RESUMEN
The year 2016 marked the 15th anniversary since anesthesia-induced developmental neurotoxicity and its resulting cognitive dysfunction were first described. Since that time, multiple scientific studies have supported these original findings and investigated possible mechanisms behind anesthesia-induced neurotoxicity. This paper reviews the existing mechanistic literature on anesthesia-induced neurotoxicity in the context of a holistic approach that emphasizes the importance of both neuronal and non-neuronal cells during early postnatal development. Sections are divided into key stages in early neural development; apoptosis, neurogenesis, migration, differentiation, synaptogenesis, gliogenesis, myelination and blood brain barrier/cerebrovasculature. In addition, the authors combine the established literature in the field of anesthesia-induced neurotoxicity with literature from other related scientific fields to speculate on the potential role of non-neuronal cells and to generate new future hypotheses for understanding anesthetic toxicity and its application to the practice of pediatric anesthesia.
Asunto(s)
Anestésicos/efectos adversos , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Neuroglía/efectos de los fármacos , Neuronas/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Animales , HumanosRESUMEN
BACKGROUND: Neonates are at high risk for bleeding complications after cardiovascular surgery. Activation of intravascular fibrinolysis is one of the principal effects of cardiopulmonary bypass that causes poor postoperative hemostasis. Antifibrinolytic medications such as tranexamic acid are often used as prophylaxis against fibrinolysis, but concentration/effect data to guide dosing are sparse for adults and have not been published for neonates. Higher concentrations of tranexamic acid than those necessary for inhibition of fibrinolysis may have adverse effects. Therefore, we investigated the concentration of tranexamic acid necessary to inhibit activated fibrinolysis in neonatal plasma. METHODS: We conducted an in vitro study using neonatal plasma derived from the placenta/cord units from 20 term, elective cesarean deliveries. Graded concentrations of tranexamic acid were added to aliquots of the pooled plasma before maximally activating fibrinolysis with high-dose tissue-type plasminogen activator. Thromboelastography was then performed with the primary outcome variable being lysis at 30 minutes. These procedures were repeated on pooled adult normal plasma and dilutions of neonatal plasma. RESULTS: The minimum concentrations of tranexamic acid to completely prevent fibrinolysis were 6.54 µg/mL (95% confidence interval, 5.19-7.91) for neonatal plasma and 17.5 µg/mL (95% confidence interval, 14.59-20.41) for adult plasma. Neonatal plasma requires a significantly lower concentration than adult plasma (P < 0.0001, 2-sided Wald test). CONCLUSIONS: Our data establish the minimal effective concentration of tranexamic acid necessary to completely prevent fibrinolysis in neonatal plasma in vitro. These data may be useful in designing a dosing scheme for tranexamic acid appropriate for neonates.
Asunto(s)
Antifibrinolíticos/sangre , Fibrinólisis/fisiología , Ácido Tranexámico/sangre , Antifibrinolíticos/farmacología , Antifibrinolíticos/uso terapéutico , Sangre Fetal/efectos de los fármacos , Sangre Fetal/metabolismo , Fibrinólisis/efectos de los fármacos , Humanos , Recién Nacido , Ácido Tranexámico/farmacología , Ácido Tranexámico/uso terapéutico , Resultado del TratamientoRESUMEN
INTRODUCTION: Pediatric patients, particularly neonates, are at high risk for bleeding complications after cardiovascular surgery because of their immature hemostatic system, small size, and the complex operations they require. Activation of intravascular fibrinolysis is one of the principle effects of cardiopulmonary bypass that causes poor postoperative hemostasis. This complication has long been recognized and treated with antifibrinolytic medications, including the lysine analog epsilon aminocaproic acid (EACA). The therapeutic plasma concentration of EACA has been scientifically determined for the adult population, but the current recommended dosage for neonates has been empirically derived from adult studies. Therefore, we investigated the appropriate concentration of EACA for neonates undergoing bypass. METHODS: We conducted an in vitro study using neonatal plasma derived from the placenta/cord units from 20 term, elective cesarean deliveries. Graded concentrations of EACA were added to aliquots of the plasma pool before activating fibrinolysis with tissue-type plasminogen activator. Standard kaolin-activated thromboelastograms were then run with the primary outcome variable being estimated percent lysis. These procedures were repeated on samples of commercially available pooled adult normal plasma for comparison. RESULTS: We found that neonatal plasma required significantly lower concentrations of EACA to completely prevent fibrinolysis than did adult plasma (44.2 microg/mL and 47.8 microg/mL for neonatal plasma and 94.4 and 131.4 microg/mL in adult plasma for 400 and 1000 U/mL of plasminogen activator, respectively, P < 0.001). CONCLUSIONS: Our data establish the minimal effective concentration of EACA necessary to completely prevent fibrinolysis in neonatal blood in vitro. This concentration is significantly less than that targeted by current dosing schemes, indicating that neonates are possibly being exposed to greater levels of EACA than is clinically necessary.
Asunto(s)
Ácido Aminocaproico/sangre , Ácido Aminocaproico/farmacología , Antifibrinolíticos/sangre , Antifibrinolíticos/farmacología , Fibrinólisis/efectos de los fármacos , Plasma/efectos de los fármacos , Adulto , Envejecimiento/sangre , Ácido Aminocaproico/administración & dosificación , Antifibrinolíticos/administración & dosificación , Cesárea , Relación Dosis-Respuesta a Droga , Sangre Fetal , Humanos , Técnicas In Vitro , Recién Nacido , Pruebas de Sensibilidad Microbiana , Activadores Plasminogénicos/farmacología , Tromboelastografía , Activador de Plasminógeno de Tipo Uroquinasa/farmacologíaRESUMEN
There is considerable interest in the use of bacteriophage vectors for mammalian cell gene transfer applications, due to their stability, excellent safety profile and inexpensive mass production. However, to date, phage vectors have been plagued by mediocre performance as gene transfer agents. This may reflect the complexity of the viral infection process in mammalian cells and the need to refine each step of this process in order to arrive at an optimal, phage-based gene transfer system. Therefore, a flexible system was designed that alowed for the introduction of multiple modifications on the surface of bacteriophage lambda. Using this novel method, multiple peptides were displayed simultaneously from both the phage head and tail. Surface head display of an ubiquitinylation motif greatly increased the efficiency of phage-mediated gene transfer in a murine macrophage cell line. Gene transfer was further increased when this peptide was displayed in combination with a tail-displayed CD40-binding motif. Overall, this work provides a novel system that can be used to rationally improve bacteriophage gene transfer vectors and shows it may be possible to enhance the efficiency of phage-mediated gene transfer by targeting and optimizing multiple steps within the viral infection pathway.
Asunto(s)
Bacteriófago lambda/genética , Técnicas de Transferencia de Gen , Vectores Genéticos , Secuencias de Aminoácidos , Animales , Transporte Biológico , Antígenos CD40/metabolismo , Línea Celular , ADN/metabolismo , Ratones , Proteínas de la Cola de los Virus/genética , Virión/genéticaRESUMEN
Bacteriophage lambda (lambda) permits the display of many foreign peptides and proteins on the gpD major coat protein. However, some recombinant derivatives of gpD are incompatible with the assembly of stable phage particles. This presents a limitation to current lambda display systems. Here we describe a novel, plasmid-based expression system in which gpD deficient lambda lysogens can be co-complemented with both wild-type and recombinant forms of gpD. This dual expression system permits the generation of mosaic phage particles that contain otherwise recalcitrant recombinant gpD fusion proteins. Overall, this improved gpD display system is expected to permit the expression of a wide variety of peptides and proteins on the surface of bacteriophage lambda and to facilitate the use of modified lambda phage vectors in mammalian gene transfer applications.