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BACKGROUND: It is unknown how accurately the current Japanese classification system for neurodevelopmental delay based on the assessment with the Kyoto Scale of Psychological Development (KSPD) at toddlerhood and pre-school periods predicts cognitive impairment at school age. METHODS: This single-center retrospective cohort study enrolled infants born at 22-29 weeks of gestational age. At 18-24 months of corrected age and 3 years of age, the patients were categorized according to the current Japanese criteria for neurodevelopmental delay based on their overall developmental quotient calculated using the KSPD-2001. Cognitive impairment at 6 years of age was classified according to the calculated or estimated full-scale intelligence quotient. The predictability of the current Japanese classification of neurodevelopmental delay for cognitive impairment at 6 years of age was investigated. RESULTS: Of 566 eligible patients, 364 (64 %) completed the protocol. The current classification for the neurodevelopmental delay showed significant agreement with the severity of cognitive impairment at 6 years of age. The sensitivity and specificity of the KSPD-2001-based assessment for any cognitive impairment at 6 years of age were 0.64 and 0.74 at 18-24 months of corrected age and 0.83 and 0.70 at 3 years of age. The corresponding sensitivity and specificity for moderate/severe cognitive impairment were 0.51 and 0.96 at 18-24 months of corrected age and 0.68 and 0.95 at 3 years of age. CONCLUSION: The KSPD-2001 is a useful tool to predict the severity of cognitive impairment at school age.
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Disfunción Cognitiva , Humanos , Masculino , Femenino , Preescolar , Recién Nacido , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Lactante , Japón , Estudios Retrospectivos , Recien Nacido Extremadamente Prematuro/crecimiento & desarrollo , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/epidemiología , Niño , Desarrollo InfantilRESUMEN
Maternal anti-SS-A antibodies may cause complete atrioventricular block or myocardial damage in a fetus. Effective treatment for this has not been established. Although antenatal steroids may be a treatment option for anti-SS-A antibody-related myocarditis or atrioventricular block, a complete atrioventricular block is usually considered irreversible once established. Previous reports have indicated that, in cases where antenatal steroids were effective for atrioventricular block, they were administered earlier in the pregnancy. Here we present a case where maternal steroid administration initiated from 27 weeks, which is beyond the recommended optimal treatment period, was effective in altering a complete atrioventricular block to a grade I atrioventricular block.
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OBJECTIVES: The objective of this study was to elucidate whether the survival and long-term neurodevelopmental outcomes of extremely preterm infants have improved in a Japanese tertiary center with an active treatment policy for infants born at 22-23 weeks of gestation. STUDY DESIGN: This single-centered retrospective cohort study enrolled extremely preterm infants treated at Saitama Medical Center, Saitama Medical University, from 2003 to 2014. Patients with major congenital abnormalities were excluded. Primary outcomes were in-hospital survival and severe neurodevelopmental impairment (NDI) at 6 years of age, which was defined as having severe cerebral palsy, severe cognitive impairment, severe visual impairment, or deafness. We assessed the changes in primary outcomes between the first (period 1; 2003-2008) and the second half (period 2; 2009-2014) of the study period and evaluated the association between birth-year and primary outcomes using multivariate logistic regression models. RESULTS: Of the 403 eligible patients, 340 (84%) survived to discharge. Among 248 patients available at 6 years of age, 43 (14%) were classified as having severe NDI. Between the 2 periods, in-hospital survival improved from 155 of 198 (78%) to 185 of 205 (90%), but severe NDI increased from 11 of 108 (10%) to 32 of 140 (23%). In multivariate logistic regression models adjusted for gestational age, birthweight, sex, singleton birth, and antenatal corticosteroids, the aOR (95% CI) of birth-year for in-hospital survival and severe NDI was 1.2 (1.1-1.3) and 1.1 (1.0-1.3), respectively. CONCLUSION: Mortality among extremely preterm infants has improved over the past 12 years; nevertheless, no significant improvement was observed in the long-term neurodevelopmental outcomes.
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Pueblos del Este de Asia , Recien Nacido Extremadamente Prematuro , Trastornos del Neurodesarrollo , Humanos , Lactante , Recién Nacido , Embarazo , Edad Gestacional , Mortalidad Hospitalaria/tendencias , Hospitales/normas , Hospitales/estadística & datos numéricos , Hospitales/tendencias , Trastornos del Neurodesarrollo/epidemiología , Estudios Retrospectivos , Centros de Atención Terciaria/normas , Centros de Atención Terciaria/estadística & datos numéricos , Centros de Atención Terciaria/tendencias , Preescolar , NiñoRESUMEN
Primitive myxoid mesenchymal tumor of infancy (PMMTI) is a rare soft tissue sarcoma in childhood. We present the case of a newborn male who experienced a severe hemorrhage in utero from the tumor on the scalp. He died at the age of 24 hours owing to hemorrhagic shock. The tumor was posthumously diagnosed as PMMTI. A literature search indicated that cases of severe hemorrhage from soft tissue sarcomas in utero or at birth are limited to infantile fibrosarcoma. This is the first case of PMMTI with massive hemorrhage. Clinicians must be aware of hemorrhagic complications of PMMTI.
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Fibrosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Recién Nacido , Humanos , Lactante , Masculino , Fibrosarcoma/complicaciones , Fibrosarcoma/patología , Sarcoma/patología , Neoplasias de los Tejidos Blandos/complicaciones , Neoplasias de los Tejidos Blandos/patología , Hemorragia/etiologíaRESUMEN
Duct-dependent systemic circulation is accompanied by a right-to-left ductal shunt, at least during systole. Although observations of paradoxical continuous left-to-right shunts in duct-dependent systemic circulation have been reported, the mechanism remains unclear. We report a continuous left-to-right ductal shunt throughout the cardiac cycle during the initial recovery phase from circulatory collapse and right ventricular (RV) dysfunction due to ductal closure in an infant with hypoplastic left heart and severe aortic coarctation. Further recovery improved his RV function and changed the ductal flow from continuous left-to-right to bidirectional, which is usually seen in duct-dependent systemic circulation. Marked RV dysfunction may contribute to the continuous left-to-right ductal shunt. A continuous left-to-right ductal shunt should not be used to rule out duct-dependent systemic circulation.
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OBJECTIVE: To establish the superiority of blood flow (BF)-based circulatory management over conventional blood pressure (BP)-based management strategies used for preventing intraventricular hemorrhage (IVH) in infants of very low birth weight (VLBW). STUDY DESIGN: We conducted a nonblinded, single-centered randomized trial with the aim to prevent IVH by managing BF. Infants with VLBW were assigned randomly to a BF-based group or BP-based (BP group) circulatory management group. The incidence of IVH was the outcome of interest. The IVH also data were compared among healthy patients and patients responsive and unresponsive to the intervention. RESULTS: A total of 219 and 220 infants with VLBW were assigned to the BF and BP groups, respectively. The IVH incidence rate was lower in the BF group, but the difference was not statistically significant (BF group, 6.8% vs BP group, 10.9%; P = .14). In 21% of patients of the BP group and 20% of the BF group, the intervention failed. In BF group, the IVH incidence rate was significantly greater in infants with unsuccessful intervention when compared with healthy individuals (6% vs 23%, P = .001). Multivariate logistic regression analysis revealed a correlation between low blood flow and IVH (aOR 3.24; 95% CI 1.49-7.08, P = .003) but not between low BP and IVH (P = .73). CONCLUSIONS: The BF management protocol did not significantly decrease the incidence of IVH. However, after further optimization, we speculate the treatment strategy holds promise in decreasing the incidence of IVH. Trial registration UMIN-CTR: UMIN000013296.
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Enfermedades del Prematuro , Recién Nacido de muy Bajo Peso , Peso al Nacer , Presión Sanguínea , Hemorragia Cerebral/epidemiología , Humanos , Incidencia , Lactante , Recién Nacido , Enfermedades del Prematuro/epidemiología , Perfusión/efectos adversosRESUMEN
We report a neonate with a successful percutaneous thrombectomy of a total thrombotic occlusion of the left pulmonary artery (LPA) after a surgical clipping for a patent ductus arteriosus (PDA). We suspected the compression of the LPA by the clipping and postoperative hemodynamic instability caused the LPA obstruction. After the surgical removal of the PDA clip and division of the PDA, we could safely retrieve the LPA thrombus with a non-hydrodynamic thrombectomy catheter for coronary arteries.
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Conducto Arterioso Permeable/cirugía , Complicaciones Posoperatorias/cirugía , Embolia Pulmonar/cirugía , Trombectomía/métodos , Femenino , Humanos , Recién NacidoRESUMEN
BACKGROUND: Many clinical trials have indicated that ibuprofen (IBU) has similar effects to indomethacin (IND) on the closure of patent ductus arteriosus (PDA) with fewer adverse effects. Owing to the scarce evidence on IBU use in Japan because of its recent approval we performed this observational study to compare the efficacy and safety of IBU with the efficiency and safety of IND. METHODS: We included infants (gestational age < 30 weeks) with hemodynamically significant PDA under a prophylactic IND protocol for intraventricular hemorrhage who were treated with either IND (n = 30) or IBU (n = 30). We compared a PDA closing effect, changes in ultrasonography findings, and adverse effects between the groups. RESULTS: There was no significant difference in the rates of PDA closure in the first treatment course (IND vs IBU: 46.7% vs 50.0%, P = 0.796) and surgical closure (IND vs IBU: 20.0% vs 20.0%, P = 1.000) between the groups. Both groups showed significant oliguria (IND vs IBU: 30.0% vs 23.3%, P = 0.559) and increased serum creatinine levels after treatment. However, an increase in serum creatinine level by >0.3 mg/dL, a criterion for acute kidney injury, was less frequent in the IBU group (35.7%) compared with that in the IND group (84.2%, P = 0.004). There were no significant differences in echocardiographic changes and jaundice and hypoglycemia incidence rates between the groups. CONCLUSIONS: Except for an increase in serum creatinine levels by >0.3 mg/dL, which was less frequent with IBU, IBU had similar efficacy and safety as IND for preterm PDA. Ibuprofen and IND should be cautiously administered.
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Conducto Arterioso Permeable , Ibuprofeno , Conducto Arterioso Permeable/diagnóstico por imagen , Conducto Arterioso Permeable/tratamiento farmacológico , Humanos , Ibuprofeno/uso terapéutico , Indometacina/uso terapéutico , Lactante , Recién Nacido de Bajo Peso , Recién Nacido , Recien Nacido Prematuro , JapónRESUMEN
Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the UCB was collected, volume-reduced, and divided into three doses. The processed UCB was infused at 12-24, 36-48, and 60-72 hours after the birth. The designed enrolment was six newborns. All six newborns received UCBC therapy strictly adhering to the study protocol together with therapeutic hypothermia. The physiological parameters and peripheral blood parameters did not change much between pre- and postinfusion. There were no serious adverse events that might be related to cell therapy. At 30 days of age, the six infants survived without circulatory or respiratory support. At 18 months of age, neurofunctional development was normal without any impairment in four infants and delayed with cerebral palsy in two infants. This pilot study shows that autologous UCBC therapy is feasible and safe.
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Trasplante de Células Madre de Sangre del Cordón Umbilical , Sangre Fetal/citología , Hipoxia-Isquemia Encefálica/etiología , Hipoxia-Isquemia Encefálica/terapia , Biomarcadores , Análisis de los Gases de la Sangre , Tratamiento Basado en Trasplante de Células y Tejidos/efectos adversos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Electroencefalografía , Femenino , Humanos , Hipoxia-Isquemia Encefálica/diagnóstico , Hipoxia-Isquemia Encefálica/metabolismo , Recién Nacido , Masculino , Proyectos PilotoRESUMEN
In fetuses, the Eustachian valve directs oxygenated blood returning from the inferior vena cava into the left atrium via the foramen ovale. If too large, the Eustachian valve can restrict right ventricular inflow, as well as induce postnatal cyanosis via an interatrial right-to-left shunt. We report a fetal case of postnatal amelioration of the tricuspid valve and right ventricle hypoplasia, despite significant right ventricular hypoplasia associated with a large Eustachian valve. Application of an appropriate respiratory management regimen to help reduce pulmonary vascular resistance is of particular importance for the reversal of the right-to-left shunt via the foramen ovale and associated increases in right ventricular inflow.
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For the first time, we report about two extremely low birth weight infants who were born at 25 and 22 weeks' gestation and who survived functional pulmonary atresia (fPA) with normal intracardiac anatomy. A slow, reflected, and bimodal blood flow pattern in the pulmonary artery (both cases) and the presence of pulmonary regurgitation (1 case) were useful for diagnosing fPA. Timely use of lipo-prostaglandin E1 to maintain adequate pulmonary flow and reduce pulmonary arterial resistance and sodium bicarbonate to improve acidosis were effective treatments to attain forward flow. As optimal management is essential for the intact survival of extremely early preterm infants and the accurate diagnosis of fPA is difficult without the awareness of the disease entity, our cases underline the importance of recognizing that fPA can occur even in extremely low birth weight infants with normal intracardiac anatomy.
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BACKGROUND: Preterm infants have immature skin, which contributes to skin problems. Very little is known about postnatal changes in the skin, despite the clinical importance of this issue. AIM: To assess temporal changes in skin water content in preterm infants. STUDY DESIGN: A prospective observational study. SUBJECTS: Infants admitted to the neonatal intensive care unit were included in this study. OUTCOME MEASURES: Skin water content was measured at five different skin regions using dielectric methods at a depth of 1.5mm. Skin water content was measured on postnatal day 1 in 101 infants, and the correlation between skin water content and gestational week was analyzed. Measurements were also made on postnatal days 2, 3, and 7, and every 7days thereafter until the corrected age of 37weeks in 87 of the 101 infants. Temporal changes were statistically analyzed after dividing participants into seven groups by gestational age. RESULTS: On postnatal day 1, skin water content correlated inversely with gestational age at all skin regions. Skin water content decreased significantly over time, converging to the level of term infants by the corrected age of 32-35weeks. CONCLUSIONS: Skin water content at a depth of 1.5mm was related to corrected age and reached the level of term infants by the corrected age of approximately 32-35weeks.
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Agua Corporal/metabolismo , Recien Nacido Prematuro/fisiología , Fenómenos Fisiológicos de la Piel , Piel/metabolismo , Femenino , Humanos , Recién Nacido , MasculinoRESUMEN
BACKGROUND: Cardiovascular instability immediately after birth is associated with intraventricular hemorrhage (IVH) in very-low-birth-weight (VLBW) infants. For circulatory management, evaluation of organ blood flow is important. In this study, the relationship between peripheral perfusion within 48 h after birth and IVH was evaluated in VLBW infants. METHODS: In this prospective observational study involving 83 VLBW infants, forehead blood flow (FBF) and lower-limb blood flow (LBF) were measured for 48 h after birth using a laser Doppler flowmeter. Blood flow was compared between infants with and without IVH. Multivariate logistic regression analysis was performed to identify the risk factors for IVH. RESULTS: IVH developed in nine infants. In eight of these patients, IVH occurred after 24 h. LBF was lower in infants with IVH at 18 and 24 h and increased to the same level as that of infants without IVH at 48 h. Multivariate logistic regression analysis identified a correlation only between LBF and IVH at 18 h. CONCLUSION: These findings were consistent with the hypoperfusion-reperfusion theory, which states that IVH develops after reperfusion subsequent to hypoperfusion. We speculate that measurement of skin blood flow in addition to systemic and cerebral circulation may be helpful in predicting IVH.
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Hemorragia Cerebral/sangre , Recién Nacido de muy Bajo Peso , Piel/irrigación sanguínea , Presión Sanguínea , Femenino , Frente/irrigación sanguínea , Humanos , Recién Nacido , Flujometría por Láser-Doppler , Masculino , Análisis Multivariante , Perfusión , Estudios Prospectivos , Flujo Sanguíneo Regional , Factores de Riesgo , Factores de Tiempo , UltrasonografíaRESUMEN
INTRODUCTION: Dopamine is one of the most frequently used inotropic drugs in neonatal intensive care units (NICUs); however, it does not seem to improve outcomes in premature infants. Given that the ultimate aim of cardiovascular management is to stabilize and maintain organ perfusion, an understanding of dopamine's effects on organ blood flow will help in judging when to use dopamine and how to titrate the dosage. Such an approach can lead to improved outcomes. This study aimed to evaluate the effects of dopamine on peripheral perfusion in very-low-birth-weight (VLBW) infants within 72 h of birth. METHODS: This prospective observational study identified and sampled 44 instances of initiation of dopamine treatment or increase in dopamine dose in 29 VLBW infants. Blood pressure, heart rate, and skin and subcutaneous blood flow were measured and compared before and after each instance. RESULTS: Blood pressure and skin and subcutaneous blood flow in the lower limbs increased after initiation of dopamine treatment or after dose increase. DISCUSSION: Dopamine increases blood pressure as well as skin and subcutaneous blood flow in VLBW infants despite its supposed vasoconstrictive action, indicating that it increases both perfusion pressure and blood flow and is devoid of overwhelming peripheral vasoconstrictive effects.
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Dopamina/farmacología , Recién Nacido de muy Bajo Peso/fisiología , Pierna/irrigación sanguínea , Flujo Sanguíneo Regional/efectos de los fármacos , Piel/irrigación sanguínea , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Recién Nacido , Masculino , Observación , Estudios ProspectivosRESUMEN
Congenital microcephaly with intracranial calcification is a rare condition presented in heterogeneous diseases. Here, we report the case of a 1-year-old boy with severe congenital microcephaly and diffuse calcification. Neuroimaging studies showed a diffuse simplified gyral pattern; a very thin cortex; ventricular dilatation; very small basal ganglia, thalamus, and brainstem; and cerebellar hypoplasia with diffuse calcification. Clinical features of intrauterine infections, such as neonatal jaundice, hepatomegaly, and thrombocytopenia, were not found. Serological tests, cultures, and polymerase chain reaction analysis were negative for viral infections. The etiology of pseudo-toxoplasmosis, rubella, cytomegalovirus, and herpes simplex syndrome is still unknown. This study describes the most severe form of pseudo-toxoplasmosis, rubella, cytomegalovirus, and herpes simplex syndrome reported to date, with the patient showing microcephaly and calcification or band-like intracranial calcification with simplified gyration and polymirogyria.
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Encefalopatías/congénito , Tronco Encefálico/anomalías , Calcinosis/congénito , Cerebelo/anomalías , Encefalopatías/patología , Tronco Encefálico/patología , Calcinosis/patología , Cerebelo/patología , Humanos , Lactante , Masculino , Microcefalia/patologíaRESUMEN
Shwachman-Diamond syndrome (SDS) is a rare hereditary disorder characterized by pancreatic exocrine insufficiency, bone marrow dysfunction and skeletal changes. Recently, the cause of SDS was identified as mutations of Shwachman-Bodian-Diamond syndrome gene (SBDS) and most mutations are caused by gene conversion between SBDS and its highly homologous pseudogene. Clinical variations especially in skeletal and bone marrow abnormalities are well known in this syndrome. To study the relationship between SBDS mutation and its clinical features, we analyzed 9 Japanese patients including one sibling and detected the three different SBDS mutations in 7 patients: a mutation that disrupts the donor splice site of intron 2, deletes 8 bp of the exon 2 and produces premature termination (258+2 T > C), a dinucleotide change that replaces a lysine at 62 nd amino acid to a termination codon (183-184 TA > CT), and a 4-bp deletion that causes premature termination by frameshift (292-295 delAAAG). The 5 patients represent compound heterozygotes of the 258+2 T > C and 183-184 TA > CT mutations. One patient is a compound heterozygote of the 258+2 T > C and 292-295 delAAAG mutations, and in the remaining one case only a 258+2 T > C mutation could be detected. Thus, the 258+2 T > C and 183-184 TA > CT mutations are prevalent among Japanese patients. No mutations were found in two cases, despite the clinical features. Of the 7 patients with SBDS mutations, persistent hematologic abnormalities and skeletal changes were not observed in 3 and 2 patients, respectively. Notably, clinical variations are present even among the patients with the identical genotype: compound heterozygotes of the 258+2 T > C and 183-184 TA > CT mutations. Further study will be required to explain the clinical heterogeneity.
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Enfermedades de la Médula Ósea/genética , Huesos/anomalías , Insuficiencia Pancreática Exocrina/genética , Mutación , Osteocondrodisplasias/genética , Proteínas/genética , Secuencia de Bases , Niño , Preescolar , Cromosomas/ultraestructura , ADN/química , Análisis Mutacional de ADN , Cartilla de ADN/química , Exones , Femenino , Mutación del Sistema de Lectura , Eliminación de Gen , Variación Genética , Heterocigoto , Humanos , Lactante , Recién Nacido , Intrones , Japón , Cariotipificación , Lisina/química , Masculino , Datos de Secuencia Molecular , Oligonucleótidos , Fenotipo , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , SíndromeRESUMEN
BACKGROUND: Neonatal hyperbilirubinemia is frequent and severe in Japanese newborns. Previously, it has been reported that half of the Japanese neonates with severe hyperbilirubinemia carried the 211G > A (p.G71R) mutation of the bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1) gene causing Gilbert syndrome. Recently, it was reported that the -3263T > G mutation in the phenobarbital response enhancer module in UGT1A1 was associated with the majority of cases of Gilbert syndrome. The gene frequency of the -3263T > G mutation was determined and the relation with neonatal hyperbilirubinemia in Japanese was studied. METHODS: UGT1A1 in 119 neonates born at Yamagata University Hospital, Yamagata, Japan, and 26 subjects who had undergone phototherapy due to severe hyperbilirubinemia at four other hospitals were studied. The gene frequency of -3263T > G mutation in Japanese, Korean, Chinese and German healthy adult controls was also determined. Hyperbilirubinemia was assessed with a Jaundice Meter and UGT1A1 was analyzed by sequence determination or restriction enzyme method. RESULTS: The gene frequency of the -3263T > G mutation was 0.26 in Japanese subjects and was similar to the prevalence in Korean, Chinese and German populations. However, there was no significant increase in the gene frequency of the mutation in the neonates who required phototherapy for hyperbilirubinemia compared to that in the neonates without severe hyperbilirubinemia. In addition, neonates with or without the mutation did not show a significant change in the level of bilirubin and the mutation also did not show a synergic effect with the 211G > A mutation on the level of bilirubin. CONCLUSION: The -3263T > G mutation is not likely to be associated with the neonatal hyperbilirubinemia in Japanese.
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Pueblo Asiatico/genética , Glucuronosiltransferasa/genética , Ictericia Neonatal/genética , Mutación Missense , Elementos de Respuesta/genética , Frecuencia de los Genes , Enfermedad de Gilbert/genética , Humanos , Recién Nacido , Japón , Ictericia Neonatal/etnología , Ictericia Neonatal/terapia , Sistemas de Lectura Abierta/genética , Fenobarbital/farmacología , Fototerapia , Regiones Promotoras Genéticas/genética , Estudios SeroepidemiológicosRESUMEN
Kawasaki disease (KD) is a systemic vasculitis and occurs among Japanese children at a high incidence. Serum bilirubin and heme oxygenase-1 (HO-1) expression are known to play a significant role in the protection of vascular endothelial cells. Japanese have unique polymorphic distribution patterns of (TA)7 or G71R of the bilirubin UDP-glucuronosyltransferase (B-UGT) gene and of (GT)n repeats of the HO-1 gene. We investigated the relationship of KD susceptibility with these polymorphisms. There were no significant differences in the distribution of allele frequencies and genotypes of these polymorphisms between KD patients and controls. These polymorphisms are not associated with KD susceptibility.
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Glucuronosiltransferasa/genética , Hemo Oxigenasa (Desciclizante)/genética , Síndrome Mucocutáneo Linfonodular/etiología , Polimorfismo Genético , Adolescente , Adulto , Anciano , Niño , Preescolar , ADN/sangre , ADN/química , ADN/genética , Análisis Mutacional de ADN/métodos , Repeticiones de Dinucleótido/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etiología , Genotipo , Hemo-Oxigenasa 1 , Heterocigoto , Homocigoto , Humanos , Lactante , Japón , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Síndrome Mucocutáneo Linfonodular/enzimología , Síndrome Mucocutáneo Linfonodular/genética , Mutación Missense , Regiones Promotoras Genéticas/genéticaRESUMEN
Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a disorder characterized by an idiopathic failure of the automatic control of breathing. CCHS is frequently complicated with neurocristopathies such as Hirschsprung's disease (HSCR). The genes involved in the RET-GDNF signaling and/or EDN3-EDNRB signaling pathways have been analyzed as candidates for CCHS; however, only a few patients have mutations of the RET, EDN3, and GDNF genes. Recently, mutations of the PHOX2B gene, especially polyalanine expansions, have been detected in two thirds of patients. We studied the RET, GDNF, GFRA1, PHOX2A, PHOX2B, HASH-1, EDN1, EDN3, EDNRB, and BDNF genes in seven patients with isolated CCHS and three patients with HSCR. We detected polyalanine expansions and a novel frameshift mutation of the PHOX2B gene in four patients and one patient, respectively. We also found several mutations of the RET, GFRA1, PHOX2A, and HASH-1 genes in patients with or without mutations of the PHOX2B gene. Our study confirmed the prominent role of mutations in the PHOX2B gene in the pathogenesis of CCHS. Mutations of the RET, GFRA1, PHOX2A, and HASH-1 genes may also be involved in the pathogenesis of CCHS. To make clear the pathogenesis of CCHS, the analysis of more cases and further candidates concerned with the development of the autonomic nervous system is required.
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Apnea Central del Sueño/genética , Edad de Inicio , Sustitución de Aminoácidos , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Factor Neurotrófico Derivado de la Línea Celular Glial , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial , Humanos , Lactante , Masculino , Factores de Crecimiento Nervioso/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ret , Proteínas Tirosina Quinasas Receptoras/genética , Respiración Artificial , SíndromeRESUMEN
Charcot-Marie-Tooth disease type 1 (CMT1) is a heterogeneous disorder. Most CMT1 patients are associated with a duplication of 17p11.2-p12 (CMT1A duplication), but a small number of patients have mutations of peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), connexin 32 (Cx32) and early growth response 2 (EGR2) genes. In our previous study, we identified the responsible mutations in 72 of 128 Japanese CMT1 patients as CMT1A duplication in 40, PMP22 mutation in 6, MPZ mutation in 12 and Cx32 mutation in 14 patients. A total of 56 Japanese CMT1 patients with no identified mutations were screened for EGR2 mutation by denaturing gradient gel electrophoresis (DGGE). We detected a heterozygous Asp383Tyr mutation of EGR2 in one patient with severe CMT1, Dejerine-Sottas syndrome. EGR2 mutation is rare cause of CMT1 in Japan as in other nations. We were unable to identify the responsible mutation in 55 of 128 CMT1 patients and need further analysis to identify their candidate genes.