Aim
Gamma‐aminobutyric acid (GABA) is a major modulator in brain maturation and its role in many different neurodevelopmental disorders has been widely reported. Although the involvement of GABA in ...different disorders has been related to its regulatory function as an inhibitory neurotransmitter in the mature brain, co‐transmitter, and signalling molecule, little is known about its role as a clinical biomarker in neuropaediatric disorders. The aim of this study is to report the cerebrospinal fluid (CSF) free‐GABA concentrations in a large cohort of patients (n=85) with different neurological disorders.
Method
GABA was measured in the CSF of neuropaediatric patients using capillary electrophoresis with laser‐induced fluorescence detection. Other neurotransmitters (amino acids and monoamines) were also analysed.
Results
GABA concentrations in CSF were abnormal, with a greater frequency (44%) than monoamines (20%) in neuropaediatric patients compared with our reference values. Although we included a few patients with inborn errors of metabolism, GABA levels in CSF were more frequently abnormal in metabolic disorders than in other nosological groups.
Interpretation
Our work suggests further research into brain GABAergic status in neuropaediatric disorders, which could also lead to new therapeutic strategies.
What this paper adds
Homeostasis of GABA seems more vulnerable than that of monoamines in the developing brain.
The highest GABA levels are found in the primary GABA neurotransmitter disorder SSADH deficiency.
GABA alterations are not specific for any clinical or neuroimaging presentation.
Resumen
Niveles de acido gama‐aminobutírico en líquido cefalorraquídeo en trastornos neuropediátricos
Objetivo
El ácido gama‐aminobutírico (GABA) es un modulador mayor en la maduración cerebral y su función en diversos trastornos del neurodesarrollo ha sido ampliamente descripta. La función del GABA en diferentes trastornos se ha relacionado con su función reguladora como neurotransmisor inhibidor en la madurez cerebral, así como co‐transmisor y como molécula indicadora, sin embargo, poco se conoce como bio‐marcador clínico en trastornos neuropediátricos. El objetivo de este estudio es reportar las concentraciones de GABA‐libre en líquido cefalorraquídeo (LCR) en una gran cohorte de pacientes (n=85) con diferentes trastornos neurológicos.
Método
El GABA fue medido en LCR de pacientes neuropediátricos utilizando electroforesis capilar con detección de fluorescencia inducida por láser. También se analizaron otros neurotransmisores (aminoácidos y mono aminos).
Resultados
Las concentraciones de GABA fueron anormales, con una mayor frecuencia (44%) que los mono aminos (20%) en pacientes neuropediátricos en comparación con nuestros valores de referencia. Aunque incluimos algunos pocos pacientes con errores congénitos del metabolismo, los niveles de GABA en LCR fueron más frecuentemente anormales en trastornos metabólicos que en otros grupos nosológicos.
Interpretación
Nuestro trabajo sugiere que es necesario más investigación sobre el estado GABAérgico del cerebro en trastornos neuropediátricos, lo cual además podría llevar a nuevas estrategias terapéuticas.
Resumo
Níveis de ácido gama‐aminobutírico no fluido cerebroespinhal em desordens neuropediátricas
Objetivo
O ácido gama‐aminobutírico (GABA) é um importante modulador da maturação cerebral, e seu papel em diferentes desordens neurodesenvolvimentais tem sido amplamente reportado. Embora o envolvimento do GABA em diferentes desordens tenha sido relacionado com sua função regulatória como neurotransmissor inibitório no cérebro maduro, co‐transmissor e molécula sinalizadora, pouco se sabe sobre o seu papel como biomarcador clínico em desordens neuropediátricas. O objetivo deste estudo é relatar as concentrações de fluido cerebroespinhal (FCE) livre de GABA em uma grande coorte de pacientes (n=85) com diferentes desordens neurológicas.
Método
GABA foi medido no FCE de pacientes neuropediátricos usando eletroforese capilar com detecção de fluorescência induzida por laser. Outros neurotransmissores (aminoácidos e monoaminas) também foram analisados.
Resultados
As concentrações de GABA no FCE foram anormais, com maior frequência (44%) do que monoaminas (20%) em pacientes neuropediátricos em comparação com nossos valores de referência. Embora tenhamos incluído alguns pacientes com erros inatos do metabilismo, os níveis de GABA no FCE foram mais frequentemente anormais nas desordens metabólicas do que em outros grupos nosológicos.
Interpretação
Nosso trabalho sugere que mais pesquisas sobre o estado GABAérgico em desordens neuropediátricas, o que também pode levar a novas estratégias terapêuticas.
What this paper adds
Homeostasis of GABA seems more vulnerable than that of monoamines in the developing brain.
The highest GABA levels are found in the primary GABA neurotransmitter disorder SSADH deficiency.
GABA alterations are not specific for any clinical or neuroimaging presentation.
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Fatty acid metabolism in the hypothalamus has an important role in food intake, but its specific role in AgRP neurons is poorly understood. Here, we examined whether carnitinea palmitoyltransferase ...1A (CPT1A), a key enzyme in mitochondrial fatty acid oxidation, affects energy balance.
To obtain Cpt1aKO mice and their control littermates, Cpt1a
mice were crossed with tamoxifen-inducible AgRP
mice. Food intake and body weight were analyzed weekly in both males and females. At 12 weeks of age, metabolic flexibility was determined by ghrelin-induced food intake and fasting-refeeding satiety tests. Energy expenditure was analyzed by calorimetric system and thermogenic activity of brown adipose tissue. To study fluid balance the analysis of urine and water intake volumes; osmolality of urine and plasma; as well as serum levels of angiotensin and components of RAAS (renin-angiotensin-aldosterone system) were measured. At the central level, changes in AgRP neurons were determined by: (1) analyzing specific AgRP gene expression in RiboTag-Cpt1aKO mice obtained by crossing Cpt1aKO mice with RiboTag mice; (2) measuring presynaptic terminal formation in the AgRP neurons with the injection of the AAV1-EF1a-DIO-synaptophysin-GFP in the arcuate nucleus of the hypothalamus; (3) analyzing AgRP neuronal viability and spine formations by the injection AAV9-EF1a-DIO-mCherry in the arcuate nucleus of the hypothalamus; (4) analyzing in situ the specific AgRP mitochondria in the ZsGreen-Cpt1aKO obtained by breeding ZsGreen mice with Cpt1aKO mice. Two-way ANOVA analyses were performed to determine the contributions of the effect of lack of CPT1A in AgRP neurons in the sex.
Changes in food intake were just seen in male Cpt1aKO mice while only female Cpt1aKO mice increased energy expenditure. The lack of Cpt1a in the AgRP neurons enhanced brown adipose tissue activity, mainly in females, and induced a substantial reduction in fat deposits and body weight. Strikingly, both male and female Cpt1aKO mice showed polydipsia and polyuria, with more reduced serum vasopressin levels in females and without osmolality alterations, indicating a direct involvement of Cpt1a in AgRP neurons in fluid balance. AgRP neurons from Cpt1aKO mice showed a sex-dependent gene expression pattern, reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus, without neuronal viability alterations.
Our results highlight that fatty acid metabolism and CPT1A in AgRP neurons show marked sex differences and play a relevant role in the neuronal processes necessary for the maintenance of whole-body fluid and energy balance.
Background: Bloodstream infections (BSIs) are the most frequent nosocomial infections in neonatal intensive care units (NICUs), especially in very low birth weight (VLBW) infants (birth weight ≤ ...1500 g). An epidemiologic surveillance system may contribute to the prevention of infection by continuous monitoring of its frequency and associated risk factors. The aim of this article was to describe the implementation of the NeoKissEs surveillance system for BSIs in VLBW newborns in a group of Spanish NICUs. Methods: We assessed the clinical cohort consisting of all VLBW newborns aged less than 28 days admitted to the participating units. In the pilot phase, 2 NICUs translated and adapted materials from the original German NEO-KISS system. During implementation, 210 health care professionals attended one of 8 educational workshops. A web-based system was created that allows entering data regarding patients and BSI episodes, data monitoring, benchmarking and providing feedback to the units. At each NICU, one neonatologist was responsible for the implementation of the system and reporting the difficulties perceived throughout the process. Results: Out of the 50 units that agreed to participate, 45 successfully started using the surveillance platform during the implementation phase, recording 1108 episodes of catheter-associated BSI (CABSI) in 3638 newborns, and finding an overall rate of CABSI of 18.4 (95% CI, 17.8-19.1) per 1000 catheter days. Conclusions: The NeoKissEs surveillance system constitutes a helpful source of information for the purpose of benchmarking the performance of neonatal units, assessing factors associated with BSI in VLBW infants and measuring the impact of future preventive interventions in NICUs. Resumen: Antecedentes: Las sepsis son las infecciones nosocomiales más frecuentes en las Unidades de Cuidados Intensivos Neonatales (UCIN), afectando especialmente a los recién nacidos de muy bajo peso al nacer (RNMBP, ≤ 1.500 g). Un sistema de vigilancia epidemiológica puede contribuir a su prevención mediante una evaluación continua de su frecuencia y factores de riesgo asociados. El objetivo de este artículo es describir la implementación del sistema de vigilancia de las sepsis nosocomiales en RNMBP (NeoKissEs) en un grupo de UCIN españolas. Métodos: Estudio de cohorte de RNMBP con < 28 días de edad ingresados en las UCIN participantes. Dos UCIN tradujeron y adaptaron materiales a partir del sistema original alemán NEO-KISS. Durante la implementación, se desarrollaron 8 talleres formativos, con participación de 210 profesionales. Se creó un sistema web para la introducción de datos de pacientes y episodios de sepsis, su monitorización, análisis comparativo y retroalimentación a las unidades. En cada UCIN, un neonatólogo fue responsable de la implementación, recogiendo información sobre las dificultades percibidas durante el proceso. Resultados: De 50 unidades que aceptaron participar, 45 utilizaron NeoKissEs durante la fase de implementación, registrando 1.108 episodios de sepsis asociados a catéter vascular en 3.638 neonatos, con una tasa de 18,4 episodios por 1.000 pacientes-día con catéter (IC del 95%: 17,8-19,1). Conclusiones: El sistema de vigilancia epidemiológica NeoKissEs representa una fuente útil de información para la comparación estandarizada de la incidencia de sepsis de las UCIN, evaluar factores de riesgo y facilitar la evaluación del efecto de futuras intervenciones preventivas.
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