下条 直樹

【緒言】完全房室ブロックを呈するリウマチ性心炎は稀であり、限局的な心筋炎所見を呈したリウマチ性心炎は報告がない。心臓MRIにて炎症部位を同定しえた症例を経験したので報告する。【症例】10歳女児。先行する感冒症状に続き失神発作が出現し入院となった。心電図波形は完全房室ブロックであり、心臓超音波検査で心室中隔に局所的な壁運動低下部位を認めた。A群β溶血連鎖球菌抗原迅速キット陽性、ASO296IU/mLであり、完全房室ブロックを併発したリウマチ性心炎と診断した。一時ペーシング、大量ガンマグロブリン静注、ステロイド、ACE阻害剤、およびアンピシリン投与を行った。入院翌日には洞調律となり、同29日目に軽快退院した。同10日目の心臓MRIで心室中隔基部に限局的なT2高信号を示す領域を認めた。発症から8ヵ月後の心臓MRIでは異常所見は消失しており、遅延造影でも同様に異常は見られなかった。【考察】心室中隔基部はHis束の走行部位であり、同部位の限局的な炎症により完全房室ブロック主体のリウマチ性心炎を発症したと考えた。同部位に発生した心臓腫瘍でも同様に完全房室ブロックを起こした症例が報告されており、炎症の部位によってはリウマチ性心炎でも完全房室ブロックの所見を呈することがあると考えられる。リウマチ性心炎の炎症部位の同定には心臓MRIが有用であった。(著者抄録)

Moyamoya syndrome is a progressive cerebrovascular disease that is characterized by stenosis of the terminal portion of the internal carotid artery and its main branches, in combination with an accompanying disease. We herein describe an 8-year-old boy exhibiting transient loss of consciousness, who had recurrent seizures in infancy with progressive brain calcification. On admission, he was alert but magnetic resonance angiography showed bilateral stenosis of the whole internal carotid artery and proliferation of vascular collaterals, and brain CT revealed calcification on bilateral putamen. Given that this fulfilled diagnostic criteria, we finally diagnosed him as having moyamoya syndrome, though the etiology was unclear. Interestingly, a whole vessel survey revealed vascular stenosis of abdominal aorta and renal arteries, in which the former has not been reported in moyamoya syndrome. We considered that brain calcification was gradually formed by decreased cerebral vascular flow from infancy, and stenosis of abdominal aorta was possibly extended from renal arteries. This is, moyamoya syndrome with brain calcification and stenosis of abdominal aorta, suggesting that morphological screening of whole vessels containing cerebral and abdominal arteries should be considered in cases of slowly progressive brain calcification. (C) 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Background: Despite the use of aggressive therapy, survival rates among high-risk neuroblastoma (NB) patients remain poor. Cancer stem cells (CSCs) are considered to be critically involved in the recurrence and metastasis of NB and are isolated as NB spheres. Methods: The gene expression profiling of adherent (control) and sphere-forming primary NB cells was conducted using a gene expression microarray. CFC1, which functions in the development of embryos and decides the left-right axis, was strongly expressed in sphere-forming cells only and was related to the unfavorable prognosis of NB patients. The knockdown and overexpression of CFC1 were performed using a lentiviral system in NB cell lines. Sphere formation, cell proliferation, colony formation in soft agar, and xenograft tumor formation were analyzed. Results: The overexpression of CFC1 increased sphere formation, cell growth, and colony formation. These phenotypes, particularly sphere formation, and xenograft tumor formation were significantly suppressed by the knockdown of CFC1. CFC1 inhibited Activin A-induced NB cell differentiation and Smad2 phosphorylation in NB cell lines, indicating its involvement in tumorigenesis related to EGF-CFC co-receptor family molecule pathways. Collectively, these results indicate that CFC1 is a candidate molecule for the development of CSC-targeted therapy for NB.

Background: Anti-NMDA-R receptor encephalitis occurs predominantly in younger women and is often comorbid with ovarian teratoma, a feature that is often absent in children. Here, we report our experience with two pediatric patients, in whom no tumors were present during treatment for encephalitis, but in whom ovarian teratomas developed without encephalitis relapse after treatment was completed. Cases: Patient 1 was a 14-year-old girl who was diagnosed due to characteristic symptoms and anti-NMDA-R antibody. MRI scanning during treatment revealed no ovarian tumors, but a tumor developed in the right ovary 10 months after onset. Another tumor developed in the left ovary 3 years after onset, and a mature ovarian teratoma was confirmed after bilateral partial ovariectomy. Patient 2 was an 11-year old girl who was also diagnosed due to characteristic symptoms and anti-NMDA-R antibody. Imaging during treatment revealed no ovarian tumors, but a 2.5-cm tumor mass was found in the left ovary 10 months after onset, and a mature ovarian teratoma was confirmed after partial ovariectomy. Discussion: This case report suggests the need for regular tumor screening after treatment for anti-NMDA receptor encephalitis because of potential subsequent tumor development, even in pediatric patients who initially present with no comorbid tumors. No analysis of relapse risk has yet been reported in cases of tumor development after treatment, and at this point, whether or not resection is needed to prevent relapse remains unclear. However, because teratomas usually grow, have an associated risk of torsion, and can be malignant, tumor removal should be considered. (C) 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Given the importance of appropriate diagnosis and appropriate assessment of cutaneous symptoms in treatment of atopic dermatitis, the basics of treatment in this guideline are composed of (1) investigation and countermeasures of causes and exacerbating factors, (2) correction of skin dysfunctions (skin care), and (3) pharmacotherapy, as three mainstays. These are based on the disease concept that atopic dermatitis is an inflammatory cutaneous disease with eczema by atopic diathesis, multi-factorial in onset and aggravation, and accompanied by skin dysfunctions. These three points are equally important and should be appropriately combined in accordance with the symptoms of each patient. In treatment, it is important to transmit the etiological, pathological, physiological, or therapeutic information to the patient to build a favorable partnership with the patient or his/her family so that they may fully understand the treatment. This guideline discusses chiefly the basic therapy in relation to the treatment of this disease. The goal of treatment is to enable patients to lead an uninterrupted social life and to control their cutaneous symptoms so that their quality of life (QOL) may meet a satisfactory level. The basics of treatment discussed in this guideline are based on the "Guidelines for the Treatment of Atopic Dermatitis 2008" prepared by the Health and Labour Sciences Research and the "Guidelines for the Management of Atopic Dermatitis 2015 (ADGL2015)" prepared by the Atopic Dermatitis Guidelines Advisory Committee, Japanese Society of Allergology in principle. The guidelines for the treatment of atopic dermatitis are summarized in the "Japanese Guideline for the Diagnosis and Treatment of Allergic Disease 2016" together with those for other allergic diseases. Copyright (C) 2016, Japanese Society of Allergology. Production and hosting by Elsevier B.V.

Brain morphology is tightly regulated by diverse signaling pathways. Hedgehog signaling is a candidate pathway considered responsible for regulating brain morphology. Nevoid basal cell carcinoma syndrome (NBCCS), caused by a PTCH1 mutation in the hedgehog signaling pathway, occasionally exhibits macrocephaly and medulloblastoma. Although cerebellar enlargement occurs in ptch1 heterozygous-deficient mice, its impact on human brain development remains unknown. We investigated the brain morphological characteristics of children with NBCCS. We evaluated brain T1-weighted images from nine children with NBCCS and 15 age-matched normal control (NC) children (mean [standard deviation], 12.2 [2.8] vs. 11.6 [2.3] years old). The diameters of the cerebrum, corpus callosum, and brain stem and the cerebellar volume were compared using two-tailed t-tests with Welch's correction. The transverse diameters (150.4 [9.9] vs. 136.0 [5.5] mm, P = 0.002) and longitudinal diameters (165.4 [8.0] vs. 151.3 [8.7] mm, P = 0.0007) of the cerebrum, cross-sectional area of the cerebellar vermis (18.7 [2.6] vs. 11.8 [1.7] cm(2), P = 0.0001), and total volume of the cerebellar hemispheres (185.1 [13.0] vs. 131.9 [10.4] cm(3), P = 0.0001) were significantly larger in the children with NBCCS than in NC children. Thinning of the corpus callosum and ventricular enlargement were also confirmed in children with NBCCS. We demonstrate that, on examination of the brain morphology, an increase in the size of the cerebrum, cerebellum, and cerebral ventricles is revealed in children with NBCCS compared to NC children. This suggests that constitutively active hedgehog signaling affects human brain morphology and the PI3K/AKT and RAS/MAPK pathways.

症例は入院時11ヵ月の男児。横紋筋肉腫に対する化学療法中にサイトメガロウイルス(CMV)抗原血症を合併した。ガンシクロビルを投与開始したが、抗原の陰性化は得られなかった。ホスカルネットに変更するも陰性化せず、ホスカルネットを併用しながら化学療法を継続した。この間2度眼底を検査したが異常は認めなかった。全ての化学療法を終えた時期に3回目の抗原血症の増悪をきたした。眼底検査で両眼に出血を伴う滲出性病変や硝子体の混濁を認め、CMV網膜炎と診断した。再度ガンシクロビルに変更し眼底所見は改善した。化学療法終了後、免疫学的回復に伴い抗原の陰性化が得られたが、最終的に左眼は視機能を失った。CMV網膜炎は移植以外でも合併することがあり、化学療法中の免疫状態に注意しながら頻回な眼底検査を要すると考えた。(著者抄録)

Fructooligosaccharides (FOS) can selectively stimulate the growth of bifidobacteria. Here, we investigated the effect of maternal FOS ingestion on maternal and neonatal gut bifidobacteria. In a randomized, double-blind, placebo-controlled study, we administered 8 g/day of FOS or sucrose to 84 women from the 26th week of gestation to one month after delivery. The bifidobacteria count was detected using quantitative PCR in maternal (26 and 36 weeks of gestation) and neonatal (one month after delivery) stools. Maternal stool frequency was recorded from 24 to 36 weeks of gestation. The number of fecal Bifidobacterium spp. and Bifidobacterium longum in the FOS group was significantly higher than that in the placebo group at 36 weeks of gestation (2.7 +/- 10(10)/g vs. 1.1 +/- 10(10)/g and 2.3 +/- 10(10)/g vs. 9.7 +/- 10(9)/g). In their neonates, these numbers did not differ between the groups. Also, stool frequency in the FOS group was slightly higher than that in the placebo group two weeks after the intervention (1.0 vs. 0.8 times/day), suggesting a potential constipation alleviation effect. In conclusion, the maternal FOS ingestion showed a bifidogenic effect in pregnant women but not in their neonates.

Background and objective The mechanism inducing either inflammation or tolerance to orally administered food allergens remains unclear. To investigate this we analyzed mouse models of food allergy (OVA23-3) and tolerance (DO11.10 [D10]), both of which express ovalbumin (OVA)-specific T-cell receptors. Methods OVA23-3, recombination activating gene (RAG)-2-deficient OVA23-3 (R23-3), D10, and RAG-2-deficient D10 (RD10) mice consumed a diet containing egg white (EW diet) for 2-28 days. Interleukin (IL)-4 production by CD4(+) T cells was measured as a causative factor of enteropathy, and anti-IL-4 antibody was used to reveal the role of Foxp3(+) OVA-specific Tregs (aiTreg) in this process. Results Unlike OVA23-3 and R23-3 mice, D10 and RD10 mice did not develop enteropathy and weight loss on the EW diet. On days 7-10, in EW-fed D10 and RD10 mice, splenic CD4(+) T cells produced significantly more IL-4 than did those in the mesenteric lymph nodes (MLNs); this is in contrast to the excessive IL-4 response in the MLNs of EW-fed OVA23-3 and R23-3 mice. EW-fed R23-3 mice had few aiTregs, whereas EW-fed RD10 mice had them in both tissues. Intravenous injections of anti-IL-4 antibody recovered the percentage of aiTregs in the MLNs of R23-3 mice. On day 28, in EW-fed OVA23-3 and R23-3 mice, expression of Foxp3 on CD4(+) T cells corresponded with recovery from inflammation, but recurrence of weight loss was observed on restarting the EW diet after receiving the control-diet for 1 month. No recurrence developed in D10 mice. Conclusions Excessive IL-4 levels in the MLNs directly inhibited the induction of aiTregs and caused enteropathy. The aiTregs generated in the attenuation of T cell-dependent food allergic enteropathy may function differently than aiTregs induced in a tolerance model. Comparing the two models enables to investigate their aiTreg functions and to clarify differences between inflammation with subsequent desensitization versus tolerance.

<p>牛乳アレルギーは，幼少期の最も一般的な食物アレルギーの一つである．症状は皮膚症状，粘膜症状，消化器症状など多岐にわたり，特に蕁麻疹，紅斑，湿疹などの皮膚症状が極めて多く認められる．短時間で急激な症状が現れるアナフィラキシーの誘発リスクも高く，また呼吸器症状やショック症状など，生命を危機的な状況に陥らせることも少なくない．牛乳は栄養価が高い食品であるが，アレルギー原因食物の一つである．牛乳アレルゲンタンのなかでもカゼインとβ-ラクトグロブリンは抗原性が高く主要アレルゲンとして報告されている．本稿では，ブロメラインによる牛乳主要アレルゲンの低減化を試みた．</p>

This is a rare case report of systemic allergic reaction to fish allergen ingested through breast milk. Mother ate raw fish more than 3 times a week. Her consumption of fish was associated with urticaria and wheeze in an infant via breast-feeding. Fish-specific IgE antibodies were detected by skin prick test but not by in vitro IgE test. This case demonstrates that fish protein ingested by mother can cause an immediate systemic allergic reaction in offspring through breast-feeding. Although fish intake is generally recommended for prevention of allergy, one should be aware that frequent intake of fish by a lactating mother may sensitize the baby and induce an allergic reaction through breast-feeding.

Alice in Wonderland syndrome (AIWS) is a rare condition in which patients report distorted size perception of objects and their own bodies. Although specific causes and pathology have not been elucidated, an association between AIWS and infection has been suggested. To our knowledge, mycoplasma-induced AIWS has not been examined. A girl aged 7 years 11 months presented with fever (temperature, 40 degrees C) and cough. Although the fever disappeared after approximately 10 days, she complained that her mother's face suddenly appeared smaller to her. Subsequently, she complained that objects intermittently appeared smaller than normal. Particle agglutination test indicated elevated serum antibodies against Mycoplasma pneumoniae. The patient was therefore diagnosed the patient with AIWS secondary to mycoplasma infection. Although mycoplasma infection is known to cause various central nervous system symptoms, this is the first report involving AIWS, suggesting that mycoplasma could affect visual function in children.

We studied the molecular evolution of the fusion protein (F) gene in the human respiratory syncytial virus subgroup A (HRSV-A). We performed time-scaled phylogenetic analyses using the Bayesian Markov chain Monte Carlo (MCMC) method. We also conducted genetic distance (p-distance), positive/negative selection, and Bayesian skyline plot analyses. Furthermore, we mapped the amino acid substitutions of the protein. The MCMC-constructed tree indicated that the HRSV F gene diverged from the bovine RSV (BRSV) gene approximately 550 years ago and had a relatively lowsubstitution rate (7.59 x 10(-4) substitutions/site/year). Moreover, a common ancestor of HRSV-A and -B diverged approximately 280 years ago, which has since formed four distinct clusters. The present HRSV-A strains were assigned six genotypes based on F gene sequences and attachment glycoprotein gene sequences. The present strains exhibited high F gene sequence similarity values and low genetic divergence. No positive selection sites were identified; however, 50 negative selection sites were identified. F protein amino acid substitutions at 17 sites were distributed in the F protein. The effective population size of the gene has remained relatively constant, but the population size of the prevalent genotype (GA2) has increased in the last 10 years. These results suggest that the HRSV-A F gene has evolved independently and formed some genotypes. (C) 2016 Elsevier B.V. All rights reserved.

Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway blockade has become a promising therapeutic target in adult cancers. We evaluated PD-L1 expression and tumor-infiltrating CD8(+) T cells in formalin-fixed, paraffin-embedded tumor specimens from 53 untreated pediatric patients with eight cancer types: neuroblastoma, extracranial malignant germ cell tumor, hepatoblastoma, germinoma, medulloblastoma, renal tumor, rhabdomyosarcoma, and atypical teratoid/rhabdoid tumor. One rhabdomyosarcoma with the shortest survival exhibited membranous PD-L1 expression and germinoma contained abundant tumor-infiltrating CD8+ T cells and PD-L1-positive macrophages. The PD-1/PD-L1 pathway tended to be inactive in pediatric cancers. (C) 2016 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.

Matrix metalloproteinases (MMPs) are a class of extra-cellular and membrane-bound proteases involved in a wide array of physiological and pathological processes including tissue remodeling, inflammation, and cytokine secretion and activation. MMP-13 has been shown to be involved in lung diseases such as acute lung injury, viral infections, and chronic obstructive pulmonary disease; however, the molecular pathogenesis of MMP-13 in these conditions is not well understood. In this study, we investigated the mechanisms and roles of MMP-13 secretion in human small airway epithelial cells (SAECs) and functional polymorphisms of the MMP13 gene. Polyinosinic-polycytidylic acid (poly(I:C)) and interferon beta (IFN-beta) stimulated the secretion of MMP-13 from SAECs by more than several hundred-fold. Stimulation of the secretion by poly(I:C) was abolished by SB304680 (p38 inhibitor), LY294002 (PI3K inhibitor), Janus kinase (JAK) inhibitor I, RNA-activated protein kinase (PKR) inhibitor, and Bay 11-7082 (NF-kappa B inhibitor), while stimulation by IFN-beta was inhibited by all except Bay 11-7082. These data suggested that the secretion of MMP-13 was mediated through IFN receptor pathways independently of nuclear factor kappa B (NF-kappa B) and that poly(I:C) stimulated IFN secretion in an NF-kappa B-dependent manner from SAECs, leading to IFN-stimulated MMP-13 secretion. Chemical MMP-13 inhibitors and MMP-13 small interfering RNA (siRNA) inhibited IFN-stimulated secretion of interferon gamma-inducible protein 10 (IP-10) and regulated on activation, normal T-cell expressed and secreted (RANTES), suggesting that MMP-13 is involved in the secretion of these virus-induced proinflammatory chemokines. We identified a novel functional polymorphism in the promoter region of the MMP13 gene. The MMP13 gene may play important roles in defense mechanisms of airway epithelial cells.

Williams syndrome is a contiguous gene deletion syndrome resulting from a heterozygous deletion on chromosome 7q11.23, and is characterized by distinctive facial features and supravalvular aortic stenosis (SVAS). This syndrome rarely presents unpredictable cardiac death, and yet, as illustrated in the present case, it is still not possible to predict it, even on close monitoring. We herein describe the case of a 6-year-old Japanese girl with Williams syndrome, who had sudden cardiac collapse due to cardiac infarction after pharyngitis. Cardiac failure followed a critical course that did not respond to catecholamine support or heart rest with extracardiac mechanical support. Although marked coronary stenosis was not present, the left coronary cusp abnormally adhered to the aortic wall, which may synergistically cause coronary ostium occlusion with SVAS. Altered hemodynamic state, even that caused by the common cold, may lead to critical myocardial events in Williams syndrome with SVAS.

BackgroundSeveral patient-/caregiver-completed questionnaires have been utilized for the assessment of asthma control. However, due to the diversity in medical/social circumstances, they may not be optimal for use in all countries. The Japanese pediatric asthma guideline (JPGL) aims at higher levels of control compared with other international guidelines, based on a strong social demand for best care. We developed a new control test to help meet that demand. MethodsA 34-item working questionnaire was developed based on input from pediatric asthma specialists and the caregivers of preschool children with asthma. The questionnaire was administered to caregivers of 565 patients aged &lt;6years who had physician-diagnosed asthma or 2-agonist-responsive recurrent wheeze. Then, 6 questions for assessing JPGL-defined control levels were selected from the 34 questions by stepwise logistic regression methods using randomly selected questionnaires completed by two-thirds of the caregivers. We named that set of questions the Best Asthma Control Test for Preschoolers (Best ACT-P). Validation of Best ACT-P was performed using the remaining completed questionnaires. ResultsThe 6 questions asked about the frequency/severity of cold-induced wheeze, nighttime awakening, exercise-induced symptoms, and disruption of family life due to asthma in the past 4weeks and hospitalization in the past 12months. The 6-item logistic model showed good statistical fit, and the scores for the physicians' ratings of the asthma control differed significantly in the hypothetical direction. ConclusionsBest ACT-P is a valid caregiver-completed questionnaire of asthma control in preschoolers in whom total control needs to be achieved.

Enterovirus focal encephalitis is a rare clinical entity that is characterized by focal neurological signs including seizure, hemiparesis, hemichorea, and headache, which are mainly followed by rapid spontaneous improvement. We herein describe the case of a 9-month-old boy who developed Coxsackie virus B5 (CVB5) focal encephalitis with seizure clusters in the eruption stage of roseola infantum-like illness, which were followed by rapid improvement and benign outcome. Lumbar puncture indicated pleocytosis, and CVB5 infection in the cerebrospinal fluid was subsequently identified on genome sequencing and virus isolation. Magnetic resonance imaging and electroencephalography showed no abnormal findings at the acute stage or on 2 month follow up. Although the pathogenesis of enterovirus focal encephalitis currently remains unclear, the pure synchronism of seizure cluster and eruption in this case suggests the involvement of local vascular impairment as the underlying pathogenesis.

To our knowledge, this is the first report of the use of real-time reverse transcription-polymerase chain reaction to assess changes in viral load in a patient with congenital rubella syndrome (CRS). Rubella-specific antibody titers were also determined. The patient was a male neonate born to a primipara with rubella infection at 10 weeks of gestation. He had no symptoms at birth, but rubella virus was detected in his pharynx, blood, and urine. His mental and physical development was normal for 1 year; however, he was diagnosed with deafness at 13 months of age. Thus, the patient was diagnosed with CRS. Rubella infection in the pharynx was almost constant until 5 months of age; however, it increased dramatically at 6 months of age. No infection was detected at 13 months. Rubella-specific immunoglobulin M titer was consistently low until 9 months of age and then decreased gradually until it became negative at 20 months of age. Rubella-specific immunoglobulin G titer was high at birth. However, it decreased at 3 months and increased again at 4 months. This titer peaked at similar to 9 months and then decreased again at 13 months. This case shows that the period after the decline in maternal antibody titers, not the neonatal period, may be the most contagious period in patients with CRS.

Constitutional 11q interstitial deletion syndrome presents with congenital anomalies including microcephaly with craniostenosis, minor dysmorphic features, vitreoretinopathy, and renal anomalies. This syndrome is occasionally associated with neuroblastoma (NB) as a life-threatening complication, which is important for clinical care. Although the corresponding locus to NB has been predicted to exist in 11q22-23 by previous deletion studies related to NB, the causative haploinsufficient genes have not yet been identified. We herein reported for the first time the simultaneous coexistence of adrenal NB and abdominal prevertebral ganglioneuroma in a 6-year-old girl with a constitutional hemizygous 11q14.1-23.3 deletion. Of the 11 haploinsufficient genes predicted with an in silico database, we focused on NCAM1 and CADM1 as the genes accountable for NB and ganglioneuroma. The deletion range, especially the 11q22.3 involvement, needs to be determined in 11q deletion cases in order to predict susceptibility to peripheral nerve tumors involving NB and ganglioneuroma. (c) 2015 Wiley Periodicals, Inc.

We studied the efficacy of drugs indicated for mitochondrial dysfunction in the treatment of 21 patients with acute encephalopathy with onset of febrile convulsive status epilepticus at our hospital from January 2006 to December 2014. Among them, 11 patients had been treated with a mitochondrial drug cocktail consisting of vitamin B1, vitamin C, biotin, vitamin E, coenzyme Q10, and L-carnitine (prescription group) and 10 patients were not treated with the cocktail (non-prescription group). We retrospectively reviewed age, trigger, clinical form, treatment start time, and sequelae. Clinical form was classified into a biphasic group presenting acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and a monophasic group. Sequelae were classified as (A) no sequelae group or (B) sequelae group, and differences in the interval between diagnosis and treatment were also evaluated. The sequelae were not different between the mitochondrial drug cocktail prescription and non-prescription groups, but significantly better in the group administered the mitochondrial drug cocktail within 24 h (P = 0.035). We expect that early treatment with a mitochondrial drug cocktail could prevent sequelae in acute encephalopathy with onset of febrile convulsive status epilepticus. (C) 2015 The Authors. Published by Elsevier B.V.

Ellis-van Creveld (EVC) syndrome is a rare autosomal recessive disorder characterized by hypoplastic nails, polydactyly, and achondroplasia. Patients usually exhibit normal cognitive function and no remarkable developmental delay. We herein present an unusual case of EVC syndrome. A Japanese 2-year-old boy was born at term, but immediately developed severe respiratory failure due to thorax deformity, postaxial polydactyly and nail hypoplasia. We identified a novel pattern of germinal compound heterozygous nonsense EVC2 mutations of c.1814C &gt; A (p. S605X) and c.2653C &gt; T (p. R885X), leading to the diagnosis of EVC syndrome. Interestingly, he also had severe developmental delay, and suddenly developed excessive abdominal distension at the age of 2. On surgery, extensive necrotic bowel with chronic intestinal pseudo-obstruction was noted. This is, to our knowledge, a most severe phenotype of EVC syndrome, illustrating that the specific pattern of EVC2 compound heterozygous mutations may cause severe developmental delay and intestinal malfunction.

Purpose: Recent epidemiological studies have shown that environmental factors during the fetal period to early childhood might affect the risk of noncommunicable diseases in adulthood. This is referred to as the developmental origins of health and disease (DOHaD) concept. The Chiba study of Mother and Children's Health (C-MACH) is a birth cohort study based on the DOHaD hypothesis and involves multiomics analysis. This study aims to explore the effects of genetic and environmental factors-particularly the fetal environment and postbirth living environment-on children's health, and to identify potential biomarkers for these effects. Participants: The C-MACH consists of three hospitalbased cohorts. The study participants are pregnant women at <13 weeks gestation. Women who underwent an examination in one of the three hospitals received an explanation of the study. The participants consented to completing questionnaire surveys and the collection and storage of biological and house/environmental samples. Participants were provided unique study numbers. All of the data and biological specimens will be stored in the Chiba University Center for Preventive Medical Sciences and Chiba University Center for Preventive Medical Sciences BioBank, respectively. Findings to date: Consent to participate was obtained from 433 women. Of these women, 376 women completed questionnaires in the early gestational period. The mean age was 32.5 (4.4) years. The mean body mass index (BMI) was 21.1 (3.0) kg/m2. Before pregnancy, 72.3% of the women had a BMI of 18.5-24.9 kg/m2. During early pregnancy, 5.0% of the participants smoked. Future plans: Primary outcomes are allergy, obesity, endocrine and metabolic disorders, and developmental disorders. Genome-level, metabolome-level, umbilical cord DNA methylation (epigenome), gut microbiota and environmental chemical exposure variables will be evaluated. We will analyse the relationships between the outcomes and analytical variables.

We studied the molecular evolution of the C-terminal 3rd hypervariable region in the attachment glycoprotein gene of human respiratory syncytial virus subgroup B (HRSV-B) genotypes BA9 and BA10. We performed time-scaled phylogenetic analyses using Bayesian Markov chain Monte Carlo methods. We also performed a genetic distance analysis (p-distance analysis), positive and negative selection analyses, and a Bayesian skyline plot (BSP) analysis. We found that genotype BA9 diverged from the common ancestor of genotypes BA7, BA8, and BA10, while genotype BA10 diverged from the ancestor of genotypes BA7 and BA8. Strains of both genotypes were distributed worldwide. BA9 and BA10 diverged between 1999 and 2001. Both BA9 and BA10 evolved rapidly (about 4.8 x 10(-3) substitutions/site/year) and formed three distinct lineages in a 10-year period. BA10 strains belonging to lineage 3 had large genetic distances (p-distance N &gt; 0.07). Thus, it may be possible to classify these strains as a new genotype, BA11. No positive selection site was detected in either genotype. Phylodynamic analyses showed that the effective population size of BA10 decreased gradually since 2010 and BA9 slightly decreased since 2009. The results suggested that the recently prevalent HRSV-B genotypes BA9 and BA10 evolved uniquely, leading to epidemics of HRSV-B worldwide over a 15-year period. (C) 2015 Elsevier B.V. All rights reserved.