component was noted in the ginseng extract. The ELISA inhibition test, specific IgE binding, and IgG4 binding to Sanyak demonstrated specific, dosedependent inhibition by Sanyak extracts but not by other control agents. The patient in this study showed the occurrence of occupational asthma induced by Sanyak and Korean ginseng. Although there is a report of occupational asthma being induced by Brazilian ginseng (1) no cases of bronchial asthma caused by Korean ginseng have been previously reported. Brazilian ginseng and Korean ginseng are different plants in terms of taxonomic classification. Brazilian ginseng (Pfaffia paniculata) belongs to the Amaranthaceae family; in contrast, the Korean ginseng (Panax ginseng) belongs to the Araliaceae family (1). This study, it is suggested that Sanyakderived allergen can induce IgE-mediated allergic reactions. We were unable to demonstrate specific IgE and IgG4 antibodies to Korean ginseng extract despite the fact that the patient showed a positive bronchial provocation and positive responses to a skin-prick test. Further studies are needed to investigate the pathogenic mechanism of occupational asthma caused by Korean ginseng. This study was funded by the Korean government (A0505171).

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype), arises outside the cerebellum from cells of the lower rhombic lip (LRL). We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the LRL and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused an aberrant accumulation of proliferating precursor cells within the LRL. These lesions persisted in the dorsal brainstem of all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that modeled faithfully the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3448. doi:10.1158/1538-7445.AM2011-3448

The chromosomal instability syndromes Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT) share many overlapping phenotypes, including cancer predisposition, radiation sensitivity, cell-cycle checkpoint defects, immunodeficiency, and gonadal dysfunction. The NBS protein Nbs1 is not only a downstream target of AT mutated (ATM) kinase but also acts upstream, promoting optimal ATM activation, ATM recruitment to breaks, and ATM accessibility to substrates. By reconstituting Nbs1 knockout mice with bacterial artificial chromosomes, we have assessed the contribution of distinct regions of Nbs1 to the ATM-dependent DNA damage response. We find that T cell and oocyte development, as well as DNA damage-induced G2/M and S phase checkpoint arrest and radiation survival are dependent on the N-terminal forkhead-associated domain, but not on the principal residues phosphorylated by ATM (S278 and S343) or on the evolutionarily conserved C-terminal region of Nbs1. However, the C-terminal region regulates irradiation-induced apoptosis. These studies provide insight into the complex interplay between Nbs1 and ATM in the DNA damage response.

// Mi-Young Cho 1,2 , Jae Youn Cheong 3 , Wonchung Lim 1,7 , Sujin Jo 4 , Youngsoo Lee 4 , Hee-Jung Wang 5 , Kyou-Hoon Han 6 and Hyeseong Cho 1,2,4 1 Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, The Graduate School, Ajou University, Suwon, Korea 2 Department of Biomedical Sciences, The Graduate School, Ajou University, Suwon, Korea 3 Department of Gastroenterology, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea 4 Genomic Instability Research Center, Ajou University School of Medicine, Suwon, Korea 5 Department of Surgery, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea 6 Biomedical Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea 7 Current address: Department of Sports Medicine, Cheongju University, Cheongju, Korea Correspondence: Hyeseong Cho, email: // Keywords : HBx, Liver cancer, Catalase, Cysteine, ROS Received : July 23, 2014 Accepted : October 23, 2014 Published : October 24, 2014 Abstract Hepatitis B virus X protein (HBx) plays a role in liver cancer development. We previously showed that ROS increased HBx levels and here, we investigated the role of antioxidants in the regulation of HBx expression and their clinical relevance. We found that overexpression of catalase induced a significant loss in HBx levels. The cysteine null mutant of HBx (Cys - ) showed a dramatic reduction in its protein stability. In clonogenic proliferation assays, Huh7-X cells produced a significant number of colonies whereas Huh7-Cys - cells failed to generate them. The Cys at position 69 of HBx was crucial to maintain its protein stability and transactivation function in response to ROS. Among 50 HBV-related hepatocellular carcinoma (HCC) specimens, 72% of HCCs showed lower catalase levels than those of surrounding non-tumor tissues. In advanced stage IV, catalase levels in non-tumor tissues were increased whereas those in tumors were further reduced. Accordingly, patients with a high T/N ratio for catalase showed significantly longer survival than those with a low T/N ratio. Together, catalase expression in HCC patients can be clinically useful for prediction of patient survival, and restoration of catalase expression in HCCs could be an important strategy for intervention in HBV-induced liver diseases.