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Background: Angiopoietin-1 (Agpt-1) and Agpt-2 are cytokine regulators of vascular endothelial integrity. Elevated plasma Agpt-2 levels and ratios of Agpt-2:Agpt-1 are associated with adverse outcomes in adult trauma and pediatric sepsis populations. However, the behavior of the angiopoietins after pediatric trauma has not been characterized, and their relationship to endothelial glycocalyx damage, indicated by plasma syndecan-1 (Syn-1) levels, has not been established., Methods: We performed a secondary analysis of prospectively collected data from 52 pediatric trauma patients and 12 control patients at a level one pediatric trauma center from 2013 to 2016. We measured Agpt-1, Agpt-2, and Syn-1 levels from plasma taken upon hospital arrival and 24 h after admission. Angiopoietin levels were compared to controls, and the correlation between Agpt-2 and Syn-1 was assessed., Results: Plasma Agpt-1 and Agpt-2 levels are elevated immediately after pediatric trauma compared with controls. At 24 h, trauma patients demonstrated significantly elevated plasma Agpt-2:Agpt-1 ratios relative to controls due to decline of Agpt-1 levels to near that of controls. Higher 24-h Agpt-2 levels are associated with more hypoperfusion, and elevated 24-h Agpt-2:Agpt-1 ratios are associated with adverse clinical outcomes. Significant positive correlations between Agpt-2 and Syn-1 upon admission and at 24 h after injury were identified., Conclusion: Our findings suggest dysregulation of circulating angiopoietins after pediatric trauma that may be linked to endothelial glycocalyx injury. Larger prospective studies are needed to validate these findings and determine the relationship of Agpt-2 with other markers of endotheliopathy.

Background: The release of damage-associated molecular pattern molecules in the extracellular space secondary to injury has been shown to cause systemic activation of the coagulation system and endothelial cell damage. We hypothesized that pediatric trauma patients with increased levels of histone-complexed DNA fragments (hcDNA) would have evidence of coagulopathy and endothelial damage that would be associated with poor outcomes., Methods: We conducted a prospective observational study of 149 pediatric trauma patients and 62 control patients at two level 1 pediatric trauma centers from 2013 to 2016. Blood samples were collected upon arrival and at 24 h, analyzed for hcDNA, coagulation abnormalities, endothelial damage, and clinical outcome. Platelet aggregation was assessed with impedance aggregometry (Multiplate) and coagulation parameters were assessed by measuring prothrombin time ratio in plasma and the use of viscoelastic techniques (Rotational Thromboelastometry) in whole blood., Results: The median age was 8.3 years, the median injury severity score (ISS) was 20, and overall mortality was 10%. Significantly higher levels of hcDNA were found on admission in patients with severe injury (ISS > 25), coagulopathy, and/or abnormal platelet aggregation. Patients with high hcDNA levels also had significant elevations in plasma levels of syndecan-1, suggesting damage to the endothelial glycocalyx. Finally, significantly higher hcDNA levels were found in non-survivors., Conclusion: hcDNA is released following injury and correlates with coagulopathy, endothelial glycocalyx damage, and poor clinical outcome early after severe pediatric trauma. These results indicate that hcDNA may play an important role in development of coagulation abnormalities and endothelial glycocalyx damage in children following trauma.

In the United States trauma is the leading cause of mortality among those under the age of 45, claiming approximately 192,000 lives each year. Significant personal disability, lost productivity, and long-term healthcare needs are common and contribute 580 billion dollars in economic impact each year. Improving resuscitation strategies and the early acute care of trauma patients has the potential to reduce the pathological sequelae of combined exuberant inflammation and immune suppression that can co-exist, or occur temporally, and adversely affect outcomes. The endothelial and epithelial glycocalyx has emerged as an important participant in both inflammation and immunomodulation. Constituents of the glycocalyx have been used as biomarkers of injury severity and have the potential to be target(s) for therapeutic interventions aimed at immune modulation. In this review, we provide a contemporary understanding of the physiologic structure and function of the glycocalyx and its role in traumatic injury with a particular emphasis on lung injury.

Trauma remains the leading cause of morbidity and mortality in the United States among children aged 1 to 21 years. The most common cause of lethality in pediatric trauma is traumatic brain injury. Early coagulopathy has been commonly observed after severe trauma and is usually associated with severe hemorrhage and/or traumatic brain injury. In contrast to adult patients, massive bleeding is less common after pediatric trauma. The classical drivers of trauma-induced coagulopathy include hypothermia, acidosis, hemodilution, and consumption of coagulation factors secondary to local activation of the coagulation system after severe traumatic injury. Furthermore, there is also recent evidence for a distinct mechanism of trauma-induced coagulopathy that involves the activation of the anticoagulant protein C pathway. Whether this new mechanism of posttraumatic coagulopathy plays a role in children is still unknown. The goal of this review is to summarize the current knowledge on the incidence and potential mechanisms of coagulopathy after pediatric trauma and the role of rapid diagnostic tests for early identification of coagulopathy. Finally, we discuss different options for treating coagulopathy after severe pediatric trauma.

Health utility instruments assess patients' valuation of specific health states, which can be converted to quality-adjusted life years for cost-utility analysis. Data from the EQ-5D, a generic health-related quality of life questionnaire from EuroQoL, can be reported as 5 health status scores or as a single health preference weight (HPW). US population-based HPWs were published by Shaw and colleagues in 2005 (Med Care 2005;43:203-220). Our aim was to test the validity of US EQ-5D HPWs and health status scores in liver transplant patients. EQ-5D scores were converted to HPWs with Shaw et al.'s model. Data were stratified by measurement period: pretransplant period, early posttransplant period (< or =12 months), intermediate posttransplant period (13-36 months), and late posttransplant period (>36 months). EQ-5D scores were compared to specific, hypothesized Short Form 36 Health Survey, Center for Epidemiologic Studies Depression Scale, and Beck Anxiety Inventory scores that were identified a priori on the basis of construct similarity. Criterion-related and construct validity were tested with nonparametric methods. Two hundred eighty-five adults participated (113 in the pretransplant period, 60 in the early posttransplant period, 47 in the intermediate posttransplant period, and 65 in the late posttransplant period), and follow-up averaged 36 +/- 36 months. Eighty-one percent of the hypothesized relationships between EQ-5D and gold-standard scales were strong (r > or = |0.5|, P < 0.001), and the remainder were moderate (r > |0.3|, P < 0.001). Differences between pretransplant and posttransplant EQ-5D HPWs were statistically significant. In conclusion, EQ-5D dimensions and the health utility index generated from Shaw's US population preference weights demonstrated criterion-related and construct validity in liver transplant patients. It is a valid instrument for cost-utility analysis in this setting., (Copyright 2008 AASLD.)

Aim: To test the effects of pre- and post-transplant clinical covariates on post-transplant health-related quality of life (HRQOL) score profiles in liver transplant recipients., Material and Methods: HRQOL was measured before and after transplantation using the SF-36 Health Survey. Clinical data [diagnosis, model of end-stage liver disease (MELD) score, post-transplant rejection and infection episodes], pre-transplant functional performance (FP), and demographics were collected. Multivariate models for the eight SF-36 scales and two summary components were developed using multiple regression. Discriminant analysis was used to test whether the score profiles differentiated among recipients with and without hepatitis C virus (HCV) infection., Results: 104 adults reported pre- and post-transplant HRQOL. Time post-transplant averaged 9+/-8 months (range 1-39). Scores on all SF-36 measures improved from pre- to post-transplant (p<0.001), and 7 of 10 models were significant (p<0.05). After controlling for pre-transplant HRQOL and time post-transplant, HCV infection had a negative effect on the role physical, bodily pain, and role emotional scales. History of a rejection episode had a negative effect on the bodily pain and vitality scales. MELD scores > or = 18 had a positive effect on the role physical scale. Pre-transplant FP and post-transplant infection episodes did not affect post-transplant HRQOL. HCV infection had a significant effect on the SF-36 score profile (canonical correlation=0.50; p<0.001)., Conclusions: Pre-transplant HCV infection, MELD score, and post-transplant rejection episodes have significant independent effects on HRQOL after liver transplantation. Their specific effects vary among the individual SF-36 scales, and HRQOL score profiles differ among HCV+ and HCV- recipients.

Adult polycystic liver disease (PCLD) is an autosomal dominant condition commonly associated with autosomal dominant polycystic kidney disease (ADPKD). However in the last decade, it has been recognized that there is a distinct form of autosomal dominant PCLD that arises without concomitant ADPKD. Early knowledge of the pathogenesis was gained from the study of hepatic cysts in patients with ADPKD. Bile duct overgrowth after embryogenesis results in cystic hepatic dilatations that are known as biliary microhamartomas or von Meyenburg complexes. Further dilatation arises from cellular proliferation and fluid secretion into these cysts. There is a variable, broad spectrum of manifestations of PCLD. Although PCLD is most often asymptomatic, massive hepatomegaly can lead to disabling symptoms of abdominal pain, early satiety, persistent nausea, dyspnea, ascites, biliary obstruction, and lower body edema. Complications of PCLD include cyst rupture and cyst infection. Also, there are associated medical problems, especially intracranial aneurysms and valvular heart disease, which clinicians need to be aware of and evaluate in patients with PCLD. In asymptomatic patients, no treatment is indicated for PCLD. In the symptomatic patient, surgical therapy is the mainstay of treatment tailored to the extent of disease for each patient. Management options include cyst aspiration and sclerosis, open or laparoscopic fenestration, liver resection with fenestration, and liver transplantation. The surgical literature discussing treatment of PCLD, including techniques, outcomes, and complication rates, are summarized in this review.

The amygdala plays a critical role in fear conditioning, a model of emotional learning and cue-induced anxiety. In the lateral amygdala, fear conditioning is associated with an enduring increase in synaptic strength mediated through AMPA receptors and with a reduction in paired-pulse facilitation, reflecting an increased probability of neurotransmitter release. Here we show that NMDA-mediated transmission in the thalamic-to-lateral amygdala pathway is not facilitated after fear conditioning, although probability of transmitter release is enhanced. Rather, the EC50 for NMDA receptor (NR)-mediated current is shifted threefold to fourfold to the right in fear-conditioned animals, suggesting a postsynaptic alteration in NMDA receptors in the maintenance phase of fear memory. Furthermore, the ability of nonselective and subunit-selective antagonists of NMDA receptors to block NMDA receptor-mediated EPSCs is reduced in lateral amygdala neurons from fear-conditioned animals, suggesting a reduction in NMDA receptors at thalamolateral amygdala synapses. In addition, Western blots show a reduction in phosphorylated-NR1, NR2A, and NR2B subunit protein expression in amygdalas from fear-conditioned animals. These data indicate that postsynaptic mechanisms are involved in synaptic plasticity in the thalamoamygdala pathway in fear conditioning and raise the possibility that: (1) downregulation of the NMDA receptor may protect against excitotoxicity of unchecked NMDA receptor recruitment during induction and consolidation of fear memories, (2) reduced NMDA current and protein may allow persistence of the "capacity to reactivate" amygdala pathways in NMDA receptor-dependent fear memories, or (3) a persistent long-term depression of NMDA transmission may occur after fear learning.