Publications by authors named "Naoki Shimojo"

137 Publications

The Milk Metabolome of Non-secretor and Lewis Negative Mothers.

Front Nutr 2020 2;7:576966. Epub 2021 Feb 2.

Department of Food Science and Technology, University of California, Davis, Davis, CA, United States.

The functional role of milk for the developing neonate is an area of great interest, and a significant amount of research has been done. However, a lot of work remains to fully understand the complexities of milk, and the variations imposed through genetics. It has previously been shown that both secretor (Se) and Lewis blood type (Le) status impacts the human milk oligosaccharide (HMO) content of human milk. While some studies have compared the non-HMO milk metabolome of Se+ and Se- women, none have reported on the non-HMO milk metabolome of Se- and Le- mothers. To determine the differences in the non-HMO milk metabolome between Se-Le- mothers and other HMO phenotypes (Se+Le+, Se+Le-, and Se-Le+), 10 milk samples from 10 lactating mothers were analyzed using nuclear magnetic resonance (NMR) spectroscopy. Se or Le HMO phenotypes were assigned based on the presence and absence of 6 HMOs generated by the Se and Le genes. After classification, 58 milk metabolites were compared among the HMO phenotypes. Principal component analysis (PCA) identified clear separation between Se-Le- milk and the other milks. Fold change analysis demonstrated that the Se-Le- milk had major differences in free fatty acids, free amino acids, and metabolites related to energy metabolism. The results of this brief research report suggest that the milk metabolome of mothers with the Se-Le- phenotype differs in its non-HMO metabolite composition from mothers with other HMO phenotypes.
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http://dx.doi.org/10.3389/fnut.2020.576966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901958PMC
February 2021

Time course of disease severity from birth to 19 years old in patients with moderate to severe atopic dermatitis in adulthood.

J Dermatol 2021 Feb 23. Epub 2021 Feb 23.

Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

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http://dx.doi.org/10.1111/1346-8138.15790DOI Listing
February 2021

[ALLERGIC DISEASES AND MICROBIOME].

Authors:
Naoki Shimojo

Arerugi 2021 ;70(1):19-25

Center for Preventive Medical Sciences, Chiba University.

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http://dx.doi.org/10.15036/arerugi.70.19DOI Listing
January 2021

Skincare interventions in infants for preventing eczema and food allergy: A cochrane systematic review and individual participant data meta-analysis.

Clin Exp Allergy 2021 Mar 25;51(3):402-418. Epub 2021 Feb 25.

National Heart and Lung Institute, Imperial College London, London, UK.

Objective: Eczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy.

Design: A prospectively planned individual participant data meta-analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy.

Data Sources: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020.

Eligibility Criteria For Selected Studies: Included studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years.

Results: Of the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta-analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3-12 months. Skincare interventions probably do not change risk of eczema by age 1-3 years (RR 1.03, 95% CI 0.81, 1.31; I =41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1-3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I =0%; moderate certainty; 2728 participants, 6 trials).

Conclusion: Regular emollients during infancy probably do not prevent eczema and probably increase local skin infections.
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http://dx.doi.org/10.1111/cea.13847DOI Listing
March 2021

Skin care interventions in infants for preventing eczema and food allergy.

Cochrane Database Syst Rev 2021 02 5;2:CD013534. Epub 2021 Feb 5.

National Heart & Lung Institute, Section of Inflammation and Repair, Imperial College London, London, UK.

Background: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy.

Objectives: Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy.

Search Methods: We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials.

Selection Criteria: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required.

Data Collection And Analysis: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured by the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen.

Main Results: This review identified 33 RCTs, comprising 25,827 participants. A total of 17 studies, randomising 5823 participants, reported information on one or more outcomes specified in this review. Eleven studies randomising 5217 participants, with 10 of these studies providing IPD, were included in one or more meta-analysis (range 2 to 9 studies per individual meta-analysis). Most studies were conducted at children's hospitals. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported our outcomes, 13 assessed emollients. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to two years. We assessed most of this review's evidence as low certainty or had some concerns of risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. Evidence for the primary food allergy outcome was rated as high risk of bias due to inclusion of only one trial where findings varied when different assumptions were made about missing data. Skin care interventions during infancy probably do not change risk of eczema by one to two years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; moderate-certainty evidence; 3075 participants, 7 trials) nor time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). It is unclear whether skin care interventions during infancy change risk of IgE-mediated food allergy by one to two years of age (RR 2.53, 95% CI 0.99 to 6.47; 996 participants, 1 trial) or allergic sensitisation to a food allergen at age one to two years (RR 0.86, 95% CI 0.28 to 2.69; 1055 participants, 2 trials) due to very low-certainty evidence for these outcomes. Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial). However, this was only seen for cow's milk, and may be unreliable due to significant over-reporting of cow's milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.34, 95% CI 1.02 to 1.77; moderate-certainty evidence; 2728 participants, 6 trials) and may increase risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) or stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although confidence intervals for slippages and stinging/allergic reactions are wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses show that effects of interventions were not influenced by age, duration of intervention, hereditary risk, FLG mutation,  or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and risk of developing eczema or food allergy.

Authors' Conclusions: Skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema, and probably increase risk of skin infection. Effects of skin care interventions on risk of food allergy are uncertain. Further work is needed to understand whether different approaches to infant skin care might promote or prevent eczema and to evaluate effects on food allergy based on robust outcome assessments.
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http://dx.doi.org/10.1002/14651858.CD013534.pub2DOI Listing
February 2021

Human Milk From Atopic Mothers Has Lower Levels of Short Chain Fatty Acids.

Front Immunol 2020 21;11:1427. Epub 2020 Jul 21.

inVIVO Planetary Health of the Worldwide Universities Network (WUN), West New York, NJ, United States.

Short chain fatty acids (SFCAs) are microbial metabolites produced in the gut upon fermentation of dietary fiber. These metabolites interact with the host immune system and can elicit epigenetic effects. There is evidence to suggest that SCFAs may play a role in the developmental programming of immune disorders and obesity, though evidence in humans remains sparse. Here we have quantified human milk (HM) SCFA levels in an international cohort of atopic and non-atopic mothers ( = 109). Our results demonstrate that human milk contains detectable levels of the SCFAs acetate, butyrate, and formate. Samples from atopic mothers had significantly lower concentrations of acetate and butyrate than those of non-atopic mothers. HM SCFA levels in atopic and non-atopic women also varied based on maternal country of residence (Australia, Japan, Norway, South Africa, USA). Reduced exposure to HM SCFA in early life may program atopy or overweight risk in breastfed infants.
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http://dx.doi.org/10.3389/fimmu.2020.01427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396598PMC
April 2021

Specific temperament in patients with nevoid basal cell carcinoma syndrome.

Pediatr Int 2021 Feb 4;63(2):177-182. Epub 2021 Feb 4.

Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Nevoid basal cell carcinoma syndrome (NBCCS) is a neurocutaneous disease, characterized by tumorigenesis and developmental anomalies due to aberrant sonic hedgehog (Shh) signaling. Patients with NBCCS typically appear calm and carefree, suggesting that a specific personality in these patients may be associated with an enhanced hedgehog pathway. Our study aimed to determine the personality type in these patients.

Methods: We enrolled 14 mentally normal patients with genetically confirmed NBCCS (seven males and seven females; mean age = 25.2 years) and 20 controls (10 males and 10 females; mean age = 27.9 years). The patients were assessed with the Japanese version of the Temperament and Character Inventory, based on the seven-dimensional model of temperament and character, and their clinical symptoms were evaluated. The amygdala volumes of six patients with NBCCS were measured using magnetic resonance imaging with image-processing software.

Results: Patients with NBCCS scored significantly lower on harm avoidance (0.89) than controls (1.00; P = 0.0084). Moreover, patients with NBCCS and developmental malformations such as rib anomalies, who may have experienced Shh signaling enhancement from the prenatal period, scored significantly lower on harm avoidance (0.80 [P = 0.0031]). The left amygdala volume was also significantly reduced in patients with NBCCS (P = 0.0426).

Conclusions: Patients with NBCCS who experienced increased Shh signaling from the prenatal period showed significantly lower harm avoidance related to serotonin. The left amygdala volume was significantly reduced in these patients. Our results indicate that Shh signaling may influence the human personality.
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http://dx.doi.org/10.1111/ped.14419DOI Listing
February 2021

JPH203, a newly developed anti-cancer drug, shows a preincubation inhibitory effect on L-type amino acid transporter 1 function.

J Pharmacol Sci 2020 Sep 24;144(1):16-22. Epub 2020 Jun 24.

Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Tochigi, Japan. Electronic address:

JPH203 is a novel anti-cancer drug targeting L-type amino acid transporter 1 (LAT1), which plays a primary role in the uptake of essential amino acids in tumor cells. Although a co-incubation inhibitory effect of JPH203 has been shown in a conventional uptake assay, its preincubation inhibitory effects have remained undetermined. Therefore, we aimed to characterize the preincubation inhibitory effects of JPH203 on LAT1 function using leucine uptake assays in LAT1-positive human colon cancer HT-29 cells. Preincubation of the cells with JPH203 (0.3 μM for 120 min) decreased the activity level to 30% of that in dimethylsulfoxide-treated cells. Similarly, in time-dependency analysis, preincubation of HT-29 cells with 10 μM JPH203 for 30, 60, and 120 min decreased the leucine uptake activity (42%, 32%, and 28% of that in control cells, respectively). Furthermore, the IC value of the combination of preincubation and co-incubation effects was lower than that of co-incubation inhibition alone (34.2 ± 3.6 nM vs. 99.2 ± 11.0 nM). In conclusion, we revealed that JPH203 has the capability to inhibit LAT1 function through preincubation effects. Moreover, preincubation synergistically enhances the co-incubation inhibitory effects. These findings provide a novel insight into the anti-cancer effects of JPH203 in cancer therapy.
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http://dx.doi.org/10.1016/j.jphs.2020.06.006DOI Listing
September 2020

Agr virulence is critical for epidermal colonization and associates with atopic dermatitis development.

Sci Transl Med 2020 07;12(551)

Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.

Atopic dermatitis (AD) is commonly associated with colonization by in the affected skin. To understand the role of in the development of AD, we performed whole-genome sequencing of strains isolated from the cheek skin of 268 Japanese infants 1 and 6 months after birth. About 45% of infants were colonized with at 1 month regardless of AD outcome. In contrast, skin colonization by at 6 months of age increased the risk of developing AD. Acquisition of dysfunctional mutations in the Agr quorum-sensing (QS) system was primarily observed in strains from 6-month-old infants who did not develop AD. Expression of a functional Agr system in was required for epidermal colonization and the induction of AD-like inflammation in mice. Thus, retention of functional virulence during infancy is associated with pathogen skin colonization and the development of AD.
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http://dx.doi.org/10.1126/scitranslmed.aay4068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426015PMC
July 2020

A Double-Blind, Randomized, Placebo-Controlled Trial of Heat-Killed K15 for Prevention of Respiratory Tract Infections among Preschool Children.

Nutrients 2020 Jul 3;12(7). Epub 2020 Jul 3.

Department of Pediatrics, Chiba University Hospital, Chiba 260-8670, Japan.

Although some probiotic bacteria have been reported to prevent infections in children, there are few well-designed double-blind studies. Here we evaluated the effects of a probiotic strain of lactic acid bacteria (LAB), K15, on viral respiratory tract infections in preschool children. A four-month, randomized, double-blind, placebo-controlled study was performed in 172 healthy children aged 3 to 6 years. Subjects were administered dextrin alone or dextrin including heat-killed K15 (5 × 10 bacteria). The number of febrile days was the primary outcome. The number of absent days from preschools and the influenza incidence were secondary outcomes. Secretory IgA (sIgA) concentrations in saliva were measured as an exploratory outcome. The primary and secondary outcomes were not significantly different between both groups. Analyses in children with little intake of fermented foods including LAB showed that the duration of a fever significantly decreased by K15 intake. The salivary sIgA level in the K15 group was maintained significantly higher than it was in the placebo group. The effects of K15 on preventing viral respiratory tract infections were not observed without the restriction of fermented foods intake. However, K15 supported anti-infectious immune systems in children who took less fermented foods and the maintenance of salivary sIgA levels in all subjects.
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http://dx.doi.org/10.3390/nu12071989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400799PMC
July 2020

Fulminant myocarditis following recurrent generalized erythrokeratoderma in a child with a heterozygous GJA1 variant.

Am J Med Genet A 2020 08 25;182(8):1933-1938. Epub 2020 May 25.

Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan.

Pathogenic germline variants in the gap junction protein alpha 1 (GJA1) gene have been identified in several congenital disorders affecting cutaneous, skeletal, and cardiac tissues. Here, we describe a 12-year-old patient with a GJA1 c.113G>A, p.(Gly38Glu) variant, who presented with fulminant myocarditis following recurrent generalized erythrokeratoderma. His mother and younger sister had the same clinical manifestations with the same GJA1 variant, but did not have cardiac dysfunction. GJA1 variants have been reported in patients with congenital cardiac malformations, while acute myocarditis in GJA1-related disorders has not been reported so far.
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http://dx.doi.org/10.1002/ajmg.a.61626DOI Listing
August 2020

Haemophilus influenzae type b capsular polysaccharide antibody levels in Japanese young patients with hematological malignancies and asplenia.

J Infect Chemother 2020 Sep 10;26(9):959-962. Epub 2020 May 10.

Department of Pediatrics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan.

Individuals with immunosuppressive condition have a high risk of invasive Haemophilus influenzae type b (Hib) infection. In Japan, routine Hib vaccination program for children under 5 years old was introduced in December 2008. However, the national policy does not make provision for individuals aged ≥5 years who have medical conditions associated with a high risk of invasive Hib disease to receive Hib vaccine. We measured serum anti-polyribosylribitol phosphate specific (anti-PRP) antibodies to Hib in patients aged ≥5 years with hematological malignancies and asplenia and evaluated their levels of anti-PRP antibodies in post administration of Hib vaccine era. A total of 65 patients (48 with hematological malignancies, and 17 with asplenia) were included in this study, of which 84% had not received Hib vaccine. In addition, 95.4% had short-term protective levels of anti-PRP antibodies (defined as ≥0.15 μg/mL) and 41.5% had long-term protective levels of anti-PRP antibodies (defined as ≥1.0 μg/mL). Five patients had low anti-PRP antibody levels despite a history of Hib vaccination. Our results suggest that young patients with underlying diseases such as hematological malignancies and asplenia may be at risk of invasive Hib disease. Hence, we recommend they should receive Hib vaccines even if they are over the age limit for routine Hib vaccination program.
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http://dx.doi.org/10.1016/j.jiac.2020.04.021DOI Listing
September 2020

Activated invariant natural killer T cells directly recognize leukemia cells in a CD1d-independent manner.

Cancer Sci 2020 Jul 19;111(7):2223-2233. Epub 2020 Jun 19.

Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of Vα24 and Vβ11 in humans. iNKT cells specifically recognize glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d. iNKT cells show direct cytotoxicity toward CD1d-positive tumor cells, especially when CD1d presents glycolipid antigens. However, iNKT cell recognition of CD1d-negative tumor cells is unknown, and direct cytotoxicity of iNKT cells toward CD1d-negative tumor cells remains controversial. Here, we demonstrate that activated iNKT cells recognize leukemia cells in a CD1d-independent manner, however still in a TCR-mediated way. iNKT cells degranulated and released Th1 cytokines toward CD1d-negative leukemia cells (K562, HL-60, REH) as well as αGalCer-loaded CD1d-positive Jurkat cells. The CD1d-independent cytotoxicity was enhanced by natural killer cell-activating receptors such as NKG2D, 2B4, DNAM-1, LFA-1 and CD2, but iNKT cells did not depend on these receptors for the recognition of CD1d-negative leukemia cells. In contrast, TCR was essential for CD1d-independent recognition and cytotoxicity. iNKT cells degranulated toward patient-derived leukemia cells independently of CD1d expression. iNKT cells targeted myeloid malignancies more than acute lymphoblastic leukemia. These findings reveal a novel anti-tumor mechanism of iNKT cells in targeting CD1d-negative tumor cells and indicate the potential of iNKT cells for clinical application to treat leukemia independently of CD1d.
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http://dx.doi.org/10.1111/cas.14428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385353PMC
July 2020

Japanese guidelines for atopic dermatitis 2020.

Allergol Int 2020 Jul 4;69(3):356-369. Epub 2020 Apr 4.

Allergy Center, National Center for Child Health and Development, Tokyo, Japan.

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion, which is frequently encountered in clinical practice. Skin barrier dysfunction leads to enhanced skin irritability to non-specific stimuli and epicutaneous sensitization. In the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability and scratching-related stimuli deteriorate eczema, leading to vicious cycle of inflammation. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.
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http://dx.doi.org/10.1016/j.alit.2020.02.006DOI Listing
July 2020

Infectious endocarditis with abdominal pain after shedding of deciduous teeth.

Pediatr Int 2020 Mar;62(3):414-416

Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan.

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http://dx.doi.org/10.1111/ped.14091DOI Listing
March 2020

Establishment of a Gorlin syndrome model from induced neural progenitor cells exhibiting constitutive GLI1 expression and high sensitivity to inhibition by smoothened (SMO).

Lab Invest 2020 04 22;100(4):657-664. Epub 2019 Nov 22.

Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1, Okura, Setagaya, Tokyo, 157-8535, Japan.

The hedgehog signaling pathway is a vital factor for embryonic development and stem cell maintenance. Dysregulation of its function results in tumor initiation and progression. The aim of this research was to establish a disease model of hedgehog-related tumorigenesis with Gorlin syndrome-derived induced pluripotent stem cells (GS-iPSCs). Induced neural progenitor cells from GS-iPSCs (GS-NPCs) show constitutive high GLI1 expression and higher sensitivity to smoothened (SMO) inhibition compared with wild-type induced neural progenitor cells (WT-NPCs). The differentiation process from iPSCs to NPCs may have similarity in gene expression to Hedgehog signal-related carcinogenesis. Therefore, GS-NPCs may be useful for screening compounds to find effective drugs to control Hedgehog signaling activity.
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http://dx.doi.org/10.1038/s41374-019-0346-2DOI Listing
April 2020

Association of the maternal microbiome in Japanese pregnant women with the cumulative prevalence of dermatitis in early infancy: A pilot study from the Chiba study of Mother and Child Health birth cohort.

World Allergy Organ J 2019 Oct 1;12(10):100065. Epub 2019 Nov 1.

Center for Preventive Medical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background: The prenatal maternal microbiome, including the gut microbiota, has been suggested to influence the incidence of allergies in offspring. Moreover, epidermal barrier dysfunction in early infancy has been attributed to the development of subsequent allergies. We hypothesized that the prenatal microbiome may affect the gut microbiota, acting as an initial trigger to alter immune development in the foetus. The maternal microbial composition may be linked to the prevalence of dermatitis in early infancy (DEI) of the offspring, leading to subsequent allergic symptoms.

Methods: This study was conducted as part of the Chiba Study of Mother and Child Health (C-MACH) birth cohort that was initiated in 2013; 434 healthy pregnant women at < 13 weeks of gestation were recruited. DEI was assessed for up to 4 months after birth, and allergic symptoms were determined in 10-month-old infants using questionnaires. Other information related to the maternal microbiome was obtained from questionnaires filled out during pregnancy. Stool samples were collected from pregnant women at 12 ( = 59) and 32 weeks ( = 58) of gestation, which were used for gut microbiota analysis using barcoded 16S rRNA gene sequencing.

Results: Symptoms of allergy, especially of inherited allergies, show a higher prevalence at 10 months after birth in the DEI group. DEI occurrence was negatively correlated with family size and cat ownership. The diversity of Proteobacteria at 12 weeks of gestation and the relative abundance of Actinobacteria at 32 weeks of gestation in maternal feces were lower at both time points of gestation in the DEI group. In addition, the diversity of Proteobacteria in prenatal feces was negatively correlated with family size at 12 weeks, and with dog ownership at both gestational time points.

Conclusions: The composition of the maternal microbiome may influence the risk of allergies in offspring, even before birth. Furthermore, the diversity of Proteobacteria and the relative abundance of Actinobacteria in maternal feces were negatively associated with DEI, which may be associated with the risk of allergy development in infancy. This early trigger may be a good predictor of allergy development during infancy and childhood.
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http://dx.doi.org/10.1016/j.waojou.2019.100065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838981PMC
October 2019

No association between prenatal antibiotic exposure and atopic dermatitis among Japanese infants.

Pediatr Allergy Immunol 2020 02 26;31(2):218-221. Epub 2019 Nov 26.

Department of Sustainable Health Science, Center for Preventive Medical Sciences, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1111/pai.13156DOI Listing
February 2020

Clinical practice guidelines for the management of atopic dermatitis 2018.

J Dermatol 2019 Dec 9;46(12):1053-1101. Epub 2019 Oct 9.

Allergy Center, National Center for Child Health and Development, Tokyo, Japan.

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.
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http://dx.doi.org/10.1111/1346-8138.15090DOI Listing
December 2019

Consensus statements on pediatric atopic dermatitis from dermatology and pediatrics practitioners in Japan: Goals of treatment and topical therapy.

Allergol Int 2020 Jan 23;69(1):84-90. Epub 2019 Sep 23.

Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.

Background: Pediatric atopic dermatitis (PAD) is a pluricausal disease and is frequently seen in dermatological and pediatric practice. Therefore, it is important to find common views in clinical practice and to promote consensus among practitioners. Aiming to obtain common views among dermatologists and pediatricians and to disseminate them widely in clinical practice, we held the PAD Consensus Forums described herein.

Methods: Questionnaire surveys of treatment goals and drug therapy were conducted to prepare topics for discussion at the PAD Consensus Forums. Reaching consensus was defined as agreement among at least 70% of the participants.

Results: As a result of discussion among 24 dermatologists and 25 pediatricians, consensus was obtained on 7 topics. These topics configure 3 consensus of treatment goals (Attainment targets were divided into the short/medium term and the long term. Attainment targets were associated with the primary evaluation domains of the Harmonising Outcome Measures for Eczema (HOME) roadmap, etc.) and 4 consensus of drug therapy (The number of applications of topical anti-inflammatory drugs in the acute phase and selection and ideal intervals between applications of topical anti-inflammatory drugs in proactive therapy, etc.).

Conclusions: The consensus is expected to help practitioners set appropriate treatment goals in clinical practice and facilitate the choice of drugs for treatment.
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http://dx.doi.org/10.1016/j.alit.2019.08.006DOI Listing
January 2020

Soluble CD14 in Breast Milk and Its Relation to Atopic Manifestations in Early Infancy.

Nutrients 2019 Sep 5;11(9). Epub 2019 Sep 5.

Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba 2608670, Japan.

Soluble CD14 (sCD14) is one of the immunomodulatory factors in breast milk (BM). Although it may be involved in the prevention of atopic symptoms and sensitization to both food and inhalant allergens, conflicting evidence exists concerning its protective effects. In this study, we investigated the relationship between sCD14 in colostrum and 1-month BM, and the development of atopic dermatitis (AD) and sensitization to food and aeroallergens at 9 months of age in infants who were exclusively or almost exclusively breastfed up to 4 months of age. BM samples were collected from lactating mothers who participated in a 2 × 2 factorial, randomized, nontreatment controlled trial study set in Tokyo, which looked at the efficacy of emollients and synbiotics in preventing AD and food allergy in children during the first year of life. A total of 258 colostrum samples and 269 1-month BM samples were analyzed. We found that one-month BM sCD14 levels in the AD group were significantly lower than in the non-AD group. Levels of sCD14 in 1-month BM were not related to allergen sensitization in the overall analysis, but egg white sensitization correlated inversely with 1-month BM sCD14 in infants without AD. The results suggest that sCD14 in BM may be involved in atopic manifestations in early infancy.
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http://dx.doi.org/10.3390/nu11092118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770418PMC
September 2019

Skin Care and Synbiotics for Prevention of Atopic Dermatitis or Food Allergy in Newborn Infants: A 2 × 2 Factorial, Randomized, Non-Treatment Controlled Trial.

Int Arch Allergy Immunol 2019 8;180(3):202-211. Epub 2019 Aug 8.

Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba, Japan,

Background: Atopic dermatitis (AD) and food allergy (FA) are common childhood diseases, which may either be interrelated or be the result of skin barrier disruption and gut mucosal dysbiosis. Although some evidence suggests the efficacy of emollients and synbiotics, there is no conclusive evidence on the use of these interventions alone or in combination.

Objectives: This study is aimed at identifying the efficacy of emollients and synbiotics in preventing AD and FA in children during the first year of life.

Methods: The babies of mothers recruited prenatally received either an emollient, synbiotic, both or neither. The intervention was carried out from birth up to 6 months of age. The age of occurrence of AD and FA were reported in multiple questionnaires at 1, 6, and 9 months and at 1 year of age. AD was diagnosed by a pediatrician at 9 months of age.

Results: A -total of 459 babies qualified for the outcome assessment at 1 year of age. Neither the emollient nor the synbiotic showed any effect on reducing the development of AD and FA at 1 year of age.

Conclusions: This study did not provide any evidence to show that emollients and synbiotics, alone or in combination are sufficient to prevent the occurrence of AD or FA in children up to 1 year of age.
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http://dx.doi.org/10.1159/000501636DOI Listing
December 2019

MicroRNAs profiling in fibroblasts derived from patients with Gorlin syndrome.

J Hum Genet 2019 Aug 14;64(8):757-765. Epub 2019 May 14.

Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan.

Gorlin syndrome (GS) is a hereditary disorder with tumorigenicity, caused by constitutive hyperactivity of hedgehog signaling. Smoothened (SMO) antagonists have been effectively used in the clinical treatment of hedgehog signaling-related cancer. However, these treatments have led to problematic side effects, including severe adverse reactions and drug resistance from additional somatic mutations. We profiled microRNAs in GS fibroblasts to explore a novel therapeutic target for controlling hyper-activated hedgehog signaling. To identify GS-related microRNAs, we analyzed dermal fibroblasts from five patients with GS and three normal controls. We used microarray comparative genomic hybridization to screen 632 human microRNAs in GS fibroblasts. We identified 16 down- and 19 upregulated microRNAs with over twofold change in expression. We validated the increased expression of four microRNAs, confirming hsa-miR-196a-5p downregulation and hsa-miR-4485 upregulation using real-time PCR. Moreover, hsa-miR-196a-5p is complementary to sites in the 3' UTR of MAP3K1, which exhibits upregulated expression at mRNA and protein levels in GS fibroblasts. In addition, hedgehog signal induction with exogenous components decreased miR-196a-5p expression and increased map3k1 expression in a mouse mesenchymal cell line. Given that MAP3K1 has been reported to activate hedgehog signaling, hsa-miR-196a-5p may contribute to the positive feedback loop in this pathway.
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http://dx.doi.org/10.1038/s10038-019-0607-3DOI Listing
August 2019

Usefulness of Gastric Aspirate Culture for Diagnosing Congenital Immunodeficiency in an Infant with Fungal Pneumonia Caused by Rasamsonia piperina.

Tohoku J Exp Med 2019 04;247(4):265-269

Department of Pediatrics, Chiba University Graduate School of Medicine.

Chronic granulomatous disease (CGD) is a type of primary immunodeficiency disease, which increases susceptibility to recurrent bacterial and fungal infections. Sputum and bronchoalveolar lavage fluid are often obtained using bronchoscopy from adult patients for pathogenic diagnosis, although this approach is much more invasive for infants. We report the case of a 2-month-old boy with CGD, in which gastric aspirate culture was used to diagnose fungal pneumonia. Rasamsonia piperina was isolated from the gastric aspirate, and the patient was successfully treated with micafungin based on the drug susceptibility test results for the fungal isolate. The acid tolerance test revealed that R. piperina could grow at pH 2, indicating high acid resistance. Although we can only report our experience with a single case, gastric aspirate culture may be a useful tool for detecting fungal respiratory pathogens in children with primary immunodeficiency. Detecting these pathogens may help improve outcomes, as early diagnosis and appropriate treatment are extremely important for immunocompromised patients with respiratory infections.
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http://dx.doi.org/10.1620/tjem.247.265DOI Listing
April 2019

Sivelestat sodium hydrate treatment for refractory Kawasaki disease.

Pediatr Int 2019 May 17;61(5):438-443. Epub 2019 May 17.

Department of Pediatrics, Graduate School of Medicine, Chiba University, Yachiyo, Japan.

Background: There is still no definite treatment for refractory Kawasaki disease (KD). In this pilot study, we evaluated the safety and efficacy of a new protocol consisting of sivelestat sodium hydrate (SSH) combined with additional i.v. immunoglobulin (IVIG) for KD resistant to initial IVIG therapy.

Methods: This study is a prospective non-randomized, open-label and single-arm study undertaken in a population of refractory KD patients at Chiba University Hospital from December 2006 to March 2016. The subjects had KD resistant to initial IVIG (2 g/kg) and received SSH (0.2 mg/kg/h for 5 days) combined with additional IVIG (2 g/kg) as a second-line therapy. We evaluated the safety and efficacy of the treatment during the study period.

Results: Forty-six KD patients were enrolled in this study and no serious adverse event was noted. Of these, 45 patients were evaluated for the incidence of coronary artery lesions, which occurred in one patient (2.2%; 95% CI: 0.5-15.2). Twenty-eight (62.2%) responded promptly and were afebrile after the therapy. The median total duration of fever was 8 days (range, 6-28 days).

Conclusions: Additional IVIG combined with SSH as a second-line therapy for KD refractory to initial IVIG therapy was safe and well tolerated and could be a promising option for severe KD. Further investigations are expected to clarify the safety and timing of SSH treatment for KD.
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http://dx.doi.org/10.1111/ped.13851DOI Listing
May 2019

Psoitis and multiple venous thromboses caused by Panton Valentine Leukocidin-positive methicillin-sensitive Staphylococcus aureus in a 12-year-old girl: A case report.

J Infect Chemother 2019 Aug 20;25(8):630-634. Epub 2019 Mar 20.

Department of Pediatrics, Graduate School of Medicine, Chiba University, Japan.

Panton Valentine Leukocidin (PVL) is one of the many toxins produced by Staphylococcus aureus. In Japan, PVL-positive S. aureus strains are mainly methicillin-resistant S. aureus (MRSA). Data regarding PVL-positive methicillin-sensitive S. aureus (MSSA) are scarce. In this report, we describe a case of severe infection by PVL-positive MSSA. A 12-year-old healthy girl was admitted with high fever and pain in the lower back. Computed tomography revealed a diagnosis of psoitis and multiple venous thromboses. Blood cultures obtained after admission revealed infection with MSSA. Her fever continued despite adequate antibiotic therapy. On the fifth hospitalization day, she developed bladder dysfunction, and an abscess was noted near the third lumbar vertebra. She underwent an emergency operation and recovered. Bacterial analyses revealed that the causative MSSA was a PVL-producing single variant of ST8 (related to USA300clone), of sequence type 2149. PVL is known to cause platelet activation. This case demonstrates the need for detailed analyses of the causative strain of bacteria in cases of S. aureus infection with deep vein thrombosis, even in cases of known MSSA infection.
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http://dx.doi.org/10.1016/j.jiac.2019.02.019DOI Listing
August 2019

Two pediatric cases of Pneumocystis jirovecii pneumonia diagnosed by polymerase chain reaction of gastric lavage.

J Infect Chemother 2019 Jun 21;25(6):477-479. Epub 2019 Feb 21.

Department of Pediatrics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo ku, Chiba City, Chiba, 260-8677, Japan.

Detecting Pneumocystis jirovecii by bronchoalveolar lavage or lung biopsy is the gold standard for diagnosis of P. jirovecii pneumonia (PJP); however, these techniques are not always applicable in children because of their high invasiveness. We report two pediatric cases of PJP diagnosed by polymerase chain reaction (PCR) of gastric lavage that were successfully treated. To date, there are no reported cases of using PCR of gastric lavage to diagnose PJP. On the day of PJP onset, both the infants required respiratory support and infiltrative shadows were observed in both lung fields on chest radiography. Furthermore, their (1 → 3)-β-D glucan levels were elevated. P. jirovecii was detected by PCR of gastric lavage and trimethoprim-sulfamethoxazole was administered for 3 weeks, following which their condition improved. They were long-term steroid users, but without any prophylaxis. PCR of gastric lavage in cases of suspected PJP may help in confirming the diagnosis in children who have mild to moderate airway symptoms, or have difficulty with invasive examination like bronchoscopy.
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http://dx.doi.org/10.1016/j.jiac.2019.01.016DOI Listing
June 2019

Worldwide Variation in Human Milk Metabolome: Indicators of Breast Physiology and Maternal Lifestyle?

Nutrients 2018 Aug 23;10(9). Epub 2018 Aug 23.

Departments of Pediatrics/Obstetrics & Gynecology, School of Public Health, University of Alberta, Edmonton, Alberta AB T6G 1C9, Canada.

Human milk provides essential substrates for the optimal growth and development of a breastfed infant. Besides providing nutrients to the infant, human milk also contains metabolites which form an intricate system between maternal lifestyle, such as the mother's diet and the gut microbiome, and infant outcomes. This study investigates the variation of these human milk metabolites from five different countries. Human milk samples ( = 109) were collected one month postpartum from Australia, Japan, the USA, Norway, and South Africa and were analyzed by nuclear magnetic resonance. The partial least squares discriminant analysis (PLS-DA) showed separation between either maternal countries of origin or ethnicities. Variation between countries in concentration of metabolites, such as 2-oxoglutarate, creatine, and glutamine, in human milk, between countries, could provide insights into problems, such as mastitis and/or impaired functions of the mammary glands. Several important markers of milk production, such as lactose, betaine, creatine, glutamate, and glutamine, showed good correlation between each metabolite. This work highlights the importance of milk metabolites with respect to maternal lifestyle and the environment, and also provides the framework for future breastfeeding and microbiome studies in a global context.
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http://dx.doi.org/10.3390/nu10091151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163258PMC
August 2018