In vivo analysis of the stratum corneum of Japanese neonates and infants using confocal Raman spectroscopy: a pilot study.

BACKGROUND: Physiological skin properties of neonates and infants change drastically after birth and are implicated in the onset of atopic dermatitis and other diseases. Studies have measured physiological skin properties in infants; however, how these properties change over time remains unclear. No reports have measured ceramide in the stratum corneum of infants using confocal Raman spectroscopy; hence, we used it to measure the physiological properties of the skin, including ceramide, in infants. MATERIALS AND METHODS: The water content and other factors in the skin of infants aged 0, 1, and 6 months were measured. All measurements were performed five times indoors at 22 ± 2°C and 50% ± 10% relative humidity in the middle of the calf at 4-µm distances, and their mean was calculated. RESULTS: The water content of the area between the skin surface and superficial layers was the lowest in newborns as compared with other ages, and the deeper the skin layer, the higher the water content. The stratum corneum, evaluated using confocal Raman spectroscopy, was the thickest in newborns and gradually thinned with age. Its water content was the lowest in newborns. The levels of natural moisturizing factor, ceramide, and cholesterol were higher in newborns and tended to decrease with age. CONCLUSION: This report is the first to evaluate ceramide in the stratum corneum of infants using confocal Raman spectroscopy and could help in conducting subsequent longitudinal measurements of physiological skin properties in neonates and infants.

Analysis of IKBKG/NEMO gene in five Japanese cases of incontinentia pigmenti with retinopathy: fine genomic assay of a rare male case with mosaicism.

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis that is usually lethal in utero in males, though exceptionally they survive very rarely either with Klinefelter syndrome or a somatic mosaicism. We performed genomic analysis of five Japanese IP patients including a rare boy case, all of whom were definite cases with retinopathy. Four patients including the boy revealed the recurrent exon 4-10 deletion in the sole known causative gene IKBKG/NEMO, which was confirmed by various specific PCR techniques. The boy's saliva DNA showed a mosaicism consisting of the deletion and intact alleles, but his blood DNA did not. Relative quantification analysis of the real-time PCR data by ∆∆CT method estimated the mosaicism ratio of the boy's saliva as 45:55 (deletion:intact). A genomic analysis for the recurrent deletion at the nucleotide sequence level has been performed directly using patient's DNA and it has been clarified that the breakpoints are within two MER67B repeats in the intron 3 and downstream of exon 10. This is the first report of the assay for the mosaicism ratio of a male IP case with a recurrent exon 4-10 deletion of IKBKG/NEMO and the sequencing analysis of the breakpoints of the recurrent deletion directly using patient's sample.

Neonatal systemic juvenile Xanthogranuloma with Hydrops diagnosed by Purpura skin biopsy: a case report and literature review.

BACKGROUND: Systemic juvenile xanthogranuloma is a very rare disease typically presents as skin lesions with yellow papules or nodules and is sometimes fatal. We report a case of congenital neonatal systemic juvenile xanthogranuloma with atypical skin appearance that made the diagnosis difficult. CASE PRESENTATION: A preterm Japanese female neonate with prenatally diagnosed fetal hydrops in-utero was born with purpuric lesions involving the trunk and face. Since birth, she had hypoxemic respiratory failure, splenomegaly, anemia, thrombocytopenia, coagulopathy, and was transfusion dependent for red blood cells, fresh frozen plasma, and platelets. Multiple cystic lesions in her liver, part of them with vascular, were detected by ultrasound. A liver biopsy was inconclusive. A skin lesion on her face similar to purpura gradually changed to a firm and solid enlarged non-yellow nodule. Technically, the typical finding on skin biopsy would have been histiocytic infiltration (without Touton Giant cells) and immunohistochemistry results which then would be consistent with a diagnosis of systemic juvenile xanthogranuloma, and chemotherapy improved her general condition. CONCLUSIONS: This case report shows that skin biopsies are necessary to detect neonatal systemic juvenile xanthogranuloma when there are organ symptoms and skin eruption, even if the skin lesion does not have a typical appearance of yellow papules or nodules.

Development of an interprofessional competency framework for collaborative practice in Japan.

Rapid aging of the population necessitates improved collaboration among healthcare professionals. Unfortunately, interprofessional collaboration has yet to be implemented effectively in Japan. Therefore, we aimed to develop an interprofessional competency framework for Japanese healthcare professionals. The project was conducted as a four-step process, starting with initial categorization of potential competency domains,, followed by guiding principle and prototype development, feedback on the prototype, and final consensus. First, authors (JH and MO) collected opinions about competency in interprofessional collaboration at two academic meetings of the Japan Association for Interprofessional Education (JAIPE) and then analyzed the data thematically. Second, a project team consisting of JAIPE and University representatives extracted the domains and statements as prototype 1. Third, seven representatives from professional organizations joined the project team and developed prototype 2. We then called for feedback on the revised prototype 2 at both an open symposium and via public comments. Following revision of prototype 2, a new project team including 20 university, professional organization and health practitioner representatives finally discussed prototype 3, developed the final draft and reached a consensus. In analysis after collecting the data, we extracted 11 themes. We developed four key principles which applied to six domains as prototype 1-3. Finally, our competency framework included two core domains of "Patient-/client-/family-/community-centered" and "Interprofessional communication", and four peripheral domains of "Role contribution", "Facilitation of relationships", "Reflection" and "Understanding of others". We developed an interprofessional competency framework in Japan which consists of two core and four peripheral domains. The interprofessional competency framework is likely to affect the understanding of "high-context" and "relationalism" in Japanese healthcare. We hope that our interprofessional competency framework will encourage the systematic implementation of interprofessional education and collaboration in Japan.

Cross-cultural adaptation of the professional version of the Readiness for Interprofessional Learning Scale (RIPLS) in Japanese.

Interprofessional education (IPE) for healthcare professionals is important in Japan because of its rapidly aging population and increasingly complex healthcare needs. However, no tools have been validated in the Japanese context to evaluate healthcare professionals' attitudes towards, or readiness for, IPE. The professional version of the Readiness for Interprofessional Learning Scale (RIPLS) with 23 items was selected for cross-cultural adaptation because it has been widely used internationally and a Japanese edition of the student version has already been developed. We followed a guideline for cross-cultural adaptation and subsequently conducted factor analysis with 368 responses from over 16 professions. Face and content validity was confirmed through the translation process. We obtained four factors with good internal consistency (Cronbach's alpha > 0.7). These results were similar to those of the original UK study, apart from one factor being divided into two different factors in this study. Studies are required to further confirm the rigor and generalisability of the results; however, the Japanese RIPLS can be used to evaluate healthcare professionals' attitudes towards IPE, which can eventually lead to a better IPE development for healthcare professionals in Japan.

Development of an interprofessional competency framework in Japan.

This article presents a project that aimed to identify a set of competencies (domains and statements) to prepare Japanese students and healthcare practitioners for collaborative practice. The Japan Association for Interprofessional Education (JAIPE) has started a government-funded project to formulate its interprofessional competency framework, in cooperation with professional organisations (e.g. Japan Society for Medical Education) in healthcare and social sciences. This three-year project is underway as part of the Initiative to Build up the Core Healthcare Personnel programme of Mie University. This project consists of five stages: literature review, data collection, prototype development, consensus formation, and finalisation. Our efforts will culminate in Japan's first interprofessional competency framework, with consensus from relevant academic societies and other stakeholders. We hope that the involvement of stakeholder participation will improve the usability of the final interprofessional competency framework.

Ectopic expression of epidermal antigens renders the lung a target organ in paraneoplastic pemphigus.

Paraneoplastic pemphigus (PNP) is an autoimmune disease of the skin and mucous membranes that can involve fatal lung complications. IgG autoantibodies target the cell adhesion molecules desmoglein (Dsg)3 and plakins, but the nature and targets of infiltrating T cells are poorly characterized. Moreover, the lung involvement in this skin Ag-specific autoimmune condition represents a paradox. To mimic autoimmunity in PNP, we grafted wild-type skin onto Dsg3(-/-) mice, which resulted in graft rejection and generation of anti-Dsg3 IgG and Dsg3-specific T cells. Transfer of splenocytes from these mice into Rag2(-/-) mice induced a combination of suprabasilar acantholysis and interface dermatitis, a histology unique to PNP. Furthermore, the recipient mice showed prominent bronchial inflammation of CD4(+) and CD8(+) T cells with high mortality. Intriguingly, ectopic Dsg3 expression was observed in the lungs of PNP mice, mirroring the observation that squamous metaplasia is often found in the lungs of PNP patients. Dsg3 and other epidermal Ags were ectopically expressed in the lungs after pulmonary injuries by naphthalene, which was sufficient for recruitment of Dsg3-specific CD4(+) T cells. These findings demonstrate that squamous metaplasia after pulmonary epithelial injury may play a crucial role in redirecting the skin-specific autoimmune reaction to the lungs in PNP.

Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis.

BACKGROUND: The stratum corneum and tight junctions (TJs) form physical barriers in the epidermis. Dendrites of activated Langerhans cells (LCs) extend beyond the TJs to capture external antigens in mice. LCs and inflammatory dendritic epidermal cells (IDECs) are observed in the skin of patients with atopic dermatitis (AD). OBJECTIVE: We sought to investigate the characteristics of LCs and IDECs and the distribution of their antigen capture receptors in relation to TJs in normal and AD skin. METHODS: We characterized the interactions of LCs and IDECs with TJs and the expression patterns of langerin and FcεRI by using whole-mount epidermal sheets from healthy subjects and patients with AD, ichthyosis vulgaris, and psoriasis vulgaris. RESULTS: As in mouse skin, activated LCs penetrate TJs in human skin. The number of LCs with TJ penetration increased approximately 5-fold in erythematous lesional skin of patients with AD but not in nonlesional skin of patients with AD or lesions of patients with ichthyosis vulgaris or psoriasis. In contrast, IDECs localized in the lower part of the epidermis, and their dendrites extended horizontally without penetration through TJs. Although langerin accumulated on the tips of dendrites of activated LCs, FcεRI was expressed diffusely on the cell surfaces on LCs and IDECs in lesional skin from patients with AD. CONCLUSIONS: These findings highlight interesting differences between LCs and IDECs in epidermis of patients with AD, where LCs, but not IDECs, extend dendrites through the TJs, likely to capture antigens from outside the TJ barrier with a polarized distribution of langerin but not FcεRI. These behavioral differences between skin dendritic cells might reflect an important pathophysiology of AD.

Application of moisturizer to neonates prevents development of atopic dermatitis.

BACKGROUND: Recent studies have suggested that epidermal barrier dysfunction contributes to the development of atopic dermatitis (AD) and other allergic diseases. OBJECTIVE: We performed a prospective, randomized controlled trial to investigate whether protecting the skin barrier with a moisturizer during the neonatal period prevents development of AD and allergic sensitization. METHODS: An emulsion-type moisturizer was applied daily during the first 32 weeks of life to 59 of 118 neonates at high risk for AD (based on having a parent or sibling with AD) who were enrolled in this study. The onset of AD (eczematous symptoms lasting >4 weeks) and eczema (lasting >2 weeks) was assessed by a dermatology specialist on the basis of the modified Hanifin and Rajka criteria. The primary outcome was the cumulative incidence of AD plus eczema (AD/eczema) at week 32 of life. A secondary outcome, allergic sensitization, was evaluated based on serum levels of allergen-specific IgE determined by using a high-sensitivity allergen microarray of diamond-like carbon-coated chips. RESULTS: Approximately 32% fewer neonates who received the moisturizer had AD/eczema by week 32 than control subjects (P = .012, log-rank test). We did not show a statistically significant effect of emollient on allergic sensitization based on the level of IgE antibody against egg white at 0.34 kUA/L CAP-FEIA equivalents. However, the sensitization rate was significantly higher in infants who had AD/eczema than in those who did not (odds ratio, 2.86; 95% CI, 1.22-6.73). CONCLUSION: Daily application of moisturizer during the first 32 weeks of life reduces the risk of AD/eczema in infants. Allergic sensitization during this time period is associated with the presence of eczematous skin but not with moisturizer use.

Sexual activity after ileal pouch-anal anastomosis in Japanese patients with ulcerative colitis.

PURPOSE: The aim of this study was to evaluate the sexual activity after restorative proctocolectomy with ileal J-pouch-anal anastomosis (ileoanal anastomosis) in Japanese patients with ulcerative colitis. METHODS: Sixty-one patients who had undergone ileoanal anastomosis and were followed for at least 6 months after surgery were randomly selected. Their quality of life was assessed using the Japanese version of the Inflammatory Bowel Disease Questionnaire. Scores of three or less for the item "Sex life" were predetermined to represent poor sexual activity. The medical staff then asked them the reasons for this using a non-structured interview and open-ended questions. RESULTS: Overall, 19 patients reported poor sexual activity. There was a significant difference in the scores for "Social functions" other than Sex life between individuals with poor and good sexual activities (21.6 ± 4.6 vs. 24.1 ± 4.2, P = 0.016). Ileoanal anastomosis after the age of 40 (OR 22, P = 0.02) and a total preoperative corticosteroid dose ≥15 g (OR 7.4, P = 0.04) were significant risk factors for poor sexual activity after ileoanal anastomosis. CONCLUSION: Our results suggest that ileoanal anastomosis results in relatively poor sexual activity, which was associated with other social functions, older age and a higher dose of corticosteroids administered to Japanese patients with ulcerative colitis.

Longitudinal Correlations between Molecular Compositions of Stratum Corneum and Breast Milk Factors during Infancy: A Prospective Birth Cohort Study.

Breast milk contains numerous factors that are involved in the maturation of the immune system and development of the gut microbiota in infants. These factors include transforming growth factor-ß1 and 2, immunoglobin A, and lactoferrin. Breast milk factors may also affect epidermal differentiation and the stratum corneum (SC) barrier in infants, but no studies examining these associations over time during infancy have been reported. In this single-center exploratory study, we measured the molecular components of the SC using confocal Raman spectroscopy at 0, 1, 2, 6, and 12 months of age in 39 infants born at our hospital. Breast milk factor concentrations from their mothers' breast milk were determined. Correlation coefficients for the two datasets were estimated for each molecular component of the SC and breast milk factor at each age and SC depth. The results showed that breast milk factors and molecular components of the SC during infancy were partly correlated with infant age in months and SC depth, suggesting that breast milk factors influence the maturation of the SC components. These findings may improve understanding of the pathogenesis of skin diseases associated with skin barrier abnormalities.

Initiation of hydroxychloroquine therapy during pregnancy can cause adverse effects and alter pregnancy outcomes: A case of acute generalised exanthematous pustulosis induced by hydroxychloroquine in a patient with systemic lupus erythematosus.

Hydroxychloroquine (HCQ) is effective for treating a number of autoimmune diseases, including systemic lupus erythematosus. HCQ is generally safe and may be prescribed to pregnant women. Although current guidelines recommend initiating HCQ when considering pregnancy, the drug can cause adverse effects such as acute generalised exanthematous pustulosis (AGEP), which should be carefully evaluated. A 30-year-old pregnant woman with systemic lupus erythematosus at 16 + 5 gestational weeks was referred to National Center for Child Health and Development for persistent proteinuria and alopecia. Tacrolimus was initiated, and the dose of prednisone was increased. At 20 + 3 weeks of gestation, HCQ was administered to allow for a dose reduction of prednisolone. Proteinuria gradually improved as the pregnancy course stabilised. At 27 + 1 weeks of gestation, generalised pustular exanthema developed, presumably due to HCQ. Based on the clinical course and the analysis of the skin lesions, she was diagnosed to have either AGEP or generalised pustular psoriasis. Despite discontinuing HCQ, the skin lesions worsened dramatically, and infliximab therapy was required. After one course of infliximab treatment, exanthema gradually subsided. The final diagnosis was AGEP, based on the clinical course and pathological findings. At 30 weeks, pyothorax developed because of the pyogenic skin lesion and the compromised immune system, and long-term antibiotic therapy was required until 32 + 4 weeks, after which she underwent caesarean section. Although introducing HCQ is occasionally necessary during pregnancy, it is preferable to initiate HCQ in the preconception period and not after pregnancy because of the possible adverse effect, which can alter perinatal prognosis. Rheumatologists should consider the potential risks of HCQ.

Clinical and Laboratory Diagnosis of Exanthems Among Japanese Children Younger Than 6 Years Old in the Post-Measles-Rubella Vaccine Era.

BACKGROUND: Exanthems are a common reason for visits to the pediatric emergency department. However, epidemiological data in the post-measles-rubella vaccine era is limited. OBJECTIVE: We sought to determine the recent causes of exanthems in children younger than 6 years old in the pediatric emergency department. METHODS: A prospective single-center study was conducted in Japan from August 2019 to March 2020. Children younger than 6 years old with exanthems were enrolled. Exanthems were classified into 7 morphological patterns. Varicella, herpes zoster, impetigo, urticaria and Kawasaki disease were diagnosed clinically. Nasopharyngeal swab specimens were collected from patients with nonspecific exanthems and evaluated by polymerase chain reaction (PCR) assays capable of detecting 24 pathogens. The final diagnosis was made by discussion of 3 physicians based on clinical course and microbiology. RESULTS: There were 9705 pediatric visits, of which 296 (3%) had exanthems and were younger than 6 years old. Clinical diagnosis was possible for 160 (54%), including urticaria in 110 (37%), Kawasaki disease in 29 (10%), impetigo in 10 (3%), varicella or herpes zoster in 7 (2%) and group A Streptococcus in 4 (1%). Among the remaining 136 (46%) children, 75 (25%) underwent testing by PCR. One or more pathogens were detected in 49 (65%), specifically enterovirus in 14 (19%), cytomegalovirus in 13 (17%), human herpesvirus type-6 in 12 (16%), adenovirus in 11 (15%) and human herpesvirus type-7 in 8 (11%). Final infectious disease diagnoses were roseola infantum in 11 (15%), enterovirus in 9 (12%), adenovirus in 6 (8%), mixed virus infection in 5 (7%), group A Streptococcus in 3 (4%), parechovirus-A in 3 (4%) and influenza in 3 (4%). CONCLUSIONS: The most common causes of pediatric exanthems were noninfectious diseases and viral exanthema. PCR assay was instrumental for etiological diagnosis of nonspecific exanthems.

Association between Maternal Characteristics and Immune Factors TGF-ß1, TGF-ß2, and IgA in Colostrum: An Exploratory Study in Japan.

Colostrum is the first food for newborns and it contains various crucial immune factors. The concentrations of immune factors in breast milk may change depending on maternal characteristics such as body mass index, collection day, and age at first pregnancy. In this exploratory study, we investigated the association between TGF-ß1, TGF-ß2, and IgA in colostrum and rarely studied factors that affect breast milk components, including the use of labor-inducing medication, colostrum secretion, sex of newborns, breast or nipple problems, and nipple care. Breast milk samples were collected from 42 mothers and analyzed for TGF-ß1, TGF-ß2, and IgA. The results suggest that parity and mode of delivery may be correlated with the concentrations of immune factors in colostrum. However, we found no association between the immune factors in colostrum and the use of labor-inducing medications, colostrum secretion, sex of newborns, breast or nipple problems, and nipple care. These findings have some implications for further analysis of the effects of immune factors in breast milk on the prognosis of allergies in children.