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INTRODUCTION: Many developed countries including Japan are experiencing declining birth rates, particularly in urban areas. A gap between the planned number of children and the actual number of children exists, that is attributed to various factors such as: childcare leave and employment policies, childcare services, financial support, husbands' contributions to household chores and childcare, marriage support, community, and couples' well-being. Therefore, we propose HAMA study for having a baby, parenting, and marriage life (HAMA = 'H'aving 'A' baby, parenting, and 'MA'rriage life) in Yokohama (an urban area) to examine these issues. METHODS AND ANALYSIS: In this large-scale cohort study, we will elucidate the actual situation of families and child-rearing in Yokohama, evaluate the current policies and propose future measures to prevent a decline in the birth rate. Overall, 10 000 young married couples (wives aged 20-39 years as of 2022) will be randomly selected, and a survey form will be sent to them annually. They will be followed-up for 5 years to examine the factors associated with the planned number of children, well-being of the couple, childcare support policies, externalisation of housework and childcare, fathers' participation in housework and childcare, wives' free time, loneliness and social connectedness, relationship with the spouse and if they are working, questions regarding their work style and work-life balance will also be included. Ultimately, a conceptual model of the planned number of children and associated factors will be developed. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of Yokohama City University (reference number: 2022-10) and will be conducted following appropriate ethical guidelines. Opportunities to withdraw consent to participate in the survey are provided to participants. The results of this survey will be published as research papers in relevant journals and will be reported to the administration of Yokohama city and other agencies.
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Coeficiente de Natalidade , Características da Família , Humanos , Fatores Socioeconômicos , Estudos de Coortes , Estudos Prospectivos , CasamentoRESUMO
HDR syndrome (OMIM #146255) is caused by haploinsufficiency of the GATA3 gene. A vascular ring has not been reported in patients with GATA3-associated HDR syndrome. We report a neonatal case of HDR syndrome and a vascular ring that were possibly due to a novel frameshift mutation in the GATA3 gene.
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BACKGROUND: Extremely low birth weight (ELBW) survivors may develop glomerulosclerosis due to low nephron number, whereas their tubular function remains unknown except for hypercalciuria and phosphaturia. METHODS: Fifty-three subjects (30 boys and 23 girls, aged 7 months-19 years, median 36 months) were studied retrospectively. The median gestational age and birth weight were 26 weeks (range 22-32) and 745 g (range 316-999), respectively. Urine calcium-to-creatinine ratio (Ca/Cr), N-acetyl-ß-D-glucosaminidase-to-creatinine ratio (NAG/Cr), ß2 microglobulin-to-creatinine ratio (ß2m/Cr), uric acid-to-creatinine ratio (UA/Cr), glucose-to-creatinine ratio (glu/Cr), and microalbumin-to-creatinine ratio (malb/Cr) were examined. We also assessed the association between urine parameters and current age, gestational age, birth weight, and predictors of renal injury. Follow-up data were analyzed in 43 subjects 4-6 years later. RESULTS: Ninety percent of subjects had at least one tubular dysfunction. Frequency of elevated values was NAG/Cr 77.5%, UA/Cr 54.1%, ß2m/Cr 38.2%, malb/Cr 30.4%, Ca/Cr 21.5%, and glu/Cr 20.5%. There were significant negative correlations between the current age and Ca/Cr, NAG/Cr, glu/Cr, and UA/Cr, suggesting tubular function maturation. Urine ß2M/Cr and glu/Cr were negatively correlated with the gestational age. There were significant associations between elevated glu/Cr and asphyxia or neonatal acute kidney injury, and elevated NAG/Cr and indomethacin use, although these were not confirmed by multivariate analysis. At follow-up, the frequency of elevated NAG/Cr, glu/Cr, UA/Cr, and malb/Cr was reduced but that of elevated Ca/Cr, IgG/Cr, and ß2m/Cr remained similar or increased. CONCLUSION: Tubular dysfunction is common in ELBW survivors. Some abnormalities resolved with age while some remained persistent or even increased.
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Recém-Nascido de Peso Extremamente Baixo ao Nascer/fisiologia , Nefropatias/fisiopatologia , Túbulos Renais/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Creatinina/urina , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Humanos , Lactente , Masculino , Estudos Retrospectivos , Sobreviventes , Ácido Úrico/sangue , Adulto JovemRESUMO
Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks' gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks' gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates.
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Hipofosfatasia/diagnóstico , Fenótipo , Irmãos , Fosfatase Alcalina/genética , Alelos , Osso e Ossos/patologia , Genótipo , Idade Gestacional , Humanos , Hipofosfatasia/genética , Mutação , Diagnóstico Pré-Natal , Radiografia , Análise de Sequência de DNARESUMO
The cover image, by Satoru Ikenoue et al., is based on the Clinical Report Discordant fetal phenotype of hypophosphatasia in two siblings, DOI: 10.1002/ajmg.a.38531.
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Radiografia , HumanosRESUMO
Intestinal volvulus without malrotation is a rare disease that causes volvulus of the small intestine despite normal intestinal rotation and fixation. We encountered a neonate with this disease who developed early jaundice and was suspected to have a fetal onset. This patient was characterized by early jaundice complicating intestinal volvulus without malrotation and is considered to have exhibited reduced fetal movement and early jaundice as a result of volvulus, necrosis, and hemorrhage of the small intestine in the fetal period. If abdominal distention accompanied by early jaundice is noted in a neonate, intestinal volvulus without malrotation and associated intraabdominal hemorrhage should be suspected and promptly treated.
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Volvo Intestinal/diagnóstico , Intestino Delgado/patologia , Icterícia Neonatal/etiologia , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/cirurgia , Humanos , Recém-Nascido , Volvo Intestinal/complicações , Volvo Intestinal/cirurgia , Intestino Delgado/anormalidades , Intestino Delgado/cirurgia , LaparotomiaRESUMO
The classification of bone dysplasia has relied on a clinical/radiographic interpretation and the identification of specific genetic alterations. The clinical presentation of the SOX9 mutation and type 2 collagen disorders overlap with the Pierre-Robin sequence and talipes equinovarus, but the former is often accompanied by the bent long bones. In its milder form, the SOX9 mutation is not necessarily associated with the bent long bones. Here, we report a patient with the Pierre-Robin sequence and talipes equinovarus who did not exhibit either bent long bones or scapular hypoplasia; thus, this patient was instead classified as having a type 2 collagen disorder. Despite this phenotypic presentation, the proposita was found to have a de novo SOX9 mutation. The peculiar location of the mutation within the dimerization domain might account for the relatively mild phenotypic effect of the SOX9 mutation to a degree that is compatible with a clinical diagnosis of type 2 collagen disorder, except for a developmental delay. We concluded that mutations in SOX9 can mimic a type 2 collagen disorder-like phenotype.
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Doenças do Colágeno/genética , Colágeno Tipo II/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Fatores de Transcrição SOX9/genética , Sítios de Ligação/genética , Pré-Escolar , Doenças do Colágeno/diagnóstico , Análise Mutacional de DNA , Deficiências do Desenvolvimento/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Multimerização Proteica , Fatores de Transcrição SOX9/químicaAssuntos
Suco Gástrico/química , Doenças do Recém-Nascido/diagnóstico , Proteína A Associada a Surfactante Pulmonar/análise , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Taquipneia Transitória do Recém-Nascido/diagnóstico , Biomarcadores/análise , Diagnóstico Diferencial , Feminino , Humanos , Recém-Nascido , MasculinoAssuntos
Insuficiência Cardíaca/diagnóstico , Peptídeo Natriurético Encefálico/urina , Triagem Neonatal , Fragmentos de Peptídeos/urina , Biomarcadores/sangue , Biomarcadores/urina , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/urina , Humanos , Recém-Nascido , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangueRESUMO
BACKGROUND: The G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is a common cause of cystic fibrosis (CF). G551D-CFTR is characterized by an extremely low open probability despite its normal trafficking to the plasma membrane. Numerous small molecules have been shown to increase the activity of G551D-CFTR presumably by binding to the CFTR protein. METHODS: We investigated the effect of curcumin, genistein and their combined application on G551D-CFTR activity using the patch clamp technique. RESULTS: Curcumin increased G551D-CFTR whole-cell and single-channel currents less than genistein did at their maximally effective concentrations. However, curcumin further increased the channel activity of G551D-CFTR that had been already maximally potentiated by genistein, up to ~50% of the WT-CFTR level. In addition, the combined application of genistein and curcumin over a lower concentration range synergistically rescued the gating defect of G551D-CFTR. CONCLUSIONS: The additive effects between curcumin and genistein not only support the hypothesis that multiple mechanisms are involved in the action of CFTR potentiators, but also pose pharmaceutical implications in the development of drugs for CF pharmacotherapy.
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Curcumina/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Fibrose Cística/tratamento farmacológico , Genisteína/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Células CHO , Cricetinae , Cricetulus , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Sinergismo Farmacológico , Proteínas de Fluorescência Verde/genética , Humanos , Mutação de Sentido Incorreto , Técnicas de Patch-Clamp , Fitoestrógenos/farmacologia , TransfecçãoRESUMO
ATP-binding cassette A3 (ABCA3) is a lipid transport protein required for synthesis and storage of pulmonary surfactant in type II cells in the alveoli. Abca3 was conditionally deleted in respiratory epithelial cells (Abca3(Δ/Δ)) in vivo. The majority of mice in which Abca3 was deleted in alveolar type II cells died shortly after birth from respiratory distress related to surfactant deficiency. Approximately 30% of the Abca3(Δ/Δ) mice survived after birth. Surviving Abca3(Δ/Δ) mice developed emphysema in the absence of significant pulmonary inflammation. Staining of lung tissue and mRNA isolated from alveolar type II cells demonstrated that â¼50% of alveolar type II cells lacked ABCA3. Phospholipid content and composition were altered in lung tissue, lamellar bodies, and bronchoalveolar lavage fluid from adult Abca3(Δ/Δ) mice. In adult Abca3(Δ/Δ) mice, cells lacking ABCA3 had decreased expression of mRNAs associated with lipid synthesis and transport. FOXA2 and CCAAT enhancer-binding protein-α, transcription factors known to regulate genes regulating lung lipid metabolism, were markedly decreased in cells lacking ABCA3. Deletion of Abca3 disrupted surfactant lipid synthesis in a cell-autonomous manner. Compensatory surfactant synthesis was initiated in ABCA3-sufficient type II cells, indicating that surfactant homeostasis is a highly regulated process that includes sensing and coregulation among alveolar type II cells.
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Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Células Epiteliais Alveolares/metabolismo , Proteínas Associadas a Surfactantes Pulmonares/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Células Epiteliais Alveolares/ultraestrutura , Animais , Animais Recém-Nascidos , Sequência de Bases , Modelos Animais de Doenças , Feminino , Expressão Gênica , Homeostase , Humanos , Recém-Nascido , Metabolismo dos Lipídeos , Camundongos , Microscopia Eletrônica de Transmissão , Gravidez , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/genética , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Proteínas Associadas a Surfactantes Pulmonares/deficiência , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Síndrome do Desconforto Respiratório do Recém-Nascido/etiologiaRESUMO
ATP-Binding Cassette A3 (ABCA3) is a lamellar body associated lipid transport protein required for normal synthesis and storage of pulmonary surfactant in type II cells in the alveoli. In this study, we demonstrate that STAT3, activated by IL-6, regulates ABCA3 expression in vivo and in vitro. ABCA3 mRNA and immunostaining were decreased in adult mouse lungs in which STAT3 was deleted from the respiratory epithelium (Stat3(Delta/Delta) mice). Consistent with the role of STAT3, intratracheal IL-6 induced ABCA3 expression in vivo. Decreased ABCA3 and abnormalities in the formation of lamellar bodies, the intracellular site of surfactant lipid storage, were observed in Stat3(Delta/Delta) mice. Expression of SREBP1a and 1c, SCAP, ABCA3, and AKT mRNAs was inhibited by deletion of Stat3 in type II cells isolated from Stat3(Delta/Delta) mice. The activities of PI3K and AKT were required for normal Abca3 gene expression in vitro. AKT activation induced SREBP expression and increased the activity of the Abca3 promoter in vitro, consistent with the role of STAT3 signaling, at least in part via SREBP, in the regulation of ABCA3. ABCA3 expression is regulated by IL-6 in a pathway that includes STAT3, PI3K, AKT, SCAP, and SREBP. Activation of STAT3 after exposure to IL-6 enhances ABCA3 expression, which, in turn, influences pulmonary surfactant homeostasis.
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Transportadores de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Regulação da Expressão Gênica/fisiologia , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/metabolismo , Fator de Transcrição STAT3/fisiologia , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Linhagem Celular Transformada , Deleção de Genes , Células HeLa , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Surfactantes Pulmonares/antagonistas & inibidores , Surfactantes Pulmonares/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genéticaRESUMO
BACKGROUND: The signal transducer and activator of transcription 3 (STAT3) mediates gene expression in response to numerous growth factors and cytokines, playing an important role in many cellular processes. To better understand the molecular mechanisms by which Stat3 influences gene expression in the lung, the effect of pulmonary epithelial cell specific deletion of Stat3 on genome wide mRNA expression profiling was assessed. Differentially expressed genes were identified from Affymetrix Murine GeneChips analysis and subjected to gene ontology classification, promoter analysis, pathway mapping and literature mining. RESULTS: Total of 791 mRNAs were significantly increased and 314 mRNAs were decreased in response to the deletion of Stat3Delta/Delta in the lung. STAT is the most enriched cis-elements in the promoter regions of those differentially expressed genes. Deletion of Stat3 induced genes influencing protein metabolism, transport, chemotaxis and apoptosis and decreased the expression of genes mediating lipid synthesis and metabolism. Expression of Srebf1 and 2, genes encoding key regulators of fatty acid and steroid biosynthesis, was decreased in type II cells from the Stat3Delta/Delta mice, consistent with the observation that lung surfactant phospholipids content was decreased. Stat3 influenced both pro- and anti-apoptotic pathways that determine cell death or survival. Akt, a potential transcriptional target of Stat3, was identified as an important participant in Stat3 mediated pathways including Jak-Stat signaling, apoptosis, Mapk signaling, cholesterol and fatty acid biosynthesis. CONCLUSION: Deletion of Stat3 from type II epithelial cells altered the expression of genes regulating diverse cellular processes, including cell growth, apoptosis and lipid metabolism. Pathway analysis indicates that STAT3 regulates cellular homeostasis through a complex regulatory network that likely enhances alveolar epithelial cell survival and surfactant/lipid synthesis, necessary for the protection of the lung during injury.
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Células Epiteliais/metabolismo , Alvéolos Pulmonares/metabolismo , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/metabolismo , Deleção de Sequência/genética , Animais , Apoptose/genética , Apoptose/fisiologia , Sequência de Bases , Células Cultivadas , Colesterol/genética , Colesterol/metabolismo , Regulação para Baixo , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Camundongos , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Surfactantes Pulmonares/metabolismo , RNA Mensageiro/metabolismo , Mucosa Respiratória/metabolismo , Transdução de Sinais , Transcrição Gênica , Regulação para CimaRESUMO
Respiration at birth depends on maturation changes in lung tissue architecture, cell differentiation, and gene expression. At the transcriptional level, maturation is controlled by the actions of a group of transcription factors mediating gene expression in the lung. A network of transcription factors regulates gene expression in the respiratory epithelium, which then influences cell maturation throughout the lung. Glucocorticoids (via the glucocorticoid receptor), acting primarily in the pulmonary mesenchyme, influence maturation in the respiratory epithelium. Elucidation of the intersecting pathways controlling perinatal lung function may provide opportunities to induce pulmonary maturation in preterm infants at risk for respiratory distress syndrome before birth, and will help identify genes and processes important for various aspects of lung function.
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Glucocorticoides/fisiologia , Pulmão/crescimento & desenvolvimento , Fatores de Transcrição/fisiologia , Transcrição Gênica , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/fisiologia , Diferenciação Celular , Proteínas de Ligação a DNA/fisiologia , Maturidade dos Órgãos Fetais , Regulação da Expressão Gênica no Desenvolvimento , Fator 3-alfa Nuclear de Hepatócito/fisiologia , Fator 3-beta Nuclear de Hepatócito/fisiologia , Humanos , Pulmão/embriologia , Receptores de Glucocorticoides/metabolismoRESUMO
The role of Stat3 in the maintenance of pulmonary homeostasis following adenoviral-mediated lung injury was assessed in vivo. Stat3 was selectively deleted from bronchiolar and alveolar epithelial cells in Stat3(DeltaDelta) mice. Although lung histology and function were unaltered by deletion of Stat3 in vivo, Stat3(DeltaDelta) mice were highly susceptible to lung injury caused by intratracheal administration of AV1-GFP, an early (E) region 1- and E3-deleted, nonproliferative adenovirus. Severe airspace enlargement, loss of alveolar septae, and sloughing of the bronchiolar epithelium were observed in Stat3(DeltaDelta) mice as early as 1 day after exposure to the virus. Although surfactant protein A, B, and C content and surfactant protein-B mRNA expression in Stat3(DeltaDelta) mice were similar, TUNEL staining and caspase-3 were increased in alveolar type II epithelial cells of Stat3(DeltaDelta) mice after exposure to virus. RNA microarray analysis of type II epithelial cells isolated from Stat3(DeltaDelta) mice demonstrated significant changes in expression of numerous genes, including those genes regulating apoptosis, supporting the concept that the susceptibility of Stat3-deficient mice to adenovirus was related to the role of Stat3 in the regulation of cell survival. AV1-Bcl-x(L), an E1- and E3-deleted, nonproliferative adenovirus expressing the antiapoptotic protein Bcl-x(L), protected Stat3(DeltaDelta) mice from adenoviral-induced lung injury. Adenoviral infection of the lungs of Stat3-deficient mice was associated with severe injury of the alveolar and bronchiolar epithelium. Thus, Stat3 plays a critical cytoprotective role that is required for epithelial cell survival and maintenance of alveolar structures during the early phases of pulmonary adenoviral infection.