RESUMO
S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid.
Assuntos
Sistemas de Transporte de Aminoácidos/genética , Proteínas de Ligação ao Cálcio/genética , Metilação de DNA , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Debilidade Muscular/genética , Mutação/genética , S-Adenosilmetionina/metabolismo , Sequência de Aminoácidos , Pré-Escolar , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Debilidade Muscular/patologia , Linhagem , Prognóstico , Estabilidade de RNA , Homologia de Sequência de Aminoácidos , Ácido Tióctico/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/metabolismoRESUMO
BACKGROUND: Ibuprofen is used for treatment and prevention of patent ductus arteriosus in low-birthweight infants. Its effects on regional circulations differ from those of indometacin. Because prophylactic indometacin reduces the frequency of severe intraventricular haemorrhage and patent ductus arteriosus, we aimed to study the efficacy of early ibuprofen in reducing these outcomes in a double-blind, multicentre trial. METHODS: Within 6 h after birth, 415 low-birthweight infants (gestational age <31 weeks) were randomly allocated ibuprofen-lysine (10 mg/kg then two doses of 5 mg/kg after 24 h and 48 h) or placebo intravenously. The primary outcome was occurrence of severe intraventricular haemorrhage; secondary outcomes were occurrence of patent ductus arteriosus and possible adverse effects of ibuprofen. Analysis was by intention to treat. FINDINGS: 17 (8%) of 205 infants assigned ibuprofen and 18 (9%) of 210 assigned placebo developed severe intraventricular haemorrhage (relative risk 0.97 [95% CI 0.51-1.82]). In 172 (84%) infants of the ibuprofen group, the ductus was closed on day 3 compared with 126 (60%) of the placebo group (relative risk 1.40 [1.23-1.59]). No important differences in other outcomes or side-effects were noted; however, urine production was significantly lower on day 1 and concentration of creatinine in serum was significantly higher on day 3 after ibuprofen. INTERPRETATION: Ibuprofen prophylaxis in preterm infants does not reduce the frequency of intraventricular haemorrhage, but does decrease occurrence of patent ductus arteriosus.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Hemorragia Cerebral/prevenção & controle , Inibidores de Ciclo-Oxigenase/uso terapêutico , Ibuprofeno/análogos & derivados , Ibuprofeno/uso terapêutico , Doenças do Prematuro/prevenção & controle , Lisina/análogos & derivados , Lisina/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Ventrículos Cerebrais , Inibidores de Ciclo-Oxigenase/efeitos adversos , Método Duplo-Cego , Permeabilidade do Canal Arterial/prevenção & controle , Humanos , Ibuprofeno/efeitos adversos , Recém-Nascido , Lisina/efeitos adversosRESUMO
We report on a male newborn with a rarely described congenital limb deficiency syndrome consisting of shortening and anterior bowing of the right lower limb at the distal third of the tibia with associated overlying soft tissue dimpling, oligodactyly of the right foot, and a left-sided oligosyndactyly of the hand. The right hand and left lower limb were clinically normal. Radiographic examination revealed complete absence of the right fibula, absence of the right-sided Vth ray, and anterior bowing and shortening of the right-sided tibia. Femora, humeri, ulnae, and radii were normal. The infant had neither facial dysmorphia nor other associated anomalies. A limb deficiency syndrome comparable to this case has been reported in a female by Hecht and Scott, the only report classified under OMIM 246570 so far. We found two other reports describing three cases comparable to our case and the female reported by Hecht and Scott, and reviewed these cases. The major common findings in all the five cases consist of fibular aplasia, tibial campomelia, and oligosyndactyly. Therefore, we propose to name it fibular aplasia-tibial campomelia-oligosyndactyly (FATCO) syndrome. Additional case reports are needed for further delineation of this rare limb deficiency syndrome.
Assuntos
Anormalidades Múltiplas/patologia , Fíbula/anormalidades , Deformidades Congênitas dos Membros/patologia , Tíbia/anormalidades , Anormalidades Múltiplas/genética , Dedos/anormalidades , Humanos , Recém-Nascido , Cariotipagem , Masculino , Síndrome , Dedos do Pé/anormalidadesRESUMO
OBJECTIVE: To evaluate the performance of a scoring system (NOSEP) to predict nosocomial sepsis in neonates at the hospital where the score was developed (internal validation) and in an independent data set from other centers (external validation). DESIGN: Multiple center prospective cohort study. SETTING: Six neonatal intensive care units from the Flanders in Belgium. PATIENTS: We analyzed two groups of patients: 62 episodes of presumed nosocomial sepsis in the internal validation cohort and 93 episodes of presumed nosocomial sepsis in a multiple center external validation cohort. INTERVENTIONS: Assessment of the predictive power of the NOSEP score 24 hrs preceding sepsis workup and the patients' basic demographic characteristics and co-morbidity was performed. Diagnosis of nosocomial sepsis and the microbiology results were registered. MAIN RESULTS: The NOSEP score's discriminative capability was very good in the internal validation (area under receiver operating characteristic curve = 0.73 +/- 0.08 [sem]). The NOSEP score performed satisfactory in the external validation (area under receiver operating characteristic curve = 0.66 +/- 0.06). The calibration capability in both validation sets as measured by goodness-of-fit tests (internal validation, p =.56; external validation, p =.48) was good. An improvement of the NOSEP score was obtained for the external centers by redefining the cut-off of the items of the NOSEP score (area under receiver operating characteristic curve for NOSEP-NEW-I = 0.71 +/- 0.05) or adding co-morbidity factors (area under receiver operating characteristic curve for NOSEP-NEW-II = 0.82 +/- 0.04), with good calibration performance (goodness-of-fit test, p >.50). Finally, the fit of the NOSEP score demonstrated no significant variation across subgroups of patients. CONCLUSIONS: The predictive power of the original NOSEP score is very good in neonates at the original neonatal intensive care unit. In other neonatal intensive care units, its discriminatory performance is satisfactory but could be improved after modification of the variables in the model or adding additional variables. To use such a NOSEP score in other neonatal intensive care units, its accuracy has to be validated and adjusted if necessary.