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Transdermal drug administration presents several advantages and it is therefore favorable as an alternative drug delivery route. However, transdermal delivery of biopharmaceutical drugs is made difficult by the skin barrier. Microneedle application and iontophoresis are strategies which can be used to overcome this barrier. Therefore, recombinant human growth hormone (rhGH) was used as a model macromolecular drug and was transdermally delivered using microneedle application and iontophoresis. Methylene blue staining, stereomicroscopy and scanning electron microscope (SEM) imaging were used to characterize the microchannels produced. To optimize the iontophoresis protocol, the effects of molecular charge and current density on transdermal delivery were evaluated in an in vitro permeation study using excised rat skin tissues. Using the optimized iontophoresis protocol, the combination effects of iontophoretic delivery via microchannels were evaluated in three different experimental designs. The flux obtained with anodal iontophoresis in citrate buffer was approximately 10-fold higher that that with cathodal iontophoresis in phosphate buffered saline (PBS). Flux also increased with current density in anodal iontophoresis. The combination of iontophoresis and microneedle application produced higher flux than single application. These results suggest that anodal iontophoresis with higher current density enhances the permeation of macromolecules through microchannels created by microneedles. In conclusion, the combination of iontophoresis and microneedles is a potential strategy for the enhancement of transdermal delivery of macromolecular drugs.

Background: The modified Marsh and Schnider pharmacokinetic models for propofol consistently produce negatively and positively biased predictions in underweight patients, respectively. We aimed to develop a new pharmacokinetic model of propofol in underweight patients., Methods: Twenty underweight (BMI<18.5 kg m -2 ) patients aged 20-68 yr were given an i.v. bolus of propofol (2 mg kg -1 ) for induction of anaesthesia. Anaesthesia was maintained with a zero-order infusion (8 mg kg -1 h -1 ) of propofol and target-controlled infusion of remifentanil. Arterial blood was sampled at preset intervals. A population pharmacokinetic analysis was performed using non-linear mixed effects modelling. The time to peak effect (t peak , maximally reduced bispectral index) was measured in 28 additional underweight patients receiving propofol 2 mg kg -1 ., Results: In total, 455 plasma concentration measurements from the 20 patients were used to characterise the pharmacokinetics of propofol. A three-compartment mammillary model well described the propofol concentration time course. BMI and lean body mass (LBM) calculated using the Janmahasatian formula were significant covariates for the rapid peripheral volume of distribution and for the clearance of the final pharmacokinetic model of propofol, respectively. The parameter estimates were as follows: V 1 (L)=2.02, V 2 (L)=12.9 (BMI/18.5) , V 3 (L)=139, Cl (L⋅min -1 )=1.66 (LBM/40) , Q 1 (L⋅min -1 )=1.44, Q 2 (L⋅min -1 )=0.87+0.0189×(LBM-40). The median t peak of propofol was 1.32 min (n=48)., Conclusions: A three-compartment mammillary model can be used to administer propofol via target effect-site concentration-controlled infusion of propofol in underweight patients., Clinical Trial Registration: KCT0001760., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Single-photon emitters play an essential role in quantum technologies, including quantum computing and quantum communications. Atomic defects in hexagonal boron nitride ( h-BN) have recently emerged as new room-temperature single-photon emitters in solid-state systems, but the development of scalable and tunable h-BN single-photon emitters requires external methods that can control the emission energy of individual defects. Here, by fabricating van der Waals heterostructures of h-BN and graphene, we demonstrate the electrical control of single-photon emission from atomic defects in h-BN via the Stark effect. By applying an out-of-plane electric field through graphene gates, we observed Stark shifts as large as 5.4 nm per GV/m. The Stark shift generated upon a vertical electric field suggests the existence of out-of-plane dipole moments associated with atomic defect emitters, which is supported by first-principles theoretical calculations. Furthermore, we found field-induced discrete modification and stabilization of emission intensity, which were reversibly controllable with an external electric field.

We report functional gold nanoparticles (AuNPs) with a pH-sensitive γ-cyclodextrin (CD) cap. These particles include two chargeable CD molecules on their surface. CD with dopamine and amine (NH 2 ) groups (hereafter termed as dCD-NH 2 ) was anchored to the gold surface and then electrostatically complexed with the CD with 2,3-dimethylmaleic acid (DMA) and chlorin e6 (Ce6) (hereafter termed as cCD-DMA), producing an ionic complex consisting of dCD-NH 2 and cCD-DMA. Under the acidic environment (pH 6.8) existing in most solid tumors, the ionic complex was destabilized because of the decoupling of DMA, resulting in the release of cCD (without DMA) from the AuNPs, resulting in extensive tumoral uptake of AuNPs with dCD-NH 2 (because of their electrostatic attraction to tumor cells). This event resulted in a significant increase in the efficiency of cellular AuNP uptake and light-driven (AuNP-mediated photothermal and Ce6-mediated photodynamic) ablation of acidic solid tumors, suggesting marked potential for tumor therapy.

Although we recently demonstrated that static magnetic fields (SMFs) of 3, 15, and 50 mT stimulate osteoblastic differentiation, the effects of SMFs on osteoclastogenesis are still poorly understood. This study focused on the suppressive effects of SMFs on receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis and bone resorption. Direct SMFs inhibit RANKL-induced multinucleated osteoclast formation, tartrate-resistant acid phosphatase activity, and bone resorption in mouse bone marrow-derived macrophage cells. The conditioned medium from osteoblasts treated with SMFs also resulted in the inhibition of osteoclast differentiation as well as resorption. The RANKL-induced expression of osteoclast-specific transcription factors, such as c-Fos and NFATc1, was remarkably downregulated by SMF at 15 mT. In addition, SMF inhibited RANKL-activated Akt, glycogen synthase kinase 3β (GSK3β), extracellular signal-regulated kinase, c-jun N-terminal protein kinase, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) formation. These findings indicate that SMF-mediated attenuation of RANKL-induced Akt, GSK3β, MAPK, and NF-κB pathways could contribute to the direct and indirect inhibition of osteoclast formation and bone resorption. Therefore, SMFs could be developed as a therapeutic agent against periprosthetic or peri-implant osteolysis. Additionally, these could be used against osteolytic diseases such as osteoporosis and rheumatoid arthritis. Bioelectromagnetics. 39:394-404, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Objective: This study aimed to identify the core symptoms of delirium, particularly in elderly people associated with major risk factors, using the Korean version of the Delirium Rating Scale-Revised-98., Methods: The study sample consisted of 200 patients (mean age: 72.7±3.9 years, male: 68.5%) who had been diagnosed with delirium. Exploratory factor analysis was used to investigate the factor structure, and confirmatory factor analysis was used to evaluate the goodness of fit of the results., Results: The results demonstrated three core domains of delirium in the elderly patients: 1) the cognitive domain (e.g., language, thought process, orientation, attention, long-term memory, and visuospatial ability); 2) the circadian domain (e.g., sleep-wake cycle and motor behavior); and 3) the short-term memory domain (short-term memory). These results were confirmed by confirmatory factor analysis., Conclusion: The findings of this study suggest a theoretical domain structure for delirium in elderly patients.

Vaccination is an effective approach to prevent the consequences of infectious diseases. Vaccines strengthen immunity and make individuals resistant to infections with pathogens. Although conventional vaccines are highly immunogenic, they are associated with some safety issues. Subunit vaccines are safe, but they require adjuvants to stimulate the immune system because of their weaker immunogenicity. Adjuvants are entities incorporated into vaccines to increase the immunogenic responses of antigens. They play a crucial role in increasing the potency and efficacy of vaccines. Different adjuvants have different modes of action; therefore, a better understanding of their immunology could provide guidance for the development of novel adjuvants. Numerous studies have been conducted using different types of adjuvants to characterize their potency and safety; however, in practice, only few are used in human or animal vaccines. This review aims to introduce the different modes of action of adjuvants and give insight into the types of adjuvants that possess the greatest potential for adjuvanticity.

Background: Atopic dermatitis is a global problem affecting children, and its prevalence in Korea is steadily increasing. Since it is a chronically relapsing inflammatory skin disease, caregiver management of young children's atopic dermatitis is crucial for positive treatment outcomes. A factor that contributes to adherence to recommended prescriptions is parents' self-efficacy. However, accurate measurements of parental self-efficacy in relation to disease-specific task management are scarce., Objectives: This study examined the psychometric properties of the Korean language version of the Parental Self-Efficacy with Eczema Care Index (K-PASECI)., Methods: One hundred twenty five mothers of children younger than 13 years old who had atopic dermatitis were recruited from three tertiary hospitals across Korea. The K-PASECI was developed in accordance with the published guidelines. Psychometric testing included factor analysis, internal consistency testing, and concurrent validity analysis by comparing K-PASECI domains with parenting self-efficacy subscales., Results: Factor analysis revealed a four-factor structure that explained 69.4% of the variance. The four factors were as follows; managing a child's symptoms and behaviour, communicating with medical staff, managing medication, and using moisturizer as part of routine management. The findings showed acceptable internal consistency (α=.94) and a moderate positive correlation with parenting self-efficacy (r=.48, p<.001)., Conclusion: The K-PASECI, a reliable and valid scale for measuring self-efficacy in parents caring for children with atopic dermatitis, may be used in clinical and research settings to measure parents' self-efficacy in Korea, as well as in other English-speaking countries.

In this study, we developed functionalized iron oxide nanoparticles for brain tumor targeting. The iron oxide (Fe 3 O 4 ) particles were stabilized with pluronic F127 and coupled with dopamine-terminated Y-shaped ligands (Tat peptide and transferrin) as a result of the noncovalent conjugation of dopamine (of Y-shaped ligands) and the iron oxide nanoparticles. Here, the hydrophobic domain of pluronic F127 coated on the iron oxide nanoparticles enabled the absorption of a model photosensitizing antitumor drug (chlorin e6) in the core/shell interface of the nanoparticles. The experimental results demonstrated that the Y-shaped ligands on the nanoparticles enabled a significant enhancement of in vitro/in vivo cellular uptake for human primary glioblastoma U87-MG cells as a result of multivalent endocytosis by Y-shaped ligands (transferrin receptor-mediated endocytosis and the following Tat peptide-mediated cellular interaction). Furthermore, the Ce6-loaded nanoparticles showed significant enhancement of in vitro/in vivo photodynamic U87-MG cell ablation under light illumination.

The leaves and stems of the plant Rubus coreanus Miquel (RCMLS) are rich in vitamins, minerals and phytochemicals which have antioxidant, anti-hemolytic, anti-inflammatory, anti-fatigue and anti-cancer effects. However, RCMLS is not included in the Korean Food Standards Codex due to the lack of safety assurance concerning RCMLS. We evaluated single and repeated oral dose toxicity of RCMLS in Sprague-Dawley rats. RCMLS did not induce any significant toxicological changes in both male and female rats at a single doses of 2500 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects in clinical signs, body weight, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at doses of 625, 1250, and 2500 mg/kg/day. The LD50 and LOAEL of RCMLS might be over 2500 mg/kg body weight/day and no target organs were identified. Therefore, this study revealed that single and repeated oral doses of RCMLS are safe.

Recent studies of propofol-induced unconsciousness have identified characteristic properties of electroencephalographic alpha rhythms that may be mediated by drug activity at γ-aminobutyric acid (GABA) receptors in the thalamus. However, the effect of ketamine (a primarily non-GABAergic anesthetic drug) on alpha oscillations has not been systematically evaluated. We analyzed the electroencephalogram of 28 surgical patients during consciousness and ketamine-induced unconsciousness with a focus on frontal power, frontal cross-frequency coupling, frontal-parietal functional connectivity (measured by coherence and phase lag index), and frontal-to-parietal directional connectivity (measured by directed phase lag index) in the alpha bandwidth. Unlike past studies of propofol, ketamine-induced unconsciousness was not associated with increases in the power of frontal alpha rhythms, characteristic cross-frequency coupling patterns of frontal alpha power and slow-oscillation phase, or decreases in coherence in the alpha bandwidth. Like past studies of propofol using undirected and directed phase lag index, ketamine reduced frontal-parietal (functional) and frontal-to-parietal (directional) connectivity in the alpha bandwidth. These results suggest that directional connectivity changes in the alpha bandwidth may be state-related markers of unconsciousness induced by both GABAergic and non-GABAergic anesthetics.

Background: Specific oral tolerance induction (SOTI) for IgE-mediated food allergy (IFA) can be successfully achieved using interfero gamma (classic SOTI)., Objective: In this study, a tolerable dose was introduced during tolerance induction with interferon gamma (dual SOTI), and its effectiveness was evaluated., Methods: The study population comprised 25 IFA patients. Blood samples were taken for analysis, including complete blood count with differential counts of eosinophils, serum total IgE levels, and specific IgE for allergenic foods. Skin prick tests were conducted with the allergens. Oral food challenges were performed to diagnose IFA. Ten patients received dual SOTI, 5 received classic SOTI, 5 received SOTI without interferon gamma (original SOTI), and 5 were not treated (controls)., Results: Patients treated with dual SOTI and classic SOTI using interferon gamma became tolerant to the allergenic food. The tolerable dose was introduced successfully in dual SOTI. It was difficult to proceed with the same dosing protocol used for classic SOTI in cases treated with original SOTI. Following dual SOTI, the systemic reaction to oral intake subsided, but the local skin reaction to contact with the allergenic food persisted., Conclusions: Dual SOTI is an improved protocol for SOTI using interferon gamma for IFA.The local skin reaction and systemic reaction to oral intake were dissociated following dual SOTI. In cases of food allergy, tolerance appears to result from desensitization to allergens.

A food allergy is an adverse health effect arising from a specific immune response that occurs reproducibly upon exposure to a given food. In those with food allergies that are thought to cause aggravation of eczema, food avoidance is important. The objective of this study was to research the nutritional status of patients with food allergies. A total of 225 subjects diagnosed with atopic dermatitis underwent a skin prick test as well as measurement of serum immunoglobulin E. Food challenge tests were conducted using seven food items: milk, eggs, wheat, soybeans, beef, pork, and chicken. At post-food challenge visits to the test clinic, participants completed a three-day dietary record, which included two week days and one weekend day, in order to evaluate energy intake and diet quality during the challenge. We analyzed nutrient intake based on differential food allergens. Subjects with a food allergy to milk showed lower intake of Ca, Zn, and vitamin B2, and subjects with a food allergy to egg showed lower intake of vitamin A, B1, B2, niacin, and cholesterol. Subjects with a food allergy to wheat and soybean showed lower intake of Ca, P, Fe, K, Zn, vitamin B2, vitamin B6, and niacin; and subjects with a food allergy to beef, pork, and chicken showed lower intake of Fe and higher intake of K, vitamin A, B2. Subjects with atopic dermatitis were lacking in several nutrients, including vitamin A and vitamin C. A greater number of food allergies showed an association with a greater number of nutrient intake deficiencies. Allergen avoidance is the basic treatment for atopic dermatitis. However, when the allergen is food, excessive restriction can lead to nutrition deficiency. Findings of this study suggest the necessity for enhanced nutritional education in order to provide substitute foods for patients with food allergies who practice food restriction.

Background: AD patients exhibit sensitisation to multiple allergens due to a Th1/Th2 imbalance. Until now, it was impossible to improve the polysensitised status and elevated serum total IgE levels. In this study, the effects of IFN-gamma on systemic polysensitisation to multiple allergens and on serum total IgE levels are investigated., Methods: A total of 44 AD patients whose food allergies were completely controlled and who were polysensitised to multiple allergens according to the SPT were selected. Twenty-two of these patients received IFN-gamma therapy twice a week for 2 months, and 22 patients did not receive this therapy. The blood eosinophil % and serum total IgE levels were assessed, and a skin prick test for 51 allergens was performed before and after the IFN-gamma therapy., Results: With IFN-gamma therapy, the polysensitisation status was improved, as demonstrated by a decrease in the positive allergen count and skin reactivity (systemic polydesensitisation). The improvement in the polysensitised status was accompanied by a decrease in serum total IgE levels. The change in serum total IgE levels was significantly correlated with the change in polysensitisation status., Conclusions: IFN-gamma therapy resulted in systemic polydesensitisation with reduced levels of serum total IgE. IFN-gamma is indicated in AD patients with high serum total IgE levels whose food allergies are well controlled and who are polysensitised to multiple allergens., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Atopic dermatitis (AD) is a chronic allergic inflammatory disease characterised by late eczematous lesions and allergenic sensitisation that occur. Skin prick testing has been used for the causative investigation of individual allergens. However, there exists no proper tool to evaluate polysensitisation status. In this study, skin sensitisation indices were suggested, and the clinical significance of polysensitisation was evaluated., Methods: A total of 188 AD patients were involved in this study. Blood tests including blood eosinophil % and serum total IgE were conducted. Skin prick tests for 50 important allergens were performed. The skin sensitisation index (SSI) was compared with the blood eosinophil % and the serum total IgE., Results: The degree of sensitisation may be related to the serum total IgE rather than the number of allergens to which a patient is sensitised. The skin sensitisation profile was associated with IgE-related laboratory results but not with clinical activity or blood eosinophil %., Conclusions: For the evaluation of polysensitisation, skin sensitisation profiles may be needed and the skin sensitisation profile was useful for the description of polysensitisation. Polysensitisation seems to be one mechanism for the elevation of serum total IgE. Further studies may be needed to ascertain the clinical significance of skin polysensitisation and the application of the skin sensitisation profile in clinical use.

Background: DJ-1 is an antioxidant protein known to reduce levels of reactive oxygen species (ROS), but its presence or function in mast cells and allergic diseases is unknown., Objectives: We sought to determine the role and mechanism of DJ-1 in allergic responses in vitro and in vivo., Methods: ROS and DJ-1 levels in serum or culture medium were measured with ELISA kits. The role of DJ-1 was evaluated in mast cell cultures and passive cutaneous anaphylaxis in normal or DJ-1 knockout (KO) mice. The mechanism of DJ-1 action was examined by using immunoblotting, immunoprecipitation, RT-PCR, and other molecular biological approaches., Results: Patients with atopic dermatitis had increased levels of ROS and diminished levels of DJ-1. DJ-1 KO mice exhibited enhanced passive cutaneous anaphylaxis and augmented ROS levels in sera and bone marrow-derived mast cells (BMMCs). Furthermore, antigen-induced degranulation and production of TNF-α and IL-4 were significantly amplified in DJ-1 KO and anti-DJ-1 small interfering RNA-transfected BMMCs compared with that seen in wild-type (WT) BMMCs. Studies with these cells and BMMCs transfected with small interfering RNAs against the phosphatases Src homology domain 2-containing protein tyrosine phosphatase (SHP) 1 and SHP-2 revealed that the DJ-1 KO phenotype could be attributed to suppression of SHP-1 activity and enhancement of SHP-2 activity, leading to strengthened signaling through linker for activation of T cells, phospholipase Cγ, and mitogen-activated protein kinases., Conclusions: A deficiency or constitutive activation of DJ-1 can have implications in mast cell-driven allergic diseases, such as asthma and anaphylaxis., (Published by Mosby, Inc.)

Introduction: Directional connectivity from anterior to posterior brain regions (or "feedback" connectivity) has been shown to be inhibited by propofol and sevoflurane. In this study the authors tested the hypothesis that ketamine would also inhibit cortical feedback connectivity in frontoparietal networks., Methods: Surgical patients (n = 30) were recruited for induction of anesthesia with intravenous ketamine (2 mg/kg); electroencephalography of the frontal and parietal regions was acquired. The authors used normalized symbolic transfer entropy, a computational method based on information theory, to measure directional connectivity across frontal and parietal regions. Statistical analysis of transfer entropy measures was performed with the permutation test and the time-shift test to exclude false-positive connectivity. For comparison, the authors used normalized symbolic transfer entropy to reanalyze electroencephalographic data gathered from surgical patients receiving either propofol (n = 9) or sevoflurane (n = 9) for anesthetic induction., Results: Ketamine reduced alpha power and increased gamma power, in contrast to both propofol and sevoflurane. During administration of ketamine, feedback connectivity gradually diminished and was significantly inhibited after loss of consciousness (mean ± SD of baseline and anesthesia: 0.0074 ± 0.003 and 0.0055 ± 0.0027; F(5, 179) = 7.785, P < 0.0001). By contrast, feedforward connectivity was preserved during exposure to ketamine (mean ± SD of baseline and anesthesia: 0.0041 ± 0.0015 and 0.0046 ± 0.0018; F(5, 179) = 2.07; P = 0.072). Like ketamine, propofol and sevoflurane selectively inhibited feedback connectivity after anesthetic induction., Conclusions: Diverse anesthetics disrupt frontal-parietal communication, despite molecular and neurophysiologic differences. Analysis of directional connectivity in frontal-parietal networks could provide a common metric of general anesthesia and insight into the cognitive neuroscience of anesthetic-induced unconsciousness.

We examined the characteristics of food allergy prevalence and suggested the basis of dietary guidelines for patients with food allergies and atopic dermatitis. A total of 2,417 patients were enrolled in this study. Each subject underwent a skin prick test as well as serum immunoglobulin E (IgE) measurement. A double-blind, placebo-controlled food challenge was conducted using milk, eggs, wheat, and soybeans, and an oral food challenge was performed using beef, pork, and chicken. Food allergy prevalence was found among 50.7% in patients with atopic dermatitis. Among patients with food allergies (n = 1,225), the prevalence of non-IgE-mediated food allergies, IgE-mediated food allergies, and mixed allergies was discovered in 94.9%, 2.2%, and 2.9% of the patients, respectively. Food allergy prevalence, according to food item, was as follows: eggs = 21.6%, milk = 20.9%, wheat = 11.8%, soybeans = 11.7%, chicken = 11.7%, pork = 8.9% and beef = 9.2%. The total number of reactions to different food items in each patient was also variable at 45.1%, 30.6%, 15.3%, 5.8%, 2.2%, and 1.0% for 1 to 6 reactions, respectively. The most commonly seen combination in patients with two food allergies was eggs and milk. The clinical severity of the reactions observed in the challenge test, in the order of most to least severe, were wheat, beef, soybeans, milk, pork, eggs, and chicken. The minimum and maximum onset times of food allergy reactions were 0.2-24 hrs for wheat, 0.5-48 hrs for beef, 1.0-24 hrs for soybeans, 0.7-24 hrs for milk, 3.0-24 hrs for pork, 0.01-72 hrs for eggs, and 3.0-72 hrs for chicken. In our study, we examined the characteristics of seven popular foods. It will be necessary, however, to study a broader range of foods for the establishment of a dietary guideline. Our results suggest that it may be helpful to identify food allergies in order to improve symptoms in patients with atopic dermatitis.

Purpose: Specific oral immunotherapy (SOIT) using interferon-γ (IFN-γ) has been successful as a food allergy treatment. Interleukin-10 (IL-10)-producing regulatory B cells (Br1s) play a role in immune tolerance to food allergens. In addition, IFN-γ shows tolerogenic effects on allergen-induced Br1 responses., Methods: Eleven patients that were allergic to cow's milk and 12 milk-tolerant subjects were selected by double-blind placebo-controlled food challenge (DBPCFC) and clinical characteristics. The immunomodulatory effects of IFN-γ on allergen-specific Br1 responses were evaluated in 6 milk allergy patients and 8 milk-tolerant subjects. Peripheral blood mononuclear cells (PBMCs) from subjects were stimulated with casein and/or IFN-γ and analyzed by flow cytometry., Results: IFN-γ had no effect on total cell counts or the proportion of Br1 cells in PBMCs. IFN-γ stimulation did not change total Br1 cell counts or the percentage of Br1s among CD5(+) B cells in the milk allergy or the milk-tolerant groups. In the milk allergy group, Br1 counts were not different between the control and the casein stimulation but significantly increased in the IFN-γ + casein stimulated cells, and the Br1 fractions were decreased after casein stimulation and recovered in the addition of IFN-γ for stimulation. In the milk-tolerant group, Br1 counts increased in the casein stimulated cells and in the IFN-γ + casein stimulated cells, but the increase was significantly less when IFN-γ was added, and the Br1 fractions were increased after casein stimulation and IFN-γ + casein stimulation, that was not significant when IFN-γ was added., Conclusions: IFN-γ-induced allergen-specific Br1 responses in the PBMCs of milk allergy patients play a role in milk allergen-specific tolerance induction in vitro. Further investigations into the molecular immunological mechanisms underlying the induction of allergen-specific Br1 responses are needed.

Anaphylaxis induced by exercise after the intake of certain foods is referred to as food-dependent exercise-induced anaphylaxis (FDEIA). Only the preventive medication such as oral sodium cromoglycate and oral combined cetirizine-montelukast was tried in FDEIA. Specific oral tolerance induction (SOTI) using IFN-gamma was tried in 2 cases of FDEIA for wheat. Merely, exercise accompanied every treatment just after the intake of allergenic foods during treatment. Patients acquired tolerance for wheat in both cases successfully. After treatment, two patients take wheat in their food living freely. Conclusively, SOTI using IFN-gamma was effective as the causative treatment for allergenic foods in FDEIA.

Atopic dermatitis is a chronic allergic inflammatory disease of the skin. Its pathophysiology involves an orchestrated sequence of allergic provocation by IgE-mediated and non-IgE-mediated Th2 responses to allergens. Allergen sensitization precedes the immunopathogenesis. Th2 cytokines such as IL-4 and IL-5 play a key role in both the sensitization and effector phases of allergic skin inflammation. Recently, the roles of new cytokines including IL-16, IL-17, IL-21, IL-22, IL-23, IL-27, IL-31, IL-33, IL-35 and thymus stromal lymphopoietin (TSLP), and Th2 polarization in the immunopathogenesis of skin inflammation and physically injured skin have been described, in addition to roles for IL-4, IL- 5, IL-9, IL-13, IFN-γ and TGF-β. Sensitization occurs via the skin for aeroallergen including house dust mites and superantigens and through the gastrointestinal tract for food allergens. Alternatively, food allergens can be sensitized through skin. Atopic dermatitis is described under the structure of sensitization phase and effector phase in this review. Especially, the clinically effective applications of cytokines in AD and relevant patents are updated in this review.

Atopic dermatitis is an immunologic disease that results in allergic inflammations of the skin. Cytokines are involved in the negative regulation of immunopathogenesis of atopic dermatitis. Negative immune regulation is also achieved by immune cells in addition to cytokines which are subsequently regulated by a counter-regulatory mechanism. Allergen tolerance is an important aspect of the treatment of atopic dermatitis. Recently, the IL-27, IL-21, and IL-10 cytokines were found to be important components of the counter regulatory mechanism that terminates immune response, and protects the host from excessive immune responses. IL-10 and TGF-β are well-known to be involved in the immune tolerance. IL-10 and IFN-γ are promising cytokines with respect to the prevention of allergen sensitization and the induction of allergen-specific tolerance. In particular, IFN-γ has unique tolerogenic effects with respect to pre-sensitized allergens, especially in atopic dermatitis. In this review, the role of cytokines in the immune tolerance and relevant patents are reviewed, and therapeutic strategies are presented based on the immunologic architecture of AD.

Background: Food allergies are important etiologic factors in atopic dermatitis. CD19 is a B-cell-specific cell-surface molecule, with a critical role in B-cell activation. Recently, B cells showed independent two subpopulations as CD19(high) and CD19(low). The allergen-specific responses of the CD19(high) and CD19(low) B-cell subpopulations were investigated in patients with non-IgE-mediated food allergy., Methods: Five milk-allergic subjects and eight milk-tolerant subjects were selected by a double-blind placebo-controlled food challenge. Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with casein or ovalbumin and stained with monoclonal antibodies to distinguish the B-cell subsets., Results: After allergen stimulation, CD19(high) B cells increased in the number and the fraction in PBMCs in the milk-tolerant group, whereas those remained unchanged in the milk-allergic group. These responses were constant, regardless of the kind of food allergen (milk or egg). The resulting CD19(high)/CD19(low) B-cell ratio increased markedly in the milk-tolerant group after allergen stimulation, but was unchanged in the milk-allergic group. IL-10, IL-17, IL-32 and TGF-β- producing regulatory B cells and Foxp3-expressing regulatory B cells were identified predominantly on CD19 low and CD5(+) B cells., Conclusions: The response of the CD19(high) B-cell subpopulation to allergen stimulation is decisive for immune tolerance of non-IgE-mediated food allergy in atopic dermatitis. CD19 high and CD5(+) B cells dominantly produce cytokines and express Foxp3. Especially, IL-17 and IL-32 expressing B cells (Br17 & Br32) are present. The exact immunological role of CD19 and cytokines including IL-17 and IL-32 around B cells in immune tolerance requires further investigation.

Busulfan is an antineoplastic agent with a narrow therapeutic window. A post-hoc population pharmacokinetic analysis of a prospective randomized trial for comparison of four-times daily versus once-daily intravenous busulfan was carried out to search for predictive factors of intravenous busulfan (iBu) pharmacokinetics (PK). In this study the population PK of iBu was characterized to provide suitable dosing recommendations. Patients were randomized to receive iBu, either as 0.8 mg/kg every 6 h or 3.2 mg/kg daily over 4 days prior to hematopoietic stem cell transplantation. In total, 295 busulfan concentrations were analyzed with NONMEM. Actual body weight and sex were significant covariates affecting the PK of iBu. Sixty patients were included in the study (all Korean; 23 women, 37 men; mean [SD] age, 36.5 [10.9] years; weight, 66.5 [11.3] kg). Population estimates for a typical patient weighing 65 kg were: clearance (CL) 7.6 l/h and volume of distribution (V(d)) 32.2 l for men and 29.1 L for women. Inter-individual random variabilities of CL and V(d) were 16% and 9%. Based on a CL estimate from the final PK model, a simple dosage scheme to achieve the target AUC(0-inf) (defined as median AUC(0-inf) with a once-daily dosage) of 26.18 mg/l·hr, was proposed: 24.79·ABW(0.5) mg q24h, where ABW represents the actual body weight in kilograms. The dosing scheme reduced the unexplained interindividual variabilities of CL and Vd of iBu with ABW being a significant covariate affecting clearance of iBU. We propose a new simple dosing scheme for iBu based only on ABW.

Food allergies are classified as IgE-mediated and non-IgE mediated type. The number of successful reports of immunotherapy, namely tolerance induction for food allergy (TIFA) are increasing, bringing hope for meaningful positive and radical treatment of food allergy. Therapeutic characteristics of the clinical course in TIFA for NFA are different from TIFA for IFA. Cytokines including IL-10, TGF-β and IFN-γ and regulatory cells such as Treg and Breg, are involved in immune tolerance. IFN-γ has been used for tolerance induction of food allergy as an immunomodulatory biologics. A definitive distinction between IgE-mediated and non-IgE-mediated food allergies is absolutely essential for diagnostic and therapeutic purposes. Original SOTI using IFN-γ is more effective then conventional SOTI without IFN-γ. Especially, IFN-γ is absolutely necessary for the tolerance induction of NFA. This review highlights and updates the advances in the conceptual immunological background and the clinical characteristics of oral tolerance induction for food allergy.

Atopic dermatitis is an allergic inflammatory skin disease that is characterized by late eczematous skin lesions which result from non-IgE-mediated immune responses. It is well known that food allergy is an important cause of atopic dermatitis. Moreover, with recent advances in the diagnosis and treatment of food allergy, it becomes possible to elucidate the role of IgE- and non-IgE-mediated food allergies. Interprerations for blood eosinophil counts and total serum IgE levels are updated based on the immunopathogenesis of AD relating with these IgE- and non-IgE-mediated food allergies. The clinical significances of skin prick test and allergen-specific IgE are re-evaluated according to the out-to in and in-to out sensitization. Atopic march is reconsturcted by the sequential sensitization of foods and aeroallergens. In this review, the revized immunopathogenesis and relevant interpretations of food allergy in atopic dermatitis are described for the evaluation of precise clinical status of AD., (© 2012 Bentham Science Publishers)

Foxp3-expressing cells among CD19(+)CD5(+) B cells were identified as regulatory B cells. Food allergy manifesting as late eczematous reactions is regarded as a non-IgE-mediated food allergy. The diagnosis for milk allergy manifesting as late eczematous reactions was made on the basis of the findings obtained from a double-blind placebo-controlled food challenge in patients with atopic dermatitis. Twelve patients with milk allergy and 12 patients who could tolerate milk were selected. On casein stimulation, the CD19(+)CD5(+)Foxp3(+) B cell (Breg) fraction in CD5(+) B cells decreased from 4.4±1.1% to 3.1±0.7% (P=0.047, n=12) in the milk allergy group and increased from 4.4±1.3% to 5.2±1.4% (P=0.001, n=10) in the milk-tolerant group. On the other hand, on allergen stimulation, the number of CD4(+)Foxp3(+) regulatory T cells (Tregs) in the milk allergy group and milk-tolerant group increased from 2.6±0.7% to 3.4±0.6% (P=0.014, n=9) and from 2.7±1.0% to 3.5±1.0% (P=0.038, n=10), respectively. In conclusion, allergen-specific responses of Bregs, rather than those of Tregs, seem to influence the immune responses (i.e., allergy or tolerance) to a food allergen., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In this study, specific oral tolerance induction using interferon-gamma (IFN-γ) could successfully treat food allergies. Allergen-specific IL-10-producing regulatory B cell (Br1) responses are characteristic in immune tolerance of food allergies. The in-vivo effects of IFN-γ on allergen-induced changes in Br1 proportion and numbers in food allergies were investigated. Oral food challenges were conducted and 20 allergic patients to cow's milk were selected. Of these 20 patients, five were treated with IFN-γ and milk (SOTI group), five were treated with only milk, five were treated with only IFN-γ, and five did not receive any treatment. In addition, 10 milk-tolerant subjects were involved in this study. Peripheral blood mononuclear cells (PBMCs) were stimulated using casein and stained for CD5, CD19, annexin V, and IL-10 before and after treatment. Allergy tolerance was induced only in the SOTI group along with induction of allergen-induced Br1 changes. Thus, IFN-γ can show tolerogenic effects in vivo when introduced with an allergen, which may be at least partly due to its effect on allergen-induced Br1 responses., (Copyright © 2012 Elsevier Inc. All rights reserved.)

IL-10 production by CD19(+)CD5(+) B cells was investigated, by determining the expression levels of CD19, a classical B cell marker. Peripheral mononuclear cells were stained with fluorescence-conjugated anti-CD5, anti-CD19, anti-IL-10, and Annexin V. Interestingly, IL-10-producing B cells were found to be localised within the CD19(low)CD5(+) B cell subset. Apoptotic changes were also observed mainly in CD19(low) cells among B cells. Thus, CD5(+) B cells should be classified as CD19(high) and CD19(low) cells, and the immunological significance of CD19 for the IL-10 production by CD5(+) B cells requires further studies.

B cells are generally considered to positively regulate immune responses by producing antigen-specific antibodies. B cells are classified into classical CD5(-) conventional B cells and CD5(+) B1 cells. The latter produce multi-specific autoantibodies and are thought to be involved in autoimmune diseases. However, evidence supporting a B cell negative regulatory function has accumulated over the past 30 years. Multiple reports have suggested that absence, or loss, of regulatory B cells exacerbates symptoms of both allergic (including contact hypersensitivity and anaphylaxis) and autoimmune (such as experimental autoimmune encephalomyelitis, chronic colitis, and collagen-induced arthritis) diseases, and in lupus-like models of autoimmunity. Regulatory B cells are characterized by production of the negative regulatory cytokines, IL-10 and TGF-β. IL-10-producing B cells were the first regulatory B cells to be recognized and were termed 'B10' cells. IL-10-producing regulatory B cells are of the CD19(+)CD5(+)IgM(hi)IgD(lo)CD1d(hi) type. Recently, a TGF-β-producing regulatory B cell subset, Br3, has been shown to be related to immune tolerance in food allergies. Moreover, forkhead box P3 (Foxp3)-expressing B cells have also been identified in humans and may act as regulatory B cells (Bregs). The functional image of regulatory B cells is similar to that of regulatory T cells. Because of the proliferative and apoptotic responses of Br1 and Br3 cells in immune tolerance in non-IgE-mediated food allergy, reciprocal roles and counter-regulatory mechanisms of Br1 and Br3 responses are also suspected. Additionally, different roles for regulatory B and T cells at different time points during initiation and progression of autoimmune disease are described.

The prevalence of atopic dermatitis (AD) in school-age children has increased in industrialized countries. As diet is one of the main factors provoking AD, some studies have suggested that food additives in processed foods could function as pseudoallergens, which comprise the non-immunoglobulin E-mediated reaction. Eosinophil cationic protein (ECP) is an eosinophil granule protein released during allergic reactions to food allergens in patients with AD. Thus, serum ECP levels may be a useful indicator of ongoing inflammatory processes in patients with AD. The purpose of this study was to investigate the effect of consuming MSG in processed foods on serum ECP levels among children with AD. This study was performed with 13 patients with AD (age, 7-11 years) who had a normal range of total IgE levels (< 300 IU/ml). All participants ate normal diets during the first week. Then, six patients were allocated to a processed food-restricted group (PRDG) and seven patients were in a general diet group (GDG). During the second week, children in the PRDG and their parents were asked to avoid eating all processed foods. On the third week, children in the PRDG were allowed all foods, as were the children in the GDG throughout the 3-week period. The subjects were asked to complete a dietary record during the trial period. Children with AD who received the dietary restriction showed decreased consumption of MSG and decreased serum ECP levels and an improved SCORing score on the atopic dermatitis index (P < 0.05). No differences in serum ECP levels or MSG consumption were observed in the GDG. Serum total IgE levels were not changed in either group. In conclusion, a reduction in MSG intake by restricting processed food consumption may lead to a decrease in serum ECP levels in children with AD and improve AD symptoms.

CD19(+)CD5(+) regulatory B cells produce transforming growth factor β (TGF-β) in both mouse and human B-cell leukemias. In this study, TGF-β was uniquely produced by normal human regulatory B cells. TGF-β-producing regulatory B-cell (Br3) responses were characterized through allergic responses to cow's milk. In total, 10 subjects allergic to milk and 13 milk-tolerant subjects were selected following double-blinded, placebo-controlled food challenges. Their peripheral blood mononuclear cells were stimulated in vitro with casein. Following allergen stimulation, the percentage of Br3s among CD5(+) B cells decreased from 11.5% ± 13.7% to 8.0% ± 9.6% (P = 0.042, n = 5) in the milk-allergy group and increased from 14.7% ± 15.6% to 18.9% ± 20.1% (P = 0.006, n = 7) in the milk-tolerant group. However, the numbers of Br3s increased only in the milk-tolerant group, from 1,954 ± 1,058 to 4,548 ± 1,846 per well (P = 0.026), whereas the numbers of Br3s in the milk-allergy group were unchanged [2,596 ± 823 to 2,777 ± 802 per well (P = 0.734)]. The numbers of apoptotic events were similar to the numbers of total Br3 responses. The percentage of non-TGF-β-producing CD5(+) B cells with apoptotic changes increased from 13.4% ± 17.1% to 16.4% ± 20.3% (P = 0.047, n = 5) in the milk-allergy group and remained unchanged [from 9.9% ± 11.9% to 9.3% ± 11.4% (P = 0.099, n = 7)] in the milk-tolerant group. Using carboxyfluorescein succinimidyl ester labeling, we observed that the percentage of proliferating Br3s among CD5(+) B cells was unchanged [from 6.1% ± 2.8% to 6.4% ± 2.9% (P = 0.145)] in the milk-allergy group and increased from 6.8% ± 3.9% to 10.2% ± 5.3% (P = 0.024) in the milk-tolerant group. In conclusion, Br3s proliferated in response to allergen stimulation in the milk-tolerant group and not in the milk-allergy group. TGF-β-producing regulatory B cells (Br3) may be involved in allergy tolerance by negatively regulating the immune system with TGF-β, and this negative regulation may be controlled by apoptosis.

Foxp3 is a transcript factor for regulatory T cell development. Interestingly, Foxp3-expressing cells were identified in B cells, especially in CD19(+)CD5(+) B cells, while those were not examined in CD19(+)CD5(-) B cells. Foxp3-expressing CD5(+) B cells in this study were identified in human PBMCs and were found to consist of 8.5±3.5% of CD19(+)CD5(+) B cells. CD19(+)CD5(+)Foxp3(+) B cells showed spontaneous apoptosis. Rare CD19(+)CD5(+) Foxp3(+) regulatory B cell (Breg) population was unveiled in human peripheral blood mononuclear cells and suggested as possible regulatory B cells (Breg) as regulatory T cells (Treg). The immunologic and the clinical relevant of Breg needs to be further investigated.

Food allergies are classified as IgE-mediated food allergies (IFAs) and non-IgE-mediated food allergies (NFAs). Recently, oral immunotherapy (OIT) has been found to be successful for treating both IFA and NFA, especially using interferon (IFN) gamma. This study was designed to clarify the clinical characteristics of IFA and NFA and compare the therapeutic characteristics of OIT using subcutaneously administered IFN-gamma for both types of food allergy. In this study, 148 patients were categorized into the IFA and NFA group following food challenge, skin-prick test and food-specific IgE tests. The patients were then treated using protocols specific for IFA and NFA using subcutaneous IFN-gamma injection as a randomized controlled trial. The principle of complete allergy resolution at prior dose in the case of IFA was also evaluated. Only the patients with IFA and NFA treated with OIT using IFN-gamma achieved tolerance successfully. Tolerance was achieved from low-dose range in IFA and in high-dose range for NFA. Complete tolerance was not obtained without achieving complete allergy resolution at each dose of the allergen before increasing the dosage in IFA. Both IFA and NFA can be successfully treated with OIT using IFN-gamma but show different clinical and therapeutic characteristics. IFN-gamma is necessary for the tolerance induction but not for tolerance maintenance. Additional study for the mechanisms of tolerance induction by IFN-gamma is needed.

Food allergy plays an important role in atopic dermatitis (AD). Adequate predictors and guidelines for when dietary manipulation is indicated for AD are needed. The clinical significance of eosinophilia as a predictor for food allergy of late eczematous reactions in AD was investigated. Three hundred three patients with AD were studied, using elimination diets and food challenge tests. Food allergy prevalence was compared in groups of eczematoid AD patients with high or normal eosinophil levels. The effects on the blood eosinophil fraction of an elimination diet and milk allergy provocation of late eczematous reactions were evaluated. The prevalence of food allergy was 51.1% (135/264) in patients with eczematoid AD. The major type of food allergy in AD was late eczematous, rather than IgE mediated. Among eczematoid AD patients, 44.9% had high eosinophil levels. In patients with eczematoid AD, the food allergy prevalence was 70.8% (85/120) in the high eosinophil group and 34.7% (50/144) in the normal blood eosinophil group. An elimination diet improved clinical severity and decreased blood eosinophil levels. In milk allergy patients, a milk challenge significantly increased the blood eosinophil level. Skin-prick tests and food-specific IgE tests were useful for diagnosing IgE-mediated food allergy. Eosinophilia appeared to be a significant predictor of food allergy in AD and an indicating factor for diet manipulation, including an elimination diet. Food allergy may be responsible for eosinophilia in AD. Food allergy patterns for AD in Korea were different from those in western countries.

CD19+CD5+ regulatory B cells regulate immune responses by producing IL-10. IL-10-producing regulatory B cell (Br1) responses by allergen stimulation were investigated in human food allergy. Six milk allergy patients and eight milk-tolerant subjects were selected according to DBPCFC. PBMCs were stimulated by casein in vitro and stained for intracellular IL-10 and apoptosis. In response to allergen stimulation, Br1 decreased from 26.2+/-18.3 to 15.5+/-8.9% (p=0.031, n=6) in the milk allergy group and increased from 15.4+/-9.0 to 23.7+/-11.2% (p=0.023, n=8) in the milk-tolerant group. Apoptotic non-IL-10-producing regulatory B cells increased from 21.8+/-9.3 to 38.0+/-16.1% (p=0.031, n=6) in the milk allergy group and unchanged from 28.8+/-13.8 to 28.0+/-15.0% (p=0.844, n=8) in the milk-tolerant group. Br1 may be involved in the immune tolerance of food allergies by producing IL-10 and simultaneously undergoing apoptosis in humans. The exact roles for Br1 in immune tolerance needs to be further investigated., (Copyright 2010 Elsevier Inc. All rights reserved.)

B cells have regulatory functions in immune responses. Antigen-specific responses of B cell subsets by allergen stimulation ex vivo were examined in milk allergy of late eczematous reactions. Eight milk allergy subjects and 13 milk tolerant subjects were selected by DBPCFC. PBMCs were stimulated by casein ex vivo and stained for B cell subsets using monoclonal antibodies. CD19+ B cells unchanged from 8.7+/-3.8% to 8.0+/-5.1% (p=0.504, n=8) in the milk allergy group and decreased in the milk tolerant group from 8.5+/-3.2% to 5.0+/-1.6% (p=0.001, n=13). The fraction of apoptotic B cells in B cells significantly decreased 4.4+/-3.1% to 1.3+/-0.4% (p=0.027, n=4) in the allergy group and insignificantly increased from 2.8+/-0.6% to 5.4+/-2.6% (p=0.059, n=6) in the milk tolerant group. CD5+ regulatory B1 cell% in B cells decreased in milk allergy subjects from 36.2+/-5.0% to 31.0+/-5.7% (p=0.010) and unchanged in milk tolerant subjects from 41.6+/-10.2% to 43.8+/-10.0% (p=0.413). IL-10 producing CD19+CD5+ regulatory B cell% in CD19+CD5+ regulatory B cells significantly decreased from 24.9+/-6.5% to 13.8+/-5.6% (p=0.002, n=5) by casein stimulation in milk allergy group and unchanged from 44.8+/-11.3% to 43.9+/-10.0% (p=0.297, n=5) in the milk tolerant group. B cell subset responses to IL-4 and IL-5 were also similar in both groups. B cell subset changes seemed to have diagnostic value. Exact immunologic roles of regulatory CD5+ B1 cells need further investigation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Food-induced anaphylaxis is a life-threatening, IgE-mediated disease. No specific therapeutic recommendations, aside from the avoidance of offending foods, exist at this time. However, specific oral tolerance induction for food allergy has been investigated by several groups. In this study, specific oral tolerance induction was attempted using interferon-gamma (IFN-gamma) as an adjuvant for IgE-mediated anaphylactic food allergies. A total of 25 patients with IgE-mediated anaphylactic food allergy to milk, eggs, or wheat were selected. IFN-gamma-induced specific oral tolerance induction (ISOTI) was conducted on 10 patients, while five patients were only treated with food, five patients received only IFN-gamma therapy, and five patients did not receive any treatment. Tolerance for IgE-mediated anaphylactic food allergy was successfully induced in all patients (10/10) with ISOTI, while no patients acquired tolerance for allergenic foods in the control groups. Food-specific IgE levels were increased, and skin prick test reactions significantly decreased after the completion of ISOTI. IFN-gamma-induced specific oral tolerance induction (ISOTI) is a promisingly effective treatment for IgE-mediated anaphylactic food allergy. IFN-gamma may be an important cytokine in tolerance induction. Simultaneous allergen stimulation with nonspecific immunomodulation of IFN-gamma was essential for specific tolerance induction in IgE-mediated anaphylactic food allergy.

Food is closely associated with the pathogenesis of atopic dermatitis. Food allergy is usually mediated by IgE antibody to specific food proteins and determination of specific IgE antibody is the basis of the common diagnostic test for food allergy. IgG4 have been reported as blocking antibody and the protective effects of blocking antibody may be clear in inhalant allergy. However, the role of IgG4 in food allergy is still a matter of debate. In this study, the clinical significance of food allergen-specific IgE/IgG4 in atopic dermatitis was investigated and compared with that of IgE. A total of 97 patients who fulfilled the diagnostic criteria for atopic dermatitis participated in this study. Skin prick test and allergy patch test were performed. Specific IgE and IgG4 concentration were measured using allergy protein chip, 'AllergyChip'. Double blinded placebo controlled food challenge test (DBPCFC) was performed for the diagnosis of allergy to milk, egg white, wheat, and soybean. DBPCFCs for milk, egg white, soybean, and wheat were performed. The positive rates were 31.7% (19/60) in milk, 36.7% (18/49) in egg white, 30.4% (7/23) in soybean, and 34.8% (8/23) in wheat. Mean IgE/IgG4 levels in DBPCFC (+) subjects is higher than those in DBPCFC (-) subjects in all food items studied. Of them, there were significantly different between two groups in egg white and wheat (Egg white in DBPCFC (+) vs. (-): 0.4 +/- 0.3 vs. 0.2 +/- 0.2, wheat in DBPCFC (+) vs. (-): 1.2 +/- 1.2 vs. 0.3 +/- 0.3, p < 0.05). Allergen-specific IgE/IgG4 may provide one of the clues to understand the mechanism of food allergy in atopic dermatitis. The present study suggests that protein microarray can be one of the useful methods to assess ongoing status of allergic diseases.

Osteopontin (OPN) is expressed in atherosclerotic lesions, particularly in diabetic patients. To determine the role of OPN in atherogenesis, ApoE-/-OPN+/+, ApoE-/-OPN+/-, and ApoE-/-OPN-/- mice were infused with Ang II, inducing vascular OPN expression and accelerating atherosclerosis. Compared with ApoE-/-OPN+/+ mice, ApoE-/-OPN+/- and ApoE-/-OPN-/- mice developed less Ang II-accelerated atherosclerosis. ApoE-/- mice transplanted with bone marrow derived from ApoE-/-OPN-/- mice had less Ang II-induced atherosclerosis compared with animals receiving ApoE-/-OPN+/+ cells. Aortae from Ang II-infused ApoE-/-OPN-/- mice expressed less CD68, C-C-chemokine receptor 2, and VCAM-1. In response to intraperitoneal thioglycollate, recruitment of leukocytes in OPN-/- mice was impaired, and OPN-/- leukocytes exhibited decreased basal and MCP-1-directed migration. Furthermore, macrophage viability in atherosclerotic lesions from Ang II-infused ApoE-/-OPN-/- mice was decreased. Finally, Ang II-induced abdominal aortic aneurysm formation in ApoE-/-OPN-/- mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocyte-derived OPN in mediating Ang II-accelerated atherosclerosis and aneurysm formation.

Skin Prick Test (SPT's) are performed to identify the causes of allergy. However, low diagnostic accuracy is a limitation to SPT, for which many possible causes have been suggested. The protein composition and allergenicity of crude allergen extracts from foods and commercial allergen extracts for SPT were analyzed. Clinical significances of SPT using crude allergen extracts from foods were compared with those using commercial allergen extracts. A total of 292 atopic dermatitis patients were involved in this study. Crude allergen extracts were prepared from milk, egg white, egg yolk, and soybean. The protein composition of food allergen extracts and commercial allergen extracts of milk, whole egg, white, egg yolk, and soybean were compared by SDS-PAGE. The allergenicity was tested by the immunoblotting method using immune sera. SPTs were performed using crude and commercial allergen. Double-blind placebo- controlled food challenge (DBPCFC) was performed to verify the SPT results and to compare the clinical significance of crude and commercial allergen extracts. Protein composition differed markedly between crude and commercial allergen extracts. By immunoblotting, crude and commercial allergen extracts showed different allergenicity. The SPT results using crude and commercial allergen extracts showed significant differences. The prevalence of milk, egg and soybean allergy was over 35% in atopic dermatitis. The accuracy of SPT using crude allergen extracts from foods was significantly higher than that using commercial allergen extracts. In the case of soybeans, the result of SPT using commercial allergen extract was clinically insignificant for the prediction of soybean allergy. The source of allergen extract was very important for the appropriate SPT in food allergy. The accuracy of SPT might be improved using the appropriate allergen source for food allergy.

Type I allergy is an immunoglobulin E (IgE)-mediated hypersensitivity disease inflicting more than quarter of the world population. In order to identify allergen sources, skin provocation test and IgE serology was performed using allergen extracts. Such process identifies allergen-containing sources but cannot identify the disease-eliciting allergenic molecules. Recently, microarray technology has been developed for allergen-specific IgE detection using rolling circle amplification. This study was carried out to evaluate protein chip technology for the quantitative measurement and limits of sensitivity of multiple allergen-specific IgE by an immunofluorescence assay. Significance of positive calibrators was tested using purified human IgE. Dermatophagoides pteronyssinus (Dp), egg white, milk, soybean, and wheat were used as allergens and human serum albumin as negative control. Sensitivity and clinical efficacy of protein chip were evaluated using allergy immune serum for Dp. The fluorescent intensities for purified human IgE as calibrator were well correlated with the concentrations of human IgE. Two-fold dilution of serum allowed an optimal reaction with Dp (1 mg/ml) at which serum Dp-specific IgE levels by protein chip were compatible with those by UniCap. The sensitivity of protein chip in this study was found at level of 1 IU/ml of IgE. Dp-specific IgE levels by protein chip correlated well with those of UniCap by comparing 10 atopic dermatitis. Additional 18 sera were tested for above multiple antigens other than Dp and significant results were obtained for many antigens as well as Dp. These results indicated that spotting of heterogeneous protein mixture on protein chip and the quantitative measurement of serum allergen-specific IgE levels using immunofluorescence assay can be successfully applied in the clinical laboratory for the diagnosis of allergy and could be applied to diagnosis of autoimmune and infectious diseases

The nuclear receptors LXRalpha and LXRbeta have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR(-/-) mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE(-/-) mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR(-/-) and apoE(-/-) mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages in vitro as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.

Determining positive food challenges are not easy as there is an absence of simple and objective tests. Histamine, an essential mediator for allergic reactions, is involved in the pathogenesis of atopic dermatitis (AD) and food challenges can change histamine levels. The significances of a prick test with histamine (histamine prick test, HPT) relating to the interpretation of food challenges in AD were evaluated. A total of 467 AD patients participated in this study. Skin prick tests, identification of specific IgE and open food challenge were conducted for the identification of food allergy. Elimination diet was performed with HPT. HPTs were conducted before and after food challenges. The wheal sizes by HPT were significantly decreased after an elimination diet. The relative changes of wheal sizes significantly correlated with those of clinical severity scores in AD patients (p<0.001). The wheal sizes in HPT were increased with a positive provocation in open food challenges. In conclusion, HPT may be a simple and objective test to interprete the results of food challenges in patients with AD. The exact mechanisms of the changes in skin reactivity by HPT need further investigation.

The avoidance of incriminated foods is one of the principal therapies for atopic dermatitis (AD). Recently, interferon (IFN)-gamma therapy has been tried in AD with limited success. The necessity of diet therapy for the success of IFN-gamma therapy in AD was evaluated. A total of 524 AD patients participated in this study and 316 patients among them were entered into open food challenge tests. As the first step, an elimination diet was administered to 43 AD patients and 30 AD patients were enrolled as an untreated control group. As the second step, 45 AD patients were treated by both IFN-gamma therapy and elimination diet alone, 30 AD patients by elimination diet alone, 50 AD patients by IFN-gamma therapy, and 43 AD patients as controls. Clinical severity reduced significantly by using only the elimination diet in 58.1% patients with varying degrees of AD. Elimination diet improved the clinical results of IFN-gamma therapy in AD. In regard to the food challenge test, 77.8% of AD patients showed an adverse reaction to at least one food. Diet therapy itself had therapeutic effects on AD and an elimination diet might be essential for the success of IFN-gamma therapy in AD.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated nuclear receptor expressed in all of the major cell types found in atherosclerotic lesions: monocytes/macrophages, endothelial cells, and smooth muscle cells. In vitro, PPARgamma ligands inhibit cell proliferation and migration, 2 processes critical for vascular lesion formation. In contrast to these putative antiatherogenic activities, PPARgamma has been shown in vitro to upregulate the CD36 scavenger receptor, which could promote foam cell formation. Thus, it is unclear what impact PPARgamma activation will have on the development and progression of atherosclerosis. This issue is important because thiazolidinediones, which are ligands for PPARgamma, have recently been approved for the treatment of type 2 diabetes, a state of accelerated atherosclerosis. We report herein that the PPARgamma ligand, troglitazone, inhibited lesion formation in male low density lipoprotein receptor-deficient mice fed either a high-fat diet, which also induces type 2 diabetes, or a high-fructose diet. Troglitazone decreased the accumulation of macrophages in intimal xanthomas, consistent with our in vitro observation that troglitazone and another thiazolidinedione, rosiglitazone, inhibited monocyte chemoattractant protein-1-directed transendothelial migration of monocytes. Although troglitazone had some beneficial effects on metabolic risk factors (in particular, a reduction of insulin levels in the diabetic model), none of the systemic cardiovascular risk factors was consistently improved in either model. These observations suggest that the inhibition of early atherosclerotic lesion formation by troglitazone may result, at least in part, from direct effects of PPARgamma activation in the artery wall.

A randomized case-controlled study was carried out to investigate for interferon alpha therapy in atopic dermatitis (AD) of Besnier's prurigo pattern with normal serum IgE and normal blood eosinophil fraction. Interferon alpha therapy was conducted on 14 non-responders to interferon gamma and subsequent thymopentin therapy among 100 atopic dermatitis patients. Eight patients who improved significantly, showed skin lesions of the Besnier's prurigo pattern with normal serum IgE and normal blood eosinophil fraction. For the randomized prospective case-controlled study, 44 patients with the above characteristics were selected. Thirteen Besnier's prurigo patients were treated with interferon alpha therapy, ten with interferon gamma, ten with thymopentin, and the remaining 11 were untreated as the control group. With interferon alpha therapy, 11 out of 13 Besnier's prurigo patients with normal IgE and normal blood eosinophil fraction improved significantly, two out of ten improved with interferon gamma therapy, and none improved with thymopentin therapy or in the untreated control group. Interferon alpha therapy was effective on AD of Besnier's prurigo pattern with normal serum IgE and normal blood eosinophil fraction. These results suggest the possibility of non-IgE-mediated AD and the heterogeneity of atopic dermatitis., (Copyright 2001 Academic Press.)

Unlabelled: We evaluated whether a thermosoftening treatment with warm saline of a nasotracheal preformed tube can improve navigability through the nasal passageways and reduce epistaxis and nasal damage. A total of 150 patients were randomly allocated to three groups: Group I (untreated tube group, n = 50), Group II (35 degrees C treated tube group, n = 50), and Group III (45 degrees C treated tube group, n = 50). In Groups II and III, the tubes were softened at 35 +/- 2 degrees C and 45 +/- 2 degrees C with warm saline, respectively. In Group I the tube was prepared at room temperature (25 +/- 2 degrees C). The incidence of epistaxis and nasal damage in Groups II and III was significantly less than that of Group I (P: < 0.05). Despite the more frequent incidence of smooth passage in Group III, no statistical difference was found among the groups. Logistic regression analysis also confirmed that epistaxis was more likely to be reduced when the tube had been thermosoftened (odds ratio = 1.46, 95% confidence interval = 1.02, 2.11). We conclude that simple thermosoftening treatment of the nasotracheal tube with warm saline helps to reduce epistaxis and nasal damage., Implications: Thermosoftening treatment of a nasotracheal tube with warm saline before intubation can effectively reduce epistaxis and nasal damage. This technique is safe, easy, and suitable for all types of tubes and does not require additional implements.

IFN-gamma/IL-4 imbalance is a central immunologic defect which is responsible for increased IgE antibody response in atopic dermatitis. Effects of hyposensitization were controversial in atopic dermatitis. Reversed IFN-gamma/IL-4 balance was induced using IFN-gamma in atopic dermatitis and specific hyposensitization with house dust mites (HDM) was tried in the status of IFN-gamma-induced immune deviation. A total of 58 atopic dermatitis patients who had obvious allergy to HDM were selected in this study. IFN-gamma-induced hyposensitization for HDM was tried in 10 patients. Twenty-two patients received IFN-gamma therapy and six were treated by simple hyposensitization. Twenty were enrolled as control subjects. The clinical severity scores decreased effectively only by IFN-gamma-induced hyposensitization for HDM. Specific hyposensitization for HDM in the status of IFN-gamma-induced immune deviation successfully improved atopic dermatitis. HDM might play a pathogenic role in subpopulation of atopic dermatitis.

Many trials have been done on steroid-resistant atopic dermatitis. Recently, intravenous immune globulin (i.v.IG) was reported to be effective in the treatment of steroid-dependent atopic dermatitis. The aim of this study was to clarify whether i.v.IG therapy is effective in steroid-resistant atopic dermatitis. Forty-one steroid-resistant atopic dermatitis patients were tested in this study. Patients who weighed less than 30 kg were administered 500 mg/kg of i.v.IG. Patients who weighed 30 kg or more were administered 15 g of i.v.IG. Patient evaluations and laboratory tests with peripheral bloods such as eosinophil percentages and serum IgE levels were performed at days 0, 1, 7, and 21. In the present study, patients who responded to i.v.IG therapy were classified as Group A. Twelve patients who showed transient effects with lower clinical significance were classified as Group B (29.3%). Remaining 12 patients (29.3%) in Group C showed no improvement at all. Serum IgE levels and blood eosinophil percentages were markedly decreased in Group A. I.v.IG therapy may be recommended in the treatment of atopic dermatitis with extremely high serum IgE levels.