Japanese guidelines for childhood asthma 2017.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2017 (JAGL 2017) includes a minor revision of the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. The section on child asthma in JAGL 2017 provides information on how to diagnose asthma between infancy and adolescence (0-15 years of age). It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. This guideline will be of interest to non-specialist physicians involved in the care of children with asthma. JAGL differs from the Global Initiative for Asthma Guideline in that JAGL emphasizes diagnosis and early intervention of children with asthma at <2 years or 2-5 years of age. The first choice of treatment depends on the severity and frequency of symptoms. Pharmacological management, including step-up or step-down of drugs used for long-term management based on the status of asthma control levels, is easy to understand; thus, this guideline is suitable for the routine medical care of children with asthma. JAGL also recommends using a control test in children, so that the physician aims for complete control by avoiding exacerbating factors and appropriately using anti-inflammatory drugs (for example, inhaled corticosteroids and leukotriene receptor antagonists).

Identification of consensus motifs associated with mitotic recombination and clinical characteristics in patients with paternal uniparental isodisomy of chromosome 11.

Uniparental disomy (UPD) is defined as the inheritance of both homologs of a given genomic region from only one parent. The majority of UPD includes an entire chromosome. However, the extent of UPD is sometimes limited to a subchromosomal region (segmental UPD). Mosaic paternal UPD (pUPD) of chromosome 11 is found in approximately 20% of patients with Beckwith-Wiedemann syndrome (BWS) and almost all pUPDs are segmental isodisomic pUPDs resulting from mitotic recombination at an early embryonic stage. A mechanism initiating a DNA double strand break (DSB) within 11p has been predicted to lead to segmental pUPD. However, no consensus motif has yet been found. Here, we analyzed 32 BWS patients with pUPD by SNP array and searched for consensus motifs. We identified four consensus motifs frequently appearing within breakpoint regions of segmental pUPD. These motifs were found in another nine BWS patients with pUPD. In addition, the seven motifs found in meiotic recombination hot spots could not be found within pUPD breakpoint regions. Histone H3 lysine 4 trimethylation, a marker of DSB initiation, could not be found either. These findings suggest that the mechanism(s) of mitotic recombination leading to segmental pUPD are different from that of meiotic recombination. Furthermore, we found seven patients with paternal uniparental diploidy (PUD) mosaicism. Comparison of clinical features between segmental pUPDs and PUDs showed that developmental disability and cardiac abnormalities were additional characteristic features of PUD mosaicism, along with high risk of tumor development. We also found that macroglossia was characteristic of segmental pUPD mosaicism.

Japanese pediatric guideline for the treatment and management of bronchial asthma 2012.

A new version of the Japanese pediatric guideline for the treatment and management of bronchial asthma was published in Japanese at the end of 2011. The guideline sets the pragmatic goal for clinicians treating childhood asthma as maintaining a "well-controlled level" for an extended period in which the child patient can lead a trouble-free daily life, not forgetting the ultimate goal of obtaining remission and/or cure. Important factors in the attainment of the pragmatic goal are: (i) appropriate use of anti-inflammatory drugs; (ii) elimination of environmental risk factors; and (iii) educational and enlightening activities for the patient and caregivers regarding adequate asthma management in daily life. The well-controlled level refers to a symptom-free state in which no transient coughs, wheezing, dyspnea or other symptoms associated with bronchial asthma are present, even for a short period of time. As was the case in the previous versions of the guideline, asthmatic children younger than 2 years of age are defined as infantile asthma patients. Special attention is paid to these patients in the new guideline: they often have rapid exacerbation and easily present chronic asthmatic conditions after the disease is established.

Japanese Guideline for Childhood Asthma 2014.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2013 (JAGL 2013) describes childhood asthma after the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. JAGL 2013 provides information on diagnosis by age group from infancy to puberty (0-15 years of age), treatment for acute exacerbations, long-term management by anti-inflammatory drugs, daily life guidance, and patient education to allow non-specialist physicians to refer to this guideline for routine medical treatment. JAGL differs from the Global Initiative for Asthma Guideline (GINA) in that JAGL emphasizes early diagnosis and intervention at <2 years and 2-5 years of age. A management method, including step-up or step-down of long-term management drugs based on the status of asthma control levels, as in JAGL, is easy to understand, and thus the Guideline is suitable as a frame of reference for routine medical treatment. JAGL has also introduced treatment and management using a control test on children, recommending that the physician aim at complete control by avoiding exacerbation factors and by appropriate use of anti-inflammatory drugs.

Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions to aberrant methylation in Beckwith-Wiedemann syndrome with epimutations.

PURPOSE: Expression of imprinted genes is regulated by DNA methylation of differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome is an imprinting disorder caused by epimutations of DMRs at 11p15.5. To date, multiple methylation defects have been reported in Beckwith-Wiedemann syndrome patients with epimutations; however, limited numbers of DMRs have been analyzed. The susceptibility of DMRs to aberrant methylation, alteration of gene expression due to aberrant methylation, and causative factors for multiple methylation defects remain undetermined. METHODS: Comprehensive methylation analysis with two quantitative methods, matrix-assisted laser desorption/ionization mass spectrometry and bisulfite pyrosequencing, was conducted across 29 DMRs in 54 Beckwith-Wiedemann syndrome patients with epimutations. Allelic expressions of three genes with aberrant methylation were analyzed. All DMRs with aberrant methylation were sequenced. RESULTS: Thirty-four percent of KvDMR1-loss of methylation patients and 30% of H19DMR-gain of methylation patients showed multiple methylation defects. Maternally methylated DMRs were susceptible to aberrant hypomethylation in KvDMR1-loss of methylation patients. Biallelic expression of the genes was associated with aberrant methylation. Cis-acting pathological variations were not found in any aberrantly methylated DMR. CONCLUSION: Maternally methylated DMRs may be vulnerable to DNA demethylation during the preimplantation stage, when hypomethylation of KvDMR1 occurs, and aberrant methylation of DMRs affects imprinted gene expression. Cis-acting variations of the DMRs are not involved in the multiple methylation defects.

Japanese Guideline for Childhood Asthma 2014.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2013 (JAGL 2013) describes childhood asthma after the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. JAGL 2013 provides information on diagnosis by age group from infancy to puberty (0-15 years of age), treatment for acute exacerbations, long-term management by anti-inflammatory drugs, daily life guidance, and patient education to allow non-specialist physicians to refer to this guideline for routine medical treatment. JAGL differs from the Global Initiative for Asthma Guideline (GINA) in that JAGL emphasizes early diagnosis and intervention at <2 years and 2-5 years of age. A management method, including step-up or step-down of long-term management drugs based on the status of asthma control levels, as in JAGL, is easy to understand, and thus the Guideline is suitable as a frame of reference for routine medical treatment. JAGL has also introduced treatment and management using a control test on children, recommending that the physician aim at complete control by avoiding exacerbation factors and by appropriate use of anti-inflammatory drugs.

Periostin controls keratinocyte proliferation and differentiation by interacting with the paracrine IL-1α/IL-6 loop.

Proliferation and differentiation of keratinocytes are normally well balanced, but this balance can be perturbed in wound healing and is dysregulated in pathological conditions such as atopic dermatitis. Epithelial-mesenchymal interaction affects this event via the cross-talk of cytokines and growth factors. Periostin, a matricellular protein, has an important role during reepithelialization in wound healing and is critical for hyperproliferation of keratinocytes in atopic dermatitis. Here we investigated how periostin regulates proliferation and differentiation of keratinocytes in the epithelial-mesenchymal interactions using a three-dimensional organotypic air-liquid interface coculture system. The release of IL-1α from keratinocytes and subsequent IL-6 production from fibroblasts were critical for keratinocyte proliferation and differentiation. Periostin secreted from fibroblasts was required for IL-1α-induced IL-6 production and enhanced IL-6 production by activation of the NF-κB pathway synergistically with IL-1α. Thus, the combination of an autocrine loop of periostin and a paracrine loop composed of IL-1α and IL-6 regulates keratinocyte proliferation and differentiation in the epithelial-mesenchymal interactions, and periostin tunes the magnitude of keratinocyte proliferation and differentiation by interacting with the paracrine IL-1α/IL-6 loop.

Acute alcohol intoxication in a 15-day-old neonate.

We describe a 15-day-old newborn girl who was fed with formula milk that was accidentally diluted with sake (Japanese wine prepared from fermented rice). The clinical features were flushed skin, tachycardia and low blood pressure indicating circulatory failure, somnolence and metabolic acidosis without hypoglycemia. The serum ethanol concentration was 43.0 mg/dL at 3 h after intake. The patient recovered under intravenous fluid replacement without complications. Follow-up examinations at 1, 2, 3, 6 and 12 months confirmed normal psychomotor development.

Efficacy of dextromethorphan and cyclosporine a for acute encephalopathy.

Acute encephalopathy with biphasic seizures and late reduced diffusion was recently established clinicoradiologically as an encephalopathy syndrome. The outcome of this encephalopathy is characterized by a low mortality rate and high incidence of neurologic sequelae. Although the exact pathogenesis of this encephalopathy is uncertain, excitotoxic injury with delayed neuronal death is proposed. On the basis of this hypothesis, we tried a combination therapy of N-methyl-D-aspartate receptor antagonist, dextromethorphan, and apoptosis inhibitor, cyclosporine A, in four patients with acute encephalopathy with biphasic seizures and late reduced diffusion. All patients recovered except for hyperactivity in one patient. Furthermore, an additional four patients with near-miss encephalopathy, who showed mild disturbance of consciousness at 24 hours after prolonged febrile seizures associated with exanthem subitum, recovered without secondary seizures by the early administration of dextromethorphan. The combination regimen of dextromethorphan and cyclosporine A could be effective for the treatment and prevention of acute encephalopathy with biphasic seizures and late reduced diffusion.

A formyl peptide substituted with a conformationally constrained phenylalanine residue evokes a selective immune response in human neutrophils.

Formyl-Met-Leu-Phe-OH (fMLP) binds to formyl peptide receptors, FPR1 and FPR2, and evokes migration and superoxide anion production in human neutrophils. To obtain a more effective and selective ligand, fMLP analogs in which the Phe residue was substituted with four isomers of cyclopropanephenylalanine were synthesized. While Z-isomer peptides induced both migration and superoxide anion production, E-isomer peptides elicited only chemotaxis. Homologous receptor desensitization experiments revealed that E-isomer peptides bound to FPR2. Although a selective agonist of chemotaxis also binds to FPR2 without increasing intracellular calcium concentration, E-isomer peptide elevated the concentration to the same level as fMLP. Understanding of mechanisms responsible for the selectivity of the reported selective agonists and ∇Phe-substituted analogs should prove useful for revealing the relationship between receptor-ligand interactions and biological responses of human neutrophils.

Case of pediatric acute promyelocytic leukemia presenting as extramedullary tumor of the mandible.

BACKGROUND: Acute promyelocytic leukemia (APL) is a malignant subtype of acute myeloid leukemia caused by the PML-retinoic acid receptor (RAR)α fusion gene. APL may be discovered in adulthood and diagnosed after spontaneous gingival bleeding or difficulty in hemostasis after oral surgery such as tooth extraction. However, APL is extremely rare in children. METHODS AND RESULTS: A 1-year-old boy presented with a mass on the mentum of the mandible. The marked periosteal reaction was seen on CT and MRI, leading to strong suspicion of a malignant bone-derived tumor such as a sarcoma. Chromosome banding by fluorescence in situ hybridization (FISH) showed PML-RARα, confirming the diagnosis of APL. Treatment with tretinoin was immediately initiated. No signs of recurrence have been noted 1 year after treatment. CONCLUSIONS: We report herein a rare case involving an infant with APL who presented with an extramedullary tumor of the mandible, whom we treated with good results.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta(2)-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Lack of an association between E-selectin gene polymorphisms and risk of Kawasaki disease.

BACKGROUND: Coronary artery lesions (CAL) are a serious complication of Kawasaki disease (KD). The increased serum E-selectin level during the acute phase of KD and the association of E-selectin gene (SELE) polymorphisms with the prevalence of coronary artery disease in adults suggest a possible association between SELE polymorphisms and the development of CAL in KD patients. METHODS: The subjects consisted of 177 KD patients, including 59 with and 118 without CAL, and 305 healthy controls. Two single nucleotide polymorphisms (SNP) of SELE, 98G>T (rs1805193) and Ser128Arg (rs5361), were genotyped by direct sequencing and the high-resolution melting curve method, respectively. The allele distributions were assessed using the chi-squared test. RESULTS: There were no significant differences in the T allele frequency at 98G>T between KD patients and controls (1.4% vs 1.0%, P = 0.55) or between KD patients with and without CAL (1.7% vs 1.3%, P = 0.77). Similarly, there were no differences in the distribution of the C allele (128Arg) at Ser128Arg between KD patients and controls (4.5% vs 3.4%, P = 0.40) or between KD patients with and without CAL (4.2% vs 4.7%, P = 0.86). CONCLUSION: Although no association was detected between these SELE polymorphisms and the prevalence of KD or the development of CAL, this may have been due to the study limitations, including a low frequency of the minor alleles and a small sample size. A larger-scale association study is needed in order for a definitive conclusion to be made as to whether these SNP are associated with susceptibility to KD or not.

Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children.

The tulobuterol patch (TP) is a beta2-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo-controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Epigen is induced during the interleukin-13-stimulated cell proliferation in murine primary airway epithelial cells.

Airway remodeling in bronchial asthma is characterized by epithelial detachment and proliferation, subepithelial fibrosis, increased smooth muscle mass, and goblet cell hyperplasia. These features are mediated by T-helper type 2 (Th2) cytokines including interleukin (IL)-13. However, the direct effects of IL-13 on the functions of airway epithelial cells are not fully understood. Murine primary airway epithelial (MPAE) cells were cultured in an air-liquid interface (ALI) culture system. AG1478, a specific inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, was used to examine whether EGFR was involved in the IL-13-stimulated proliferation of MPAE cells. The expressions of EGFR ligands were investigated by reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical analyses. The cell counting in cross-sections and [(3)H]thymidine incorporation assays revealed a significant increase in the number of MPAE cells cultured with IL-13 compared with a phosphate-buffered saline (PBS) control. AG1478 abolished the IL-13-stimulated proliferation of MPAE cells. The expression of epigen, one of the EGFR ligands, was enhanced in MPAE cells cultured with IL-13. The findings suggest that EGFR is involved in the IL-13-stimulated proliferation of MPAE cells, and that epigen is important for the proliferation process in airway remodeling.

Japanese guideline for childhood asthma.

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2010 (JAGL 2010) describes childhood asthma based on the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2008 (JPGL 2008) published by the Japanese Society of Pediatric Allergy and Clinical Immunology. JAGL 2010 provides information on diagnosis by age groups from infancy to puberty, treatment for acute exacerbations, long-term management by medication, daily life guidance, and patient education to allow physicians, not specialized in childhood asthma, to refer to this guideline for routine medical treatment. JAGL differs from the Global Initiative for Asthma Guideline (GINA) in that the former emphasizes long-term management of childhood asthma based on asthma severity and early diagnosis and intervention at <2 years and 2-5 years of age. However, a management method, including step-up or step-down of long-term management agents based on the status of asthma symptoms, is easy to understand and thus JAGL is suitable for routine medical treatment. JAGL also introduced treatment and management using a control test for children, recommending treatment and management aimed at complete control through avoiding exacerbation factors and appropriate use of antiinflammatory agents.

Characterization of childhood-onset complex partial seizures associated with autism spectrum disorder.

Autism spectrum disorder (ASD) has a close relationship with epilepsy. A previous study showed complex partial seizures (CPS) to be the most frequent type of epileptic seizures in cases of ASD. Patients with childhood-onset CPS were retrospectively studied to investigate the prevalence of ASD and to characterize the association between CPS and ASD. The study cohort comprised 86 patients with CPS manifesting at 1 to 9 years of age. Symptomatic CPS and Panayiotopoulos syndrome were excluded. Patients with ASD (ASD group) were compared with those without ASD (non-ASD group). Of the 86 patients with childhood-onset CPS, 36 (42%) also had ASD. This ASD group was predominantly male (68.6%), with higher rates of intellectual disability (69%), and reported frequent seizures (60% had monthly or more frequent seizures). CPS without secondary generalization were more common in the ASD group (69%) than in the non-ASD group (36%), as were frontal paroxysms on EEG (54.5% vs 30%, respectively). In the non-ASD group, 82% of cases had been seizure free for 2 or more years, in comparison to 50% in the ASD group. ASD is frequently associated with childhood-onset CPS. Male gender, cognitive deficits, frequent seizures, and frontal paroxysms are risk factors for the association of ASD with CPS.

Low serum albumin level is risk factor for patients with percutaneous endoscopic gastrostomy.

OBJECTIVE: In Japan, percutaneous endoscopic gastrostomy (PEG) has been used mainly in patients with stroke and dementia, who undertake oral ingestion voluntarily. We have used PEG for patients with various diseases in Saga Medical School Hospital, including postoperative recovery, malignant disease, and neurodegenerative diseases. This study evaluated prognostic factors in these patients regarding long-term survival. METHODS: We analyzed retrospectively all patients who received PEG at our hospital. During the period of 1998-2007, 84 patients (32 females, 52 males; mean age, 60.3 years, range 20-89 years) were followed for more than 1 year. We analyzed sex, age, total lymphocyte count, serum albumin level, presence of malignant diseases, cerebrovascular diseases, neurodegenerative disorders, poor general condition after surgical procedures, dementia before PEG, pneumonia before PEG, and complications of PEG placement. RESULTS: As for diseases, 23 patients had malignant diseases, 27 had cerebrovascular diseases, 19 had neurodegenerative disorders, 16 were in poor general condition after surgery for nonmalignant diseases, and 12 had dementia. Multivariate analysis indicated that risk factors for 1-year survival were low serum albumin level (≤2.9 g/dL), low lymphocyte count, and complications of malignant diseases. Low serum albumin level, low lymphocyte count, and malignant diseases were risk factors, and only the albumin level was a risk factor in those without malignant diseases. CONCLUSION: Low serum albumin level was a risk factor for 1-year survival with PEG, which suggests that nutrient management before and during PEG placement should be monitored carefully.