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Background: Autoantibodies (AAbs) against immunoglobulin E (IgE) antibodies (Abs) and their high-affinity receptor alpha subunits (FcεRIα) are key factors in the elicitation of type IIb autoimmune chronic spontaneous urticaria (type IIb aiCSU). In this study, we aimed to develop a new method to detect functional anti-FcεRIα and anti-IgE AAbs, which can crosslink the plural FcεRІα molecules and IgE Abs on the surface of mast cells and basophils, in sera from aiCSU patients using the amplified luminescence proximity homogeneous assay (Alpha)., Methods: Sera were obtained from 14 aiCSU patients, as diagnosed by recurrent chronic spontaneous urticaria episodes and positive results for the autologous serum skin test and/or histamine release test (HRT). The AAbs to FcεRIα and IgE Abs were determined in sera from aiCSU patients using enzyme-linked immunosorbent assay (ELISA) and Alpha by cross-linking (AlphaCL) of IgE Abs and/or FcεRІα., Results: Serum anti-FcεRIα and anti-IgE AAb levels were not significantly different between aiCSU patients and healthy subjects in ELISA. Anti-FcεRIα AAbs were detected in 10 of 14 aiCSU patients who displayed positive (5/5) and negative (5/9) results in the HRT for anti-FcεRIα AAbs by AlphaCL, whereas no signals were observed in healthy subjects. Additionally, anti-IgE AAbs were detected in two of four aiCSU patients who displayed positive results in the HRT for anti-IgE AAbs., Conclusions: A new assay method using AlphaCL can detect anti-FcεRIα and anti-IgE AAbs with FcεRIα- and IgE-crosslinking abilities in sera from aiCSU patients. This simple and practical assay method may be available as a diagnostic tool for urticaria patients., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Atopic dermatitis (AD) mostly develops in early childhood and tends to resolve with age. However, its time course in severity before and after adolescence varies widely among patients. To investigate the course of disease severity from birth to 19 years old of adult patients with AD, we conducted a nationwide Web-based survey of 3090 Japanese adult subjects diagnosed with AD, using a questionnaire to choose a pattern that most resembled their own out of 10 courses of AD severity. Patients in the 20s and 30s age groups tended to choose the option "gradually improved" or "improved by the age of 12", but patients in the 40s or older age group tended to choose the option "aggravation between the age of 12 and 19". Those who chose "AD development at age 20 or older" increased as the generation was older. This survey revealed that the time course of AD severity from birth to 19 years old varies depending on the generation targeted in this study. It is presumed that the acquired factors affecting the natural history of AD have changed over the past 50 years in Japan., (© 2021 Japanese Dermatological Association.)

Background: Recurrent angioedema (RecAE) has a substantial impact on patients' daily lives. However, there have been no disease-specific patient-reported outcomes (PROs) available in Japan to measure disease activity and health-related QoL impairment in such patients., Methods: Japanese versions of the Angioedema Activity Score (AAS) and the Angioedema Quality of Life Questionnaire (AE-QoL) were examined for their validity and reliability. By using these questionnaires, the relationship between disease activity and QoL impairment among the Japanese population of RecAE were analyzed in real-world setting., Results: The Japanese AAS and AE-QoL domains showed good internal consistency of 0.967 and > 0.835. For known group validity, AAS28 and AE-QoL total scores were higher in more severe patients than those with milder disease and QoL impairment, respectively. AAS28 showed strong correlation with indexes of disease activity, while the AE-QoL total score correlated with Dermatology Life Quality Index (DLQI). Sufficient reproductivity of the AAS and AE-QoL was shown by their intraclass correlation coefficients of 0.890 and 0.700. The Japanese population is characterized by the total score of AAS28, 34.3 ± 38.8 (mean ± SD); and AE-QoL, 38.7 ± 25.2. Each domain score of AE-QoL was 32.4 ± 29.7 in "Functioning", 35.0 ± 27.8 in "Fatigue/mood", 50.7 ± 30.6 in "Fears/shame", or 24.7 ± 29.8 in "Food". Changes in AAS28 and AE-QoL positively correlated to Patient global assessment of disease activity and DLQI, respectively., Conclusions: The Japanese AAS and AE-QoL are valid and reliable instruments for Japanese patients with RecAE, and active disease affecting QoL. They help assess disease activity and QoL of RecAE in routine patient care and clinical trials., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by an almost daily recurrence of wheal and flare with itch for more than 6 weeks, in association with the release of stored inflammatory mediators, such as histamine, from skin mast cells and/or peripheral basophils. The involvement of the extrinsic coagulation cascade triggered by tissue factor (TF) and complement factors, such as C3a and C5a, has been implied in the pathogenesis of CSU. However, it has been unclear how the TF-triggered coagulation pathway and complement factors induce the activation of skin mast cells and peripheral basophils in patients with CSU. In this review, we focus on the role of vascular endothelial cells, leukocytes, extrinsic coagulation factors and complement components on TF-induced activation of skin mast cells and peripheral basophils followed by the edema formation clinically recognized as urticaria. These findings suggest that medications targeting activated coagulation factors and/or complement components may represent new and effective treatments for patients with severe and refractory CSU.

Omalizumab (OMA) is highly effective for refractory chronic spontaneous urticaria (CSU), but its high cost exerts a great economic burden on patients and society. Current knowledge is lacking regarding the economic impact of long-term administration of OMA on patients with CSU in the real-world setting. We retrospectively investigated drug costs relevant to CSU treatment during the period before through to 12 months after starting OMA in actual clinical practice. This study involved 32 patients who received at least two injections of OMA (300 mg/4 weeks) and achieved good responses of urticaria control test score of 12 or more and/or weekly urticaria activity score of 6 or less within 12 weeks. Median drug costs of the overall patient cohort increased from ¥14 496/month to ¥104 522 after starting OMA, but reduced to ¥48 810 in 12 months along with reduced amount of OMA administration and concomitant medication use. In patients pretreated with antihistamine alone or plus alternative medicines such as H 2 blocker and antileukotriene prior to OMA, the increased drug costs by adding OMA decreased to approximately 30% in 12 months mainly due to the OMA dose reduction and interval extension of OMA. The drug cost reduction was also observed in patients pretreated with intensive multi-agents, due to discontinuation of expensive immunosuppressants. In conclusion, the introduction of OMA significantly increased the total drug costs relevant to CSU management, but the costs decreased to half in 12 months, along with dose-reduced and interval-extended OMA and discontinued concomitant drugs in patients with CSU who responded well to OMA., (© 2020 Japanese Dermatological Association.)

The pathogenesis of chronic spontaneous urticaria (CSU), also called chronic idiopathic urticaria, has been considered to be associated with the activation of the extrinsic blood coagulation cascade. However, the trigger for the extrinsic coagulation cascade in patients with CSU remains unclear. We previously reported that histamine and lipopolysaccharide (LPS) synergistically induced the expression of tissue factor (TF), a trigger for the extrinsic coagulation cascade, in human umbilical vein endothelial cells (HUVEC). Because the elevation of tumor necrosis factor (TNF)-α, interleukin (IL)-33, IL-1β and vascular endothelial growth factor (VEGF) in serum has also been observed in patients with CSU, we examined the effects of LPS, TNF-α, IL-33, IL-1β, VEGF and histamine on TF expression in HUVEC by reverse transcription polymerase chain reaction and flow cytometry, as well as examining the activity that triggers the extrinsic coagulation cascade and induces intercellular gap formation of HUVEC in the presence of plasma by Actochrome ® TF activity assay and impedance sensor, respectively. The expression of TF mRNA and surface protein of TF on HUVEC in response to histamine or VEGF were synergistically enhanced by the treatment with LPS, TNF-α, IL-33 or IL-1β. Moreover, the activation of the extrinsic coagulation pathway and intercellular gap formation of HUVEC in response to histamine or VEGF were also synergistically increased in the presence of TNF-α and LPS. Thus, TF expression on vascular endothelial cells was strongly enhanced by co-stimulation with CSU-related molecules in blood. Blocking a common pathway of LPS, TNF-α, IL-33 and IL-1β, and/or that of VEGF and histamine may be an effective therapeutic measure for patients with severe and refractory CSU., (© 2020 Japanese Dermatological Association.)

Meshed skin grafting is a common technique in operations to minimize surgery on the donor site area. However, the donor site area is empirically determined by surgeons due to the lack of a reliable formula to calculate the donor area required to cover a skin defect. To determine the minimal size for donor skin, the expansion rates of 1.5:1, 3:1, and 6:1 meshed skin graft and the area actually covered by them were investigated in real-world operations. About 51 patients who received 57 operations with meshed skin grafts were enrolled in this study. The average clinical coverage rates of area in cases in which 1.5:1, 3:1, or 6:1 meshed skin grafting was performed were 1.02, 1.29, or 2.18, respectively. Those rates were notably low when recipient sites were concave. The average expansion rates of 1.5:1, 3:1, and 6:1 meshed skin grafts were about 1.16, 1.61, and 2.32, respectively. These results indicate that the size of donor skin should be about 85%, 60%, and 45% size of the recipient site to achieve the target 1.5:1, 3:1, and 6:1 meshed skin graft, respectively. In addition, the donor area should be adjusted in consideration of the shape of the recipient sites., (© 2020 Wiley Periodicals LLC.)

Immune checkpoint inhibitors (ICI) have been administrated as a standard medication in many cases of malignant melanoma (MM). They may be effective even for MM in advanced stages. However, it is still challenging to reduce the burden of MM, which were or became refractory to ICI, especially those without BRAF gene mutation. Re-administration of ICI after other modalities of treatment may be an option of treatment, but the efficacy and safety of retreatment with ICI have not been well established. We experienced four patients with advanced MM retreated with programmed cell death 1 (PD-1) inhibitor. All cases were refractory to the first PD-1 inhibitor, nivolumab, and then treated with dacarbazine (DTIC), followed by pembrolizumab. Two of the four cases achieved a partial response by switching to pembrolizumab as the second PD-1 inhibitor, and the other two cases resulted in progressive disease. In all cases, no new severe adverse events developed upon PD-1 inhibitor retreatment. Even if the first PD-1 inhibitor proves to be ineffective, it is worth re-administrating PD-1 inhibitor following a bridging therapy with DTIC., (© 2020 Japanese Dermatological Association.)

Background: Fish roe allergy is a common health problem in countries where sea food is a major part of the diet, such as Japan. β'-component (β'-c) in fish roe has been identified as a major antigen for patients who show hypersensitivity to various fish roes. However, little is known about causative antigens for patients reactive to fish roe of specific species., Methods: Serum and basophils were obtained from patients who had reactivity to roes of Gadus chalcogrammus (GC) and/or other fish species. GC roe specific antigens were analyzed by immunoblotting, histamine release assay (HRA) and mass spectrometry. Recombinant-fragments of vitellogenin (Vg) were obtained by the Escherichia coli expression system., Results: Serum IgE of a patient with specific reactions to GC roe bound to 15, 28, 40 and 70 kDa-proteins in GC roe extract. Mass spectrometry analysis revealed that proteins in these bands contained fragments corresponding to Vg. Immunoblotting of Vg immunoprecipitated by rabbit anti-Vg antiserum from the extract revealed 15, 28 and 54 kDa fragments bound by the patient's IgE. These bindings were inhibited by the pretreatment of recombinant phosvitin (rPv) and β'-c (rβ'-c). Fractions obtained by native gel electrophoresis containing 15, 28 and 54 kDa proteins, but not the other fractions, induced significant histamine release from the patient's basophils. Sera of the other patients with GC roe specific-IgE showed IgE binding to rPv and/or rβ'-c., Conclusions: The 15, 28 and 54 kDa-fragments of Vg which include structures of Pv and β'-c, could be antigens for GC roe specific type-I-hypersensitivity., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

IgE and mast cells play a pivotal role in various allergic diseases, including asthma, allergic rhinitis, and urticaria. Treatment with omalizumab, a monoclonal anti-IgE antibody, has significantly improved control of these allergic diseases and introduced a new era for the management of severe allergic conditions. About 10 years of experience with omalizumab treatment for severe allergic asthma confirmed its effectiveness and safety, reducing symptoms, frequency of reliever use, and severe exacerbations in patients with intractable conditions. Omalizumab is particularly useful in childhood asthma, where atopic conditions often determine clinical courses of asthma. Recently, omalizumab is approved for the treatment of chronic spontaneous urticaria (CSU) with the fixed dose of 300 mg. Although the mechanisms underlying the actions of omalizumab in CSU are not fully clarified, nearly 90% of patients with CSU showed a complete or a partial response to omalizumab treatment. Furthermore, omalizumab is just approved for the treatment of severe Japanese cedar pollinosis (JC) based on the successful results of an add-on study of omalizumab for inadequately controlled severe pollinosis despite antihistamines and nasal corticosteroids. For proper use of omalizumab to treat severe JC, co-administration of antihistamines is necessary, while patients should meet the criteria including strong sensitization to Japanese cedar pollen (≥class 3) and poor control under standard treatment. In the management of severe allergic diseases using omalizumab, issues including cost and concerns about relapse after its discontinuation should be overcome. At the same time, possibilities for application to other intractable allergic diseases should be considered., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: None declared.

Urticaria is a common skin disorder characterized by the rapid appearance and disappearance of local skin edema and flares with itching. It is characterized by various macroscopic skin eruptions unique to patients and/or subtypes of urticaria with respect to shape, size, color, and/or duration of eruptions. Nevertheless, the mechanism underlying multifarious eruptions in urticaria is largely unknown. The eruptions are believed to be evoked by histamine release from mast cells in the skin. However, the majority of visible characteristics of urticaria cannot be explained by a simple injection of histamine to the skin. To explain the multifarious eruptions of urticaria, we developed a single reaction-diffusion model suggesting the self-activation and self-inhibition regulation of histamine release from mast cells. Using the model, we found that various geometrical shapes of eruptions typically observed in patients can be explained by the model parameters and randomness or strength of the initial stimuli to mast cells. Furthermore, we verified that the wheal-expanding speed of urticaria, which is shown to be much smaller than that of the intradermal injection experimental system may be explained by our model and a simple diffusion equation. Our study suggests that the simple reaction-diffusion dynamics, including the independent self-activating and -inhibitory regulation of histamine release, may account for the essential mechanism underlying the formation of multifarious eruptions in urticaria., Competing Interests: The authors have declared that no competing interests exist.

Basophils and mast cells have high affinity IgE receptors (FcεRI) on their plasma membrane and play important roles in FcεRI-associated allergic diseases, such as pollen allergy, food allergy, chronic spontaneous urticarial (CSU), and atopic dermatitis (AD). To date, several reports have revealed that high IgE antibody concentrations activate mast cells-which reside in tissue-in the absence of any antigens (allergens). However, IgE antibody-induced activation of basophils-which circulate in blood-has not been reported. Here, we investigated whether IgE antibodies may regulate functions of human peripheral basophils without antigens in vitro. We successfully removed IgE antibodies bound to FcεRI on the surface of human peripheral basophils by treating with 0.1% lactic acid. We also demonstrated that high IgE antibody concentrations (>1 μM) induced histamine release, polarization, and CD203c upregulation of IgE antibody-stripped basophils. Thus, high IgE antibody concentrations directly activate basophils, which express IgE-free FcεRI on the cell surface. This mechanism may contribute to the pathogenesis of patients with AD and CSU who have higher serum IgE concentrations compared to healthy donors.

Sweat allergy is defined as a type I hypersensitivity against the contents of sweat, and is specifically observed in patients with atopic dermatitis (AD) and cholinergic urticaria (CholU). The allergic reaction is clinically revealed by positive reactions in the intradermal skin test and the basophil histamine release assay by sweat. A major histamine-releasing antigen in sweat, MGL_1304, has been identified. MGL_1304 is produced at a size of 29 kDa by Malassezia (M.) globosa and secreted into sweat after being processed and converted into the mature form of 17 kDa. It induces significant histamine release from basophils of patients with AD and/or CholU with MGL_1304-specific IgE, which is detected in their sera. Patients with AD also show cross-reactivity to MGL_1304-homologs in Malassezia restricta and Malassezia sympodialis, but MGL_1304 does not share cross antigenicity with human intrinsic proteins. Malassezia or its components may penetrate the damaged epidermis of AD lesions and interact with the skin immune system, resulting in the sensitization and reaction to the fungal antigen. As well as the improvement of impaired barrier functions by topical interventions, approaches such as anti-microbial treatment, the induction of tolerance and antibody/substance neutralizing the sweat antigen may be beneficial for the patients with intractable AD or CholU due to sweat allergy. The identification of antigens other than MGL_1304 in sweat should be the scope for future studies, which may lead to better understanding of sweat allergy and therapeutic innovations., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by daily or almost daily recurring skin edema and flare with itch. Recently, the activation of the blood coagulation cascade has been suggested to be involved in CSU, but the trigger of the coagulation cascade remains unclear. In this article, we review recent understanding of the relationship between the pathogenesis of CSU and extrinsic coagulation reactions. In CSU, vascular endothelial cells and eosinophils may play a role as TF-expressing cells for activating the extrinsic coagulation pathway. Moreover, the expression of TF on endothelial cells is synergistically enhanced by the activation of Toll-like receptors and histamine H 1 receptors. The activated coagulation factors may induce plasma extravasation followed by degranulation of skin mast cells and edema formation recognized as wheal in CSU. Molecules involved in this cascade could be a target for new and more effective treatments of urticaria., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. The skin of patients with AD presents as a disbalance of the microbiome with a strong colonization by Staphylococcus aureus, which positively correlates with the severity of the disease. However, the effect of colonized S. aureus on the skin immune system has not been fully elucidated., Objective: The aim of this study is to explore whether S. aureus isolated from AD skin is able to skew T cell responses via Langerhans cells (LC) as compared to a standard strain of S. aureus and S. epidermidis., Methods: We prepared monocyte-derived LC (MoLC) from healthy controls and patients with AD, and stimulated MoLC with a standard strain of S. aureus NCTC8325, S. aureus TF3378 isolated from AD skin, or S. epidermidis. Stimulated MoLC were co-cultured with autologous CD4 pos T cells and then T cell responses were analyzed by T cell polarization assays, cytokine analysis and real-time PCR., Results: MoLC stimulated by S. aureus TF3378 induced significantly high and rapid proliferation of T cells as compared to those by S. aureus NCTC8325 and S. epidermidis. Cytokine productions from T cells cultured with S. aureus TF3378-stimulated MoLC showed significantly high amounts of IL-2 and less IFN-γ production with imbalanced Th1/Th2 (decreased TBX21/GATA3 ratio) mRNA expression. The T cell proliferation with increased IL-2 production via S. aureus TF3378-stimulated MoLC was diminished by treatment of proteinase K., Conclusion: S. aureus TF3378 on AD skin can skew T cell responses via LC toward imbalanced Th1/Th2 skin immunity., (Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Non-invasive real time evaluation of living cell conditions and functions are increasingly desired in the field of clinical diagnosis. For diagnosis of type I allergy, the identification of antigens that induces activation of mast cells and basophils is crucial to avoid symptoms of allergic diseases. However, conventional tests, such as detection of antigen-specific IgE antibody and skin tests, are either of low reliability or are invasive. To overcome such problems, we hereby applied an impedance sensor for label-free and real-time monitoring of mast cell reactions in response to stimuli. When IgE-sensitized RBL-2H3 cells cultured on the electrodes were stimulated with various concentrations of antigens, dose-dependent cell index (CI) increases were detected. Moreover, we confirmed that the impedance sensor detected morphological changes rather than degranulation as the indicator of cell activation. Furthermore, the CI of human IgE receptor-expressing cells (RBL-48 cells) treated with serum of a sweat allergy-positive patient, but not with serum from a sweat allergy-negative patient, significantly increased in response to purified human sweat antigen. We thus developed a technique to detect the activation of living cells in response to stimuli without any labeling using the impedance sensor. This system may represent a high reliable tool for the diagnosis of type I allergy., Competing Interests: The authors declare no conflict of interest.

MGL_1304, a major allergen in human sweat for patients with atopic dermatitis and/or cholinergic urticaria, is secreted from Malassezia globosa on human skin. The amounts of MGL_1304 and IgE against MGL_1304 are evaluated by the histamine release test using basophils or mast cells sensitized with serum containing IgE against MGL_1304, and enzyme linked sorbent assay (ELISA) using MGL_1304 and anti-MGL_1304 antibodies. Here, we identified a human monoclonal IgE (ABS-IgE) that binds to the high affinity IgE receptor (FcεRI) and MGL_1304 with high affinity (KD = 1.99 nM) but does not release histamine from basophils and mast cells. An ELISA using ABS-IgE as a standard IgE revealed that the amount of IgE against MGL_1304 (1000 U/ml) in the standard sera of patients with AD, employed in our previous report, is 32 ng/ml. A sandwich ELISA using ABS-IgE as a detection antibody showed approximately 10 times lower detection limit for MGL_1304 than ELISA in which MGL_1304 is directly bound to an ELISA plate. Moreover, ABS-IgE prevented histamine release from mast cells and basophils by neutralizing MGL_1304 not only in a free form in solution, but also on FcεRI expressed on the cell surface without cell activation. ABS-IgE may be used both to quantify the amount of MGL_1304 and anti-MGL_1304 IgE, and possibly for the treatment of diseases caused/aggravated by type I allergy to MGL_1304., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder manifesting with ectopic connective tissue mineralization, caused by mutations in the ABCC6 gene, with ~35% of all mutations being premature termination mutations. In this study, we investigated the therapeutic potential of the nonsense codon read-through-inducing drug, PTC124, in treating PXE. The ability of this drug to facilitate read-through of nonsense mutations was examined in HEK293 cells transfected with human ABCC6 expression constructs harboring seven different PXE-associated nonsense mutations, and was evaluated by immunofluorescence and In-Cell ELISA. Our data demonstrated that PTC124 did not exhibit cytotoxicity in concentrations up to 20 μg ml(-1), and the facilitated read-through varied not only with dose but also with sequence context. Considering the redundancy of the genetic code, it was postulated that in case of the most common recurrent nonsense mutation, p.R1141X, the read-through may result in substitution of the arginine 1,141 by glycine, tryptophan, or cysteine. Their potential pathogenicity was tested in a recently developed zebrafish messenger RNA (mRNA) rescue assay, and demonstrated that all three mRNA transcripts were able to rescue abcc6a morpholino-induced phenotype of zebrafish. Thus, our results suggest that read-through of nonsense mutations in ABCC6 by PTC124 may have potential for pharmacologic treatment of PXE.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, and food additives (FAs) may exacerbate allergic symptoms in patients with chronic idiopathic urticaria and food-dependent exercise-induced anaphylaxis (FDEIA). Augmentation of histamine release from human mast cells and basophils by those substances is speculated to be the cause of exacerbated allergic symptoms. We sought to investigate the mechanism of action of aspirin on IgE-mediated histamine release., Methods: The effects of NSAIDs, FAs or cyclooxygenase (COX) inhibitors on histamine release from human basophils concentrated by gravity separation were evaluated., Results: Benzoate and tartrazine, which have no COX inhibitory activity, augmented histamine release from basophils similar to aspirin. In contrast, ibuprofen, meloxicam, FR122047 and NS-398, which have COX inhibitory activity, did not affect histamine release. These results indicate that the augmentation of histamine release by aspirin is not due to COX inhibition. It was observed that aspirin augmented histamine release from human basophils only when specifically activated by anti-IgE antibodies, but not by A23187 or formyl-methionyl-leucyl-phenylalanine. When the IgE receptor signaling pathway was activated, aspirin increased the phosphorylation of Syk. Moreover, patients with chronic urticaria and FDEIA tended to be more sensitive to aspirin as regards the augmentation of histamine release, compared with healthy controls., Conclusions: Aspirin enhanced histamine release from basophils via increased Syk kinase activation, and that the augmentation of histamine release by NSAIDs or FAs may be one possible cause of worsening symptoms in patients with chronic urticaria and FDEIA.

Pseudoxanthoma elasticum (PXE) is a heritable ectopic mineralization disorder caused by loss-of-function mutations in the ABCC6 gene which is primarily expressed in the liver. There is currently no effective treatment for PXE. In this study, we characterized bone marrow derived mesenchymal stem cells (MSCs) and evaluated their ability to contribute to liver regeneration, with the aim to rescue PXE phenotype. The MSCs, isolated from GFP-transgenic mice by magnetic cell sorting, were shown to have high potential for hepatic differentiation, with expression of Abcc6, in culture. These cells were transplanted into the livers of 4-week-old immunodeficient Abcc6⁻/⁻ mice by intrasplenic injection one day after partial hepatectomy, when peak expression of the stromal cell derived factor-1 (SDF-1) in the liver was observed. Fluorescent bioimaging analyses indicated that transplanted MSCs homed into liver between day 1 and 7, and significant numbers of GFP-positive cells were confirmed in the liver by immunofluorescence. Moreover, enhanced engraftment efficiency was observed with MSCs with high expression levels of the chemokine receptor Cxcr4, a receptor for SDF-1. These data suggest that purified MSCs have the capability of differentiating into hepatic lineages relevant to PXE pathogenesis and may contribute to partial correction of the PXE phenotype.

Background: Dermographic urticaria (DU) is characterized by strong itch and wheals induced by mechanical scratching. H(1)-receptor antagonists may reduce symptoms of DU to some extent, but other treatments being used for chronic spontaneous urticaria, such as H(2)-receptor antagonists and corticosteroids, are not usually effective for DU., Case Summary: We here report six cases of antihistamine-resistant DU treated with oral ciclosporin. Four cases suffering from severe itches that spontaneously occurred before the appearance of wheals in response to scratching were substantially improved by use of ciclosporin for 21, 16, 32, and 8 months, and one of them reached complete remission. Two cases did not obtain a benefit from the treatment, because of insufficient effects and/or side effects., Discussion: Oral ciclosporin may be of value as a potential treatment of anti-histamine-resistant DU.

We previously reported that fucoidan, a dietary fiber purified from seaweed, inhibited IgE production in B cells from mice spleen in vitro and ovalbumin-sensitized mice in vivo. In this study, we examined the effect of fucoidan on IgE production in human peripheral blood mononuclear cells (PBMC) in vitro. PBMC, obtained from healthy donors or patients with atopic dermatitis (AD) with high levels of serum IgE, were cultured with IL-4 and anti-CD40 antibody in the presence or absence of fucoidan. Fucoidan significantly reduced IgE production in PBMC without affecting cell proliferation and IFN-γ production. Fucoidan also inhibited immunoglobulin germline transcripts of B cells in PBMC, and decreased the number of IgE-secreting cells. The inhibitory effects of fucoidan were similarly observed for both PBMC from patients with AD and those with healthy donors. Our findings indicate that fucoidan suppresses IgE induction by inhibiting immunoglobulin class-switching to IgE in human B cells, even after the onset of AD.

Background: Many patients with atopic dermatitis showed immediate-type hypersensitivity against sweat antigen. Therefore, to deal with sweating is important to prevent itching and aggravations of dermatitis of patient with atopic dermatitis. We had searched a substance that inactivated sweat antigen adopting histamine release test. And we found that tannic acid which selected by screening various natural products inactivated sweat antigen., Methods: We evaluate skin care products (spray, after-bathing water and aerosol-spray) containing tannic acid for patients with atopic dermatitis. We administered in a tannic acid-containing spray and after-bathing water on 17 patients with atopic dermatitis., Results: After treatment, total clinical assessment score and itching in the afternoon had significantly decreased from that on day 0. To evaluate the effect of tannic acid containing-aerosol spray on itching of patients with AD, we assessed symptoms of atopic dermatitis patients who used a tannic acid containing-aerosol spray every day for 4 weeks in a cross-over, double-blind study. Clinical severity of atopic dermatitis and degrees of itching in daily life of patients were evaluated by physicians and patients themselves, respectively. Degrees of itching in morning and those at night were significantly more largely improved by the use of tannic acid-containing aerosol spray than those by the use of placebo control aerosol spray. The overall efficacy of tannic acid-containing aerosol sprays was also significantly higher than those of tannic acid free spray., Conclusion: Sweat antigen inactivating skin care products may be effective to reduce itching of patients with atopic dermatitis.

Delayed pressure urticaria (DPU) is characterized by deep dermal wheals that appear in response to a local continuous pressure. Although it has been reported to complicate as many as 40% of cases of Caucasian patients with chronic urticaria, no definitive cases of Asian/Japanese patients have been reported in English literature. Here, we identified 17 cases of DPU, among 540 Japanese patients with urticaria (3.1%), based on careful history taking, pressure challenge test and, ideally, skin biopsy. Twelve out of 17 patients (70.5%) who undertook pressure challenge test developed wheal and erythema in the area of pressure 1-12 h later. Six out of 15 patients (40%) were positive for the autologous serum skin test. All cases were complicated with ordinary chronic urticaria, and all specimens of skin biopsies performed for 12 patients showed substantial eosinophil infiltration. All cases were resistant to antihistamines with or without other non-steroidal medications and eventually treated with 0.25-1.5 mg/day of betamethasone. However, 12 of them (70.6%) were able to cease steroid use because of cure or remission. For those cured or in remission, the duration of steroid administration and that from the onset to diagnosis was 11.2 +/- 11.0 and 54.8 +/- 60.2 months (mean +/- SD), respectively. DPU may be identified as a relatively rare complication of Japanese patients with chronic idiopathic urticaria. A proper diagnosis and a small amount of steroid may be beneficial for the treatment of DPU.

In the treatment of metastatic breast cancer, trastuzumab, a recombinant monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is effective when tumor cells overexpress HER2 protein. Although some cases of extramammary Paget's disease (EMPD) also express HER2 protein, no case of EMPD has been reported to be treated with trastuzumab. A 75-year-old man who suffered from EMPD of the scrotum and inguinal region underwent a local excision and lymph node dissection. Tumor cells invaded the dermis and lymph nodes. Although he was postoperatively treated with adjuvant chemotherapies, metastatic skin lesions appeared and spread over his left thigh, rapidly and widely. Tumor cells disseminated along lymph vessels in the dermis and overexpressed HER2 protein. We administered paclitaxel and trastuzumab according to a protocol for HER2-positive metastatic breast cancers. The skin metastasis dramatically decreased during the regimen and a histopathological examination showed that most of HER2-positive tumor cells diminished. Six months later, metastases were found in the central nervous system (CNS), but no other metastases were found in the skin, visceral organs or lymph nodes. Trastuzumab and paclitaxel-combination with the assessment of central nervous system lesions should be considered as an option for the treatment of HER2-positive EMPD.

A technique of fast spin echo three-dimensional magnetic resonance (MR) myelography with flow compensation was developed for the evaluation of the cervical spinal lesions. The whole spinal cord and roots in the spinal canal can be visualized non-invasively on voxel images by the maximum intensity projection process to achieve the best static contrast of the cerebrospinal fluid. This method of MR myelography is applicable as a screening test for the patients with cervical spinal lesions.