RESUMEN
CONTEXT: The hyperinsulinism/hyperammonemia (HI/HA) syndrome, the second-most common form of congenital hyperinsulinism, has been associated with dominant mutations in GLUD1, coding for the mitochondrial enzyme glutamate dehydrogenase, that increase enzyme activity by reducing its sensitivity to allosteric inhibition by GTP. OBJECTIVE: To identify the underlying genetic etiology in 2 siblings who presented with the biochemical features of HI/HA syndrome but did not carry pathogenic variants in GLUD1, and to determine the functional impact of the newly identified mutation. METHODS: The patients were investigated by whole exome sequencing. Yeast complementation studies and biochemical assays on the recombinant mutated protein were performed. The consequences of stable slc25a36 silencing in HeLa cells were also investigated. RESULTS: A homozygous splice site variant was identified in solute carrier family 25, member 36 (SLC25A36), encoding the pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine as well as guanine nucleotides across the inner mitochondrial membrane. The mutation leads to a 26-aa in-frame deletion in the first repeat domain of the protein, which abolishes transport activity. Furthermore, knockdown of slc25a36 expression in HeLa cells caused a marked reduction in the mitochondrial GTP content, which likely leads to a hyperactivation of glutamate dehydrogenase in our patients. CONCLUSION: We report for the first time a mutation in PNC2/SLC25A36 leading to HI/HA and provide functional evidence of the molecular mechanism responsible for this phenotype. Our findings underscore the importance of mitochondrial nucleotide metabolism and expand the role of mitochondrial transporters in insulin secretion.
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Hiperinsulinismo Congénito , Hiperamonemia , Hiperinsulinismo , Hiperinsulinismo Congénito/genética , Glutamato Deshidrogenasa/genética , Guanosina Trifosfato/metabolismo , Células HeLa , Humanos , Hiperamonemia/genética , Hiperinsulinismo/genética , Hipoglucemia , Mutación , NucleótidosRESUMEN
OBJECTIVE: This study aimed to determine the incidence of umbilical venous catheter associated infection (UVCAI) in very preterm infants based on UVC tip position. STUDY DESIGN: In this retrospective cohort study, infants born at ≤32 weeks were divided into groups with a UVC tip in either a low-lying or good position. The primary outcome was UVCAI. Survival analysis represented time to infection between groups. Subgroup analyses were based on duration of UVC indwelling time. RESULTS: Of 1,983 infants, 1,638 infants were eligible; 33% had low-lying UVC and 67% had good position UVC. Survival analyses suggested a significantly higher probability of infection was associated with low UVC (adjusted hazard ratio [HR]: 1.9, 95% confidence interval [CI]: 1.1-3.2; p = 0.001). The risk of infection was higher for UVC of >7 days duration (adjusted HR: 2.2, 95% CI: 1.1-4.2). Extravasation as a complication was significantly higher in the low UVC versus good position UVC (1.3 vs. 0.1%; odds ratio: 14.4, 95% CI: 1.8-119). CONCLUSION: Low-lying UVC was associated with higher risk of infection and extravasation. KEY POINTS: · Low-lying UVC are at higher risk of UVCAI.. · Presence of UVC in situ for > 7 days carries higher risk of UVCAI.. · There was a higher risk of UVC extravasation with low UVCs..
Asunto(s)
Infecciones Relacionadas con Catéteres/etiología , Cateterismo Venoso Central/efectos adversos , Catéteres de Permanencia/efectos adversos , Recien Nacido Prematuro , Cateterismo Venoso Central/métodos , Femenino , Humanos , Recién Nacido , Masculino , Errores Médicos/efectos adversos , Estudios Retrospectivos , Venas UmbilicalesRESUMEN
INTRODUCTION: The availability of and variability in healthcare professionals in neonatal units in different countries has not been well characterized. Our objective was to identify variations in the healthcare professionals for preterm neonates in 10 national or regional neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of neonates. METHOD: Online, pre-piloted questionnaires about the availability of healthcare professionals were sent to the directors of 390 tertiary neonatal units in 10 international networks: Australia/New Zealand, Canada, Finland, Illinois, Israel, Japan, Spain, Sweden, Switzerland, and Tuscany. RESULTS: Overall, 325 of 390 units (83%) responded. About half of the units (48%; 156/325) cared for 11-30 neonates/day and had team-based (43%; 138/325) care models. Neonatologists were present 24 h a day in 59% of the units (191/325), junior doctors in 60% (194/325), and nurse practitioners in 36% (116/325). A nurse-to-patient ratio of 1:1 for infants who are unstable and require complex care was used in 52% of the units (170/325), whereas a ratio of 1:1 or 1:2 for neonates requiring multisystem support was available in 59% (192/325) of the units. Availability of a respiratory therapist (15%, 49/325), pharmacist (40%, 130/325), dietitian (34%, 112/325), social worker (81%, 263/325), lactation consultant (45%, 146/325), parent buddy (6%, 19/325), or parents' resource personnel (11%, 34/325) were widely variable between units. CONCLUSIONS: We identified variability in the availability and organization of the healthcare professionals between and within countries for the care of extremely preterm neonates. Further research is needed to associate healthcare workers' availability and outcomes.