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Background: Over-aggressive intravenous fluid therapy with crystalloids has adverse effects in trauma patients. We assessed the role of large-volume (≥5l) administration of crystalloids within 24h of injury as an independent risk-factor for mortality, in-hospital complications, and prolonged mechanical ventilation.Methods: A retrospective cohort analysis of adult trauma patients admitted to a level 1-trauma center between December 2011 and December 2012. Patient demographics, clinical and laboratory values, and total resuscitation fluid administered within the first 24h of injury were obtained. Outcomes included mortality, in-hospital complications and ventilator-days. Multivariable logistic regression and Poisson regression analyses were performed to investigate any association between the administration of ≥5L crystalloids with the aforementioned outcomes while controlling for selected clinical variables.Results: A total of 970 patients were included in the analysis. 264 (27%) received ≥5L of crystalloids in the first 24h of injury. 118 (12%) had in-hospital complications and 337 (35%) required mechanical ventilation. The median age was 46 years (interquartile range (IQR) 27-65) years and 73% (n = 708) were males. The median injury severity score (ISS) was 17 (IQR 9-25). Overall mortality rate was 7% (n = 67). Multivariable logistic regression analysis showed several variables independently associated with mortality (p < 0.05), including resuscitation with ≥5L crystalloid in the first 24h (adjusted odds ratio (aOR) 2.55), older age (aOR 1.03), higher ISS (aOR 1.09), and lower temperature (aOR 0.68). The variables independently associated with in-hospital complications (p < 0.05) were older age, longer ICU stay, and platelet transfusion within 24h of the injury. Need for mechanical ventilation was more common in patients who received ≥5L crystalloids (RR 2.31) had higher ISS (RR 1.02), developed in-hospital complications (RR 1.91) and had lower presenting temperature (RR 0.87).Conclusion: Large-volume crystalloid resuscitation is associated with increased mortality and longer time ventilated, but not with in-hospital complications such as pneumonia and sepsis. Based on this data, we recommend judicious use of crystalloids in the resuscitation of trauma patients. [ABSTRACT FROM AUTHOR]

Background: The polo-like kinases (Plks) are a group of serine/threonine kinases which have roles in many aspects of cellular function including the regulation of mitotic activity and cellular stress responses. This study focuses on Plk4, the most divergent member of the Plk family, which is necessary for proper cellular proliferation. More specifically, alterations in Plk4 levels cause significantly adverse mitotic defects including abnormal centrosome duplication and aberrant mitotic spindle formation. We sought to clarify the effect of reduced Plk4 levels on the cell by examining transcript profiles of Plk4 wild-type and heterozygous mouse embryonic fibroblasts (MEFs). Subsequently, the levels of several key proteins involved in the DNA damage response were examined., Results: 143 genes were found to be significantly up-regulated in the heterozygous MEFs compared to their wild-type counterparts, while conversely, 9 genes were down-regulated. Numerous genes with increased transcript levels in heterozygous MEFs were identified to be involved in p53-dependent pathways. Furthermore, examination of the promoter regions of all up- and down-regulated genes revealed that the majority contained putative p53 responsive elements. An analysis of transcript levels in MEFs after exposure to either ionizing or ultraviolet radiation revealed a significant change between wild type and heterozygous MEFS for Plk4 transcript levels upon only UV exposure. Furthermore, changes in protein levels of several important cell check-point and apoptosis regulators were examined, including p53, Chk1, Chk2, Cdc25C and p21. In heterozygous MEFs, p53, p21 and Chk2 protein levels were at significantly higher levels. Furthermore, p53 activity was increased 5 fold in the Plk4 heterozygous MEFs., Conclusion: Global transcript profiles and levels of key proteins involved in cellular proliferation and DNA damage pathways were examined in wild-type and Plk4 heterozygous MEFs. It was determined that Plk4 haploinsufficiency leads to changes in the levels of RNA accumulation for a number of key cellular genes as well as changes in protein levels for several important cell cycle/DNA damage proteins. We propose a model in which reduced Plk4 levels invoke an increase in p53 levels that leads to the aforementioned changes in global transcription profiles.