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Reciprocal chromosomal translocation is one of genomic variations. When cytogenetically de novo reciprocal translocations are identified in patients with some clinical manifestations, the genes in the breakpoints are considered to be related to the clinical features. In this study, we encountered a patient with severe developmental delay, intractable epilepsy, growth failure, distinctive features, and skeletal manifestations. Conventional karyotyping revealed a de novo translocation described as 46,XY,t(3;4)(q27;q31.2). Chromosomal microarray testing detected a 1.25-Mb microdeletion at 3q27.3q28. Although the skeletal manifestations may have been affected by this deletion, the neurological features of this patient were severe and could not be fully explained by this deletion. Since no genomic copy number aberration was detected on chromosome 4, long-read whole-genome sequencing analysis was performed and a precise breakpoint was confirmed. A 460-bp deletion was detected between the two breakpoints; however, no gene was disrupted. FBXW7, the gene responsible for developmental delay, hypotonia, and impaired language, is in the 0.5-Mb telomeric region. Most of the patient's clinical features were considered consistent with symptoms of FBXW7-related disorders, but were more severe. FBXW7 expression in the immortalized lymphoblasts of the patient was reduced compared to that in controls. Based on these findings, we suspect that FBXW7 is affected by downstream position effects of chromosomal translocations. The severe neurological features of the patient may have been affected not only by the 3q27-q28 deletion but also by impaired expression of FBXW7 derived from the breakage of chromosome 4.
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PURPOSE: Personalized pharmacotherapy, including for the pediatric population, provides optimal treatment and has emerged as a major trend owing to advanced drug therapeutics and diversified drug selection. However, it is essential to understand the growth and developmental characteristics of this population to provide appropriate drug therapy. In recent years, clinical pharmacogenetics has accumulated knowledge in pediatric pharmacotherapy, and guidelines from professional organizations, such as the Clinical Pharmacogenetics Implementation Consortium, can be consulted to determine the efficacy of specific drugs and the risk of adverse effects. However, the existence of a large knowledge gap hinders the use of these findings in clinical practice. METHODS: We provide a narrative review of the knowledge gaps in pharmacokinetics (PK) and pharmacodynamics (PD) in the pediatric population, focusing on the differences from the perspective of growth and developmental characteristics. In addition, we explored PK/PD in relation to pediatric clinical pharmacogenetics. RESULTS: The lack of direct and indirect biomarkers for more accurate assessment of the effects of drug administration limits the current knowledge of PD. In addition, incorporating pharmacogenetic insights as pivotal covariates is indispensable in this comprehensive synthesis for precision therapy; therefore, we have provided recommendations regarding the current status and challenges of personalized pediatric pharmacotherapy. The integration of clinical pharmacogenetics with the health care system and institution of educational programs for health care providers is necessary for its safe and effective implementation. A comprehensive understanding of the physiological and genetic complexities of the pediatric population will facilitate the development of effective and personalized pharmacotherapeutic strategies.
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Farmacogenética , Farmacocinética , Niño , Humanos , Preparaciones FarmacéuticasRESUMEN
Outcomes are extremely poor in Down syndrome-associated acute lymphocytic leukemia, particularly in recurrent cases. A 2-year-old boy with Down syndrome-associated acute lymphocytic leukemia achieved complete remission after standard chemotherapy. However, he experienced recurrence twice in the bone marrow and central nervous system. Salvage treatments included whole-brain/whole-spine irradiation. Thereafter, the patient received a second cord blood transplantation after the reduced-intensity conditioning. The graft was characterized by killer cell immunoglobulin-like receptor ligands mismatch. The patient has subsequently survived for 6.5 years without recurrence. We speculate that killer cell immunoglobulin-like receptor ligand-mismatched cord blood transplantation enhanced the graft-versus-leukemia effect through natural killer cells, and conferred long-term remission.
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Trasplante de Células Madre de Sangre del Cordón Umbilical , Síndrome de Down , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Niño , Humanos , Preescolar , Supervivencia sin Enfermedad , Síndrome de Down/complicaciones , Síndrome de Down/terapia , Enfermedad Aguda , Enfermedad Crónica , Recurrencia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores KIR , Acondicionamiento PretrasplanteRESUMEN
Children with acute lymphocytic leukemia rarely develop secondary hematological neoplasms. A 5-year-old boy was diagnosed with standard-risk precursor B-cell acute lymphocytic leukemia. The patient exhibited aberrant chromosomal changes in the bone marrow at 6 months postchemotherapy: 46,XY,der(6) t(1;6)(q12;p22) dup(6)(p22p12)[15]. Clinically, the patient has sustained complete remission and has not developed myeloid malignancy over the subsequent period (27 mo). The cytogenetic aberration was observed in 11% of CD34+ cells isolated from the bone marrow. We infer that the abnormal clone acquires self-renewal potency, differentiation, and growth advantage. Further long-term observation is needed to determine the nature of this cytogenetic aberration.
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Hematopoyesis Clonal , Humanos , Masculino , Niño , Preescolar , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Aberraciones Cromosómicas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/tratamiento farmacológicoRESUMEN
INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.
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Antivirales , Infecciones por Citomegalovirus , Citomegalovirus , Neutropenia , Valganciclovir , Humanos , Valganciclovir/uso terapéutico , Valganciclovir/administración & dosificación , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/virología , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Antivirales/efectos adversos , Femenino , Lactante , Masculino , Estudios Prospectivos , Administración Oral , Citomegalovirus/aislamiento & purificación , Citomegalovirus/efectos de los fármacos , Citomegalovirus/genética , Recién Nacido , Japón , Resultado del Tratamiento , Pérdida Auditiva/virología , ADN Viral/sangre , Ganciclovir/análogos & derivados , Ganciclovir/administración & dosificación , Ganciclovir/uso terapéutico , Ganciclovir/efectos adversos , Neutrófilos/efectos de los fármacosRESUMEN
BACKGROUND: The urine protein to creatinine ratio (UPCR) correlates well with the 24-h urine protein test (24-h UPT) and is a reliable indicator of proteinuria. However, in nephrotic syndrome, the correlation between the UPCR and the 24-h UPT tends to decrease. To address this, we introduced the fractional excretion of total protein (FETP), which reflects serum total protein and creatinine levels because severe hypoproteinemia and/or elevated serum creatinine levels tend to occur under these conditions. The 24-h UPT corrected for body surface area (BSA) (24-h UPT/BSA) was used to take body size into consideration. The correlation coefficients for 24-h UPT/BSA and FETP and 24-h UPT/BSA and UPCR were calculated. The statistical significance of the differences between these coefficients was also calculated. METHODS: Thirty-six pediatric patients with nephrotic syndrome were included in this study. The FETP was calculated as total protein clearance/creatinine clearance (%). Correlation coefficients were calculated for 24-h UPT/BSA and FETP and 24-h UPT/BSA and UPCR. The statistical significance of the differences between these coefficients was also calculated. RESULTS: The mean ± standard error of FETP was 0.11% ± 0.013%. The correlation coefficients of FETP and UPCR with 24-h UPT/BSA were 0.91 and 0.81, respectively. The FETP demonstrated a significantly stronger correlation with 24-h UPT/BSA than with UPCR (p = 0.01). CONCLUSIONS: The FETP correlated more strongly with 24-h UPT/BSA than with UPCR in patients with nephrotic syndrome. The FETP is a reliable indicator of proteinuria in nephrotic syndrome, especially in patients with severe hypoproteinemia or elevated serum creatinine levels.
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Hipoproteinemia , Síndrome Nefrótico , Humanos , Niño , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/orina , Creatinina/orina , Proteinuria/diagnóstico , Proteinuria/orina , UrinálisisRESUMEN
We examined whether the administration of growth hormone (GH) improves insulin resistance in females of a non-obese hyperglycemic mouse model after birth with low birth weight (LBW), given that GH is known to increase muscle mass. The intrauterine Ischemia group underwent uterine artery occlusion for 15 min on day 16.5 of gestation. At 4 weeks of age, female mice in the Ischemia group were divided into the GH-treated (Ischemia-GH) and non-GH-treated (Ischemia) groups. At 8 weeks of age, the glucose metabolism, muscle pathology, and metabolome of liver were assessed. The insulin resistance index improved in the Ischemia-GH group compared with the Ischemia group (p = 0.034). The percentage of type 1 muscle fibers was higher in the Ischemia-GH group than the Ischemia group (p < 0.001); the muscle fiber type was altered by GH. In the liver, oxidative stress factors were reduced, and ATP production was increased in the Ischemia-GH group compared to the Ischemia group (p = 0.014), indicating the improved mitochondrial function of liver. GH administration is effective in improving insulin resistance by increasing the content of type 1 muscle fibers and improving mitochondrial function of liver in our non-obese hyperglycemic mouse model after birth with LBW.
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Modelos Animales de Enfermedad , Hiperglucemia , Resistencia a la Insulina , Hígado , Animales , Femenino , Humanos , Ratones , Embarazo , Hormona de Crecimiento Humana/farmacología , Hormona de Crecimiento Humana/administración & dosificación , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Proteínas Recombinantes/farmacologíaRESUMEN
Many disease-causing genes have been identified by determining the breakpoints of balanced chromosomal translocations. Recent progress in genomic analysis has accelerated the analysis of chromosomal translocation-breakpoints at the nucleotide level. Using a long-read whole-genome sequence, we analyzed the breakpoints of the cytogenetically balanced chromosomal translocation t(5;15)(q21;26.3), which was confirmed to be of de novo origin, in a patient with a neurodevelopmental disorder. The results showed complex rearrangements with seven fragments consisting of five breakpoint-junctions (BJs). Four of the five BJs showed microhomologies of 1-3-bp, and only one BJ displayed a signature of blunt-end ligation, indicating chromothripsis as the underlying mechanism. Although the BJs did not disrupt any disease-causing gene, the clinical features of the patient were compatible with MEF2C haploinsufficiency syndrome. Complex rearrangements were located approximately 2.5-Mb downstream of MEF2C. Therefore, position effects were considered the mechanism of the occurrence of MEF2C haploinsufficiency syndrome.
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Trastornos del Neurodesarrollo , Translocación Genética , Humanos , Masculino , Lactante , Encéfalo/patología , Trastornos del Neurodesarrollo/genéticaRESUMEN
Interstitial microdeletions in the long arm of chromosome 3 are rare. In this study, we identified two patients with approximately 5-Mb overlapping deletions in the 3q26.2q26.31 region. Both patients showed neurodevelopmental delays, congenital heart defects, and distinctive facial features. One of them showed growth deficiency and brain abnormalities, as shown on a magnetic resonance imaging scan. Haploinsufficiency of NLGN1 and FNDC3B present in the common deletion region was considered to be responsible for neurodevelopmental delay and the distinctive features, respectively. The possibility of unmasked variants in PLD1 was considered and analyzed, but no possible pathogenic variant was found, and the mechanism of the congenital heart defects observed in the patients is unknown. Because 3q26.2q26.31 deletions are rare, more information is required to establish genotype-phenotype correlations associated with microdeletions in this region.
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Cardiopatías Congénitas , Malformaciones del Sistema Nervioso , Humanos , Deleción Cromosómica , Fenotipo , Cardiopatías Congénitas/genética , Malformaciones del Sistema Nervioso/genéticaRESUMEN
Most chromosomal aberrations revealed by chromosomal microarray testing (CMA) are simple; however, very complex chromosomal structural rearrangements can also be found. Although the mechanism of structural rearrangements has been gradually revealed, not all mechanisms have been elucidated. We analyzed the breakpoint-junctions (BJs) of two or more clustered copy number variations (CNVs) in the same chromosome arms to understand their conformation and the mechanism of complex structural rearrangements. Combining CMA with long-read whole-genome sequencing (WGS) analysis, we successfully determined all BJs for the clustered CNVs identified in four patients. Multiple CNVs were intricately intertwined with each other, and clustered CNVs in four patients were involved in global complex chromosomal rearrangements. The BJs of two clustered deletions identified in two patients showed microhomologies, and their characteristics were explained by chromothripsis. In contrast, the BJs in the other two patients, who showed clustered deletions and duplications, consisted of blunt-end and nontemplated insertions. These findings could be explained only by alternative nonhomologous end-joining, a mechanism related to polymerase theta. All the patients had at least one inverted segment. Three patients showed cryptic aberrations involving a disruption and a deletion/duplication, which were not detected by CMA but were first identified by WGS. This result suggested that complex rearrangements should be considered if clustered CNVs are observed in the same chromosome arms. Because CMA has potential limitations in genotype-phenotype correlation analysis, a more detailed analysis by whole genome examination is recommended in cases of suspected complex structural aberrations.
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Variaciones en el Número de Copia de ADN , Genoma Humano , Humanos , Variaciones en el Número de Copia de ADN/genética , Reordenamiento Génico/genética , Aberraciones Cromosómicas , Análisis de SecuenciaRESUMEN
BACKGROUND: Congenital cytomegalovirus (CMV) infection (cCMV) can cause sensorineural hearing loss and neurodevelopmental disabilities in children. Oral valganciclovir (VGCV) therapy has been reported to improve long-term audiological and neurodevelopmental outcomes in patients with cCMV. The levels of CMV DNA in whole blood have been monitored in previous studies. However, quantitative methods using whole blood have not been standardized. Recently, the plasma viral load has been standardized and widely used in CMV-associated diseases. METHODS: CMV viral loads in whole blood and plasma were serially measured in 24 patients with a confirmatory diagnosis of cCMV during oral VGCV therapy using an in-house real-time PCR assay. Plasma samples were assayed using the Cobas 6800 system (Roche Diagnostics) in addition to an in-house assay. RESULTS: Plasma CMV viral loads were remarkably decreased at the end of therapy compared to before therapy. A significant correlation of CMV levels between whole blood and plasma was observed (Spearman's ρ = 0.566). The levels of CMV DNA before therapy were significantly correlated with the period of decreasing the viral loads to below the detection limit, not only in whole blood (Spearman's ρ = 0.901) but also in plasma (Spearman, ρ = 0.804). Finally, CMV viral loads between the in-house assay and commercially available standardized assay in 75 plasma samples with positive PCR results for CMV were compared; a significant correlation was observed between the results of both assays. CONCLUSIONS: There was a significant correlation between the two assays (Spearman, ρ = 0.882), suggesting that CMV plasma viral loads measured by the standardized assay are widely used to monitor the levels of CMV DNA in patients with cCMV during oral VGCV therapy.
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Infecciones por Citomegalovirus , Citomegalovirus , Niño , Humanos , Valganciclovir/uso terapéutico , Citomegalovirus/genética , Carga Viral/métodos , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/congénito , Reacción en Cadena en Tiempo Real de la Polimerasa , ADN Viral/genéticaRESUMEN
Recently, germline mutations in SAMD9 and SAMD9L were increasingly found in children with monosomy 7. We report the outcomes in 2 infants with the SAMD9/SAMD9L variant, who presented with anemia and thrombocytopenia (patient 1), and neutropenia and nonsymptomatic white-matter-encephalopathy (patient 2). Both patients received cord blood transplantation and experienced critical post-cord blood transplantation adverse events; patients 1 and 2 developed fulminant engraftment syndrome and life-threatening graft-versus-host disease, respectively. Of note, selective loss of chromosome 7 in bone marrow-derived CD34 + cells was inferred.
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Cromosomas Humanos Par 7 , Trasplante de Células Madre de Sangre del Cordón Umbilical , Niño , Humanos , Lactante , Hematopoyesis Clonal , Mutación de Línea Germinal , Hematopoyesis , Péptidos y Proteínas de Señalización Intracelular/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by 6 primary features of rod-cone dystrophy, central obesity, polydactyly, cognitive impairment, hypogonadism and/or genitourinary malformations, and kidney abnormalities. At least 21 genes associated with BBS have been reported. To date, BBS associated with BBS12 variants has never been described in the Japanese population. We report a Japanese infant female with BBS with compound heterozygous BBS12 variants. METHODS: In addition to the pediatric examination, fundus photography, full-field electroretinogram(ffERG) and whole exome sequencing (WES) were underwent. RESULTS: The infant exhibited obesity, polydactyly, cognitive impairment, genitourinary malformations, and kidney dysfunction. At the age of 2 years, ffERG revealed severe reduction in both rod- and cone-mediated electroretinographic responses consistent with a severe form of rod-cone dystrophy, with minimal retinal abnormalities. WES revealed novel compound heterozygous BBS12 variants (c.591T > A, p.Tyr197* and c.1372dupA, p.Thr458Asnfs*5) in the infant. Her parents carried each of the variants, as confirmed by Sanger sequencing. CONCLUSIONS: The current observations will contribute to an expanded understanding of genotype-phenotype associations in BBS12-associated BBS.
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Síndrome de Bardet-Biedl , Distrofias de Conos y Bastones , Polidactilia , Femenino , Humanos , Síndrome de Bardet-Biedl/diagnóstico , Síndrome de Bardet-Biedl/genética , Electrorretinografía , Mutación , Polidactilia/complicacionesRESUMEN
The aim of the study was to determine the pathogenesis of non-obese children with type 2 diabetes, and its relationship with fat distribution. The study participants included 36 obese children with type 2 diabetes (age: 13.5 years, BMI: 28.3, BMI percentile: 91.9) and 30 non-obese children with type 2 diabetes (age: 13.5 years, BMI: 23.1, BMI percentile: 74.0). The proportion of female participants was significantly higher in non-obese children than in obese children (73.3% vs. 41.7%, p < 0.001). Abdominal fat distribution, evaluated by subcutaneous fat (SF) area, visceral fat (VF) area, and the ratio of VF area to SF area (V/S ratio), measured using computed tomography, and serum lipid levels and liver function were compared between the two groups. Non-obese children with type 2 diabetes had significantly smaller SF area and also smaller VF area than obese children with type 2 diabetes (SF area: 158.3 m2 vs. 295.3 m2, p < 0.001, VF area: 71.0 m2 vs. 94.7 m2, p = 0.032). Whereas non-obese children with type 2 diabetes had significantly greater V/S ratio than obese children with type 2 diabetes (0.41 vs. 0.31, p = 0.007).The prevalence of dyslipidemia and liver dysfunction were similar in the two groups. In conclusion, non-obese children with type 2 diabetes had excess accumulation of VF despite a small amount of SF, which might be associated with glucose intolerance and other metabolic disorders.
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Diabetes Mellitus Tipo 2 , Intolerancia a la Glucosa , Humanos , Femenino , Niño , Adolescente , Diabetes Mellitus Tipo 2/metabolismo , Grasa Subcutánea , Índice de Masa Corporal , Intolerancia a la Glucosa/metabolismo , Grasa Intraabdominal/diagnóstico por imagen , Grasa Intraabdominal/metabolismoRESUMEN
Islet-cell associated antibodies are predictive and diagnostic markers for type 1 diabetes. We studied the differences in the early clinical course of children with type 1 diabetes with a single antibody and those with multiple antibodies against pancreatic ß-cells. Sixty-seven children with type 1 diabetes aged less than 15 years diagnosed between 2010 and 2021 were included in the study and subdivided into two subgroups: children who were single positive for either glutamic acid decarboxylase (GAD) antibodies (n = 16) or insulinoma-associated antigen-2 (IA-2) antibodies (n = 13) and those positive for both antibodies (n = 38) at diagnosis. We compared the patients' clinical characteristics, pancreatic ß-cell function, and glycemic control during the 5 years after diagnosis. All clinical characteristics at diagnosis were similar between the two groups. One and two years after diagnosis, children who tested positive for both antibodies showed significantly lower postprandial serum C-peptide (CPR) levels than those who tested positive for either GAD or IA-2 antibodies (p < 0.05). In other periods, there was no significant difference in CPR levels between the two groups. There was a significant improvement in glycosylated hemoglobin (HbA1c) levels after starting insulin treatment in both groups (p < 0.05), but no significant difference in HbA1c levels between the groups. Residual endogenous insulin secretion may be predicted based on the number of positive islet-cell associated antibodies at diagnosis. Although there are differences in serum CPR levels, optimal glycemic control can be achieved by individualized appropriate insulin treatment, even in children with type 1 diabetes.
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Autoanticuerpos , Diabetes Mellitus Tipo 1 , Glutamato Descarboxilasa , Insulina , Insulinoma , Humanos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Masculino , Femenino , Niño , Adolescente , Hemoglobina Glucada , Insulinoma/tratamiento farmacológico , Péptido C/sangre , Insulina/uso terapéuticoRESUMEN
BACKGROUND: This nationwide survey aimed to determine the status of jaundice management in Japan. METHODS: A questionnaire about bilirubin level measurements and neonatal jaundice treatment was sent to 330 institutions providing neonatal care. The responses were analyzed according to institution level. RESULTS: Of 330 institutions, 172 responded (52.1% response rate). Total bilirubin levels were measured in the central laboratory using spectrophotometry at 134 institutions and a blood gas analyzer at 81 institutions. Unbound bilirubin (UB) levels were measured by 79 institutions, while transcutaneous bilirubin measurements were taken at 63 institutions. There was no association between institution level and UB or transcutaneous bilirubin measurement. For phototherapy criteria, the Murata-Imura criteria were adopted by 67 institutions, Nakamura criteria by 36, and Morioka criteria by 39. Light-emitting diodes (LED) were used by 160 institutions versus fluorescent lights by 31. When a blue LED was used, 119 institutions used the high mode. There is no standard for increasing light intensity. No association was found between institution level and phototherapy criteria. UB was measured in 14 of 63 institutions using the Murata-Imura criteria. CONCLUSIONS: There is a large variation in the management and treatment of neonatal jaundice among institutes in Japan.
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Ictericia Neonatal , Recién Nacido , Humanos , Ictericia Neonatal/diagnóstico , Ictericia Neonatal/terapia , Japón , Recambio Total de Sangre , Fototerapia , BilirrubinaRESUMEN
BACKGROUND: In Japan, the mortality rate of extremely low birth weight (ELBW) infants is notably low in comparison with other developed countries, but the prevalence of chronic lung disease (CLD) and retinopathy of prematurity (ROP) is relatively high. This study aimed to estimate the mortality and morbidity of ELBW infants born in 2015 who were admitted to neonatal intensive care units (NICUs) in Japan and to examine the factors that affected the short-term outcomes of these infants. We also compared the mortality of ELBW infants born in 2005, 2010, and 2015. METHODS: We analyzed the mortality, morbidity, and factors related to short-term outcomes of ELBW infants, using data from 2782 infants born in 2015 and registered at NICUs in Japan. RESULTS: The mortality rates during NICU stays were 17.0%, 12.0%, and 9.8% for ELBW infants born in 2005, 2010, and 2015, respectively. Among ELBW infants born in 2015, multiple logistic regression analysis showed that short gestational age and low birthweight Z-score contributed to the increased risk of death. Births by cesarean section and antenatal corticosteroid administration were significantly associated with a reduced risk of death. Among infants who survived, CLD was observed in 53.1% and ROP requiring treatment was observed in 30.4%. CONCLUSIONS: Mortality in ELBW infants decreased significantly from 2005 to 2015. As CLD and ROP may affect quality of life and long-term outcomes of infants who survived, prevention strategies and management for these complications are critical issues in neonatal care in Japan.
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Mortalidad Infantil , Recien Nacido con Peso al Nacer Extremadamente Bajo , Cesárea , Morbilidad , Japón/epidemiología , Retinopatía de la Prematuridad/epidemiología , Prevalencia , Lesión Pulmonar/epidemiología , Humanos , Masculino , Femenino , Calidad de VidaRESUMEN
Since it was proposed in this journal in 2001, the cranial vault asymmetry index (CVAI) has been an important parameter for assessing cranial shape. However, different publications currently use different variables in the denominator of the CVAI formula. We thus investigated the use of long and short diagonal lengths as variables in the denominator of the CVAI formula. We searched the databases of PubMed, Google Scholar, and Scopus for articles published between 2016 and 2022 that cited the original work article of CVAI. Articles were included if they were written in English and if the denominator of the CVAI formula was specified. For multiple articles by the same author, only the most recent article was included. In total, 30 articles were included; 10 articles used the longer diagonal length as the denominator and 20 articles used the shorter diagonal length. No uniform trend was observed by a country or journal of publication. Application of the CVAI formula using different denominators yielded interchangeable results, and the resulting values had only negligible differences clinically. However, it would be necessary to create a standard formula for using the CVAI as a parameter for reporting cranial shape assessments consistently.
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Plagiocefalia no Sinostótica , Humanos , Cráneo , Bibliometría , Bases de Datos FactualesRESUMEN
Background and Objectives: Baloxavir marboxil is a novel cap-dependent endonuclease inhibitor prescribed for influenza treatment. Unlike neuraminidase inhibitors like oseltamivir, which impair viral release from infected host cells, baloxavir blocks influenza virus proliferation by inhibiting viral mRNA transcription. This study aimed to compare the effectiveness of baloxavir and oseltamivir for the treatment of early childhood influenza. Materials and Methods: Of 1410 patients diagnosed with influenza between 2015 and 2018 at a Japanese primary care outpatient clinic, 1111 pediatric patients aged 0-6 years who were treated with baloxavir (n = 555) or oseltamivir (n = 556) were enrolled retrospectively. The following clinical factors were compared between patients treated with baloxavir and oseltamivir: age, sex, time from fever onset to drug administration (<24 h or 24-48 h), time from drug administration to fever reduction, influenza type (A or B), and influenza vaccination before disease onset. The duration of the fever, which was used as an index of clinical effectiveness, was compared using the log-rank test. Clinical factors associated with fever duration were determined using multivariate logistic regression analysis. Results: Median age (3.0 vs. 2.5 years), influenza type A (99% vs. 47%), median duration from drug administration to fever resolution (1 day vs. 2 days), and influenza vaccination (done, 41% vs. not done, 65%) were significantly different between the baloxavir and oseltamivir groups (p < 0.001). The number of patients with a fever duration of one day was 553 (99.6%) in the baloxavir group and 6 (1.1%) in the oseltamivir group (p < 0.001). Baloxavir use was only significantly associated with fever duration in the multivariate analysis (odds ratio 50,201, p < 0.001). Apparent adverse effects were not observed in the baloxavir-treated group. Conclusions: Baloxavir treatment resulted in a shorter fever duration than oseltamivir treatment in early childhood influenza.
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Dibenzotiepinas , Gripe Humana , Preescolar , Humanos , Niño , Oseltamivir/uso terapéutico , Gripe Humana/tratamiento farmacológico , Estudios Retrospectivos , Dibenzotiepinas/uso terapéutico , Fiebre/tratamiento farmacológicoRESUMEN
Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.