Vitamin C and thiamine for the treatment of refractory septic shock in surgical critically ill patients: a retrospective before-and-after study / Vitamina C y tiamina para el tratamiento del shock séptico refractario en pacientes críticos quirúrgicos: un estudio retrospectivo antes-después

Introduction: This study aimed to evaluate whether early vitamin C and thiamine administration was associated with a lower 28-day and in-hospital mortality in surgical critically ill patients with refractory septic shock. Patients and methods: We performed a retrospective before-and-after study on patients with refractory septic shock. According to local protocol, hydrocortisone is initiated in case of refractory septic shock. In January 2017, the protocol was changed and vitamin C and thiamine were included. Patients who were admitted in 2015-2016 and 2017-2018 were included in the control and treatment groups, respectively. The primary end point was 28-day and in-hospital mortality. Secondary end points were ICU mortality, ICU and hospital length of stay, duration of vasopressors and mechanical ventilation, use of renal replacement therapy (RRT), and the modification in serum procalcitonin and SOFA score during the first 72 h. Results: A total of 120 patients were included (58 in the treatment group and 62 in the control group). Log-rank test in Kaplan-Meier curves showed lower 28-day and in-hospital mortality over time in the treatment group (p=0.021 and p=0.035, respectively) but it not reached statistical significance in ICU mortality over time (p=0.100). The need of RRT was less frequent in treatment group (17.2% vs. 37.1%, p=0.024). There were no differences in other secondary outcomes. Conclusions: Intravenous vitamin C and thiamine administration in surgical patients with refractory septic shock may be associated with a lower 28-day and in-hospital mortality. Further prospective studies are needed in refractory septic shock. (AU)

Introducción: El objetivo de este estudio fue evaluar si la administración precoz de vitamina C y tiamina estaba asociada a una reducción en la mortalidad a los 28 días y hospitalaria en pacientes críticos quirúrgicos con shock séptico refractario. Pacientes y métodos: Realizamos un estudio retrospectivo antes-después en pacientes con shock séptico refractario. Según el protocolo local, se inicia tratamiento con hidrocortisona en situación de shock séptico refractario. En enero de 2017 se cambió el protocolo y se incluyó vitamina C y tiamina. Los pacientes que fueron ingresados en 2015-2016 y 2017-2018 se incluyeron en el grupo control y tratamiento, respectivamente. Los objetivos primarios fueron la mortalidad a los 28 días y hospitalaria. Los objetivos secundarios fueron la mortalidad en UCI, la duración de estancia en UCI y hospitalaria, la duración del tratamiento vasopresor y de la ventilación mecánica, el uso de técnicas de reemplazo renal (TRR), y la modificación en la procalcitonina sérica y la puntuación SOFA durante las primeras 72h. Resultados: Se incluyeron un total de 120 pacientes (58 en el grupo tratamiento y 62 en el grupo control). El test Log-rank en las curvas de Kaplan-Meier mostró mortalidad a los 28 días y hospitalaria más baja a lo largo del tiempo en el grupo tratamiento (p=0,021 and p=0,035, respectivamente) pero no alcanzó significación estadística en la mortalidad en UCI a lo largo del tiempo (p=0,100). La necesidad de TRR fue menos frecuente en el grupo tratamiento (17,2% vs. 37,1%, p=0,024). No hubo diferencias en otros resultados secundarios. Conclusiones: La administración de vitamina C y tiamina intravenosa en pacientes quirúrgicos con shock séptico refractario podría estar asociada a una menor mortalidad a los 28 días y hospitalaria. Se necesitan más estudios prospectivos en pacientes con shock séptico refractario. (AU)

Function of Armcx3 and Armc10/SVH Genes in the Regulation of Progenitor Proliferation and Neural Differentiation in the Chicken Spinal Cord.

The eutherian X-chromosome specific family of Armcx genes has been described as originating by retrotransposition from Armc10/SVH, a single Arm-containing somatic gene. Armcx3 and Armc10/SVH are characterized by high expression in the central nervous system and they play an important role in the regulation of mitochondrial distribution and transport in neurons. In addition, Armcx/Arm10 genes have several Armadillo repeats in their sequence. In this study we address the potential role of this gene family in neural development by using the chick neural tube as a model. We show that Armc10/SVH is expressed in the chicken spinal cord, and knocking-down Armc10/SVH by sh-RNAi electroporation in spinal cord reduces proliferation of neural precursor cells (NPCs). Moreover, we analyzed the effects of murine Armcx3 and Armc10 overexpression, showing that both proteins regulate progenitor proliferation, while Armcx3 overexpression also specifically controls neural maturation. We show that the phenotypes found following Armcx3 overexpression require its mitochondrial localization, suggesting a novel link between mitochondrial dynamics and regulation of neural development. Furthermore, we found that both Armcx3 and Armc10 may act as inhibitors of Wnt-ß-catenin signaling. Our results highlight both common and differential functions of Armcx/Armc10 genes in neural development in the spinal cord.

The strength of SMAD1/5 activity determines the mode of stem cell division in the developing spinal cord.

The different modes of stem cell division are tightly regulated to balance growth and differentiation during organ development and homeostasis. However, the mechanisms controlling such events are not fully understood. We have developed markers that provide the single cell resolution necessary to identify the three modes of division occurring in a developing nervous system: self-expanding, self-renewing, and self-consuming. Characterizing these three modes of division during interneuron generation in the developing chick spinal cord, we demonstrated that they correlate to different levels of activity of the canonical bone morphogenetic protein effectors SMAD1/5. Functional in vivo experiments showed that the premature neuronal differentiation and changes in cell cycle parameters caused by SMAD1/5 inhibition were preceded by a reduction of self-expanding divisions in favor of self-consuming divisions. Conversely, SMAD1/5 gain of function promoted self-expanding divisions. Together, these results lead us to propose that the strength of SMAD1/5 activity dictates the mode of stem cell division during spinal interneuron generation.

Sonic hedgehog signaling switches the mode of division in the developing nervous system.

The different modes of stem cell division are tightly regulated to balance growth and differentiation during organ development and homeostasis, and these regulatory processes are subverted in tumor formation. Here, we developed markers that provided the single-cell resolution necessary to quantify the three modes of division taking place in the developing nervous system in vivo: self-expanding, PP; self-replacing, PN; and self-consuming, NN. Using these markers and a mathematical model that predicts the dynamics of motor neuron progenitor division, we identify a role for the morphogen Sonic hedgehog in the maintenance of stem cell identity in the developing spinal cord. Moreover, our study provides insight into the process linking lineage commitment to neurogenesis with changes in cell-cycle parameters. As a result, we propose a challenging model in which the external Sonic hedgehog signal dictates stem cell identity, reflected in the consequent readjustment of cell-cycle parameters.