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Background: Realistic reconstruction of the in vivo human atherosclerotic environment requires the coculture of different cell types arranged in atherosclerotic vessel-like structures with exposure to flow and circulating cells, presenting challenges for disease modeling. This study aimed to develop a 3-dimensional tubular microfluidic model with quadruple coculture of human aortic smooth muscle cells, human umbilical cord vein endothelial cells, and foam cells to recreate a complex human atherosclerotic vessel in vitro to study the effects of flow and circulating immune cells., Methods: We developed a coculture protocol utilizing BFP (blue fluorescent protein)-labeled human aortic smooth muscle cells, GFP (green fluorescent protein)-labeled human umbilical cord vein endothelial cells, and THP-1 macrophage-derived, Dil-labeled oxidized LDL (low-density lipoprotein) foam cells within a fibrinogen/collagen I-based 3-dimensional ECM (extracellular matrix). Perfusion experiments were conducted for 24 hours on both atherosclerotic vessels and healthy vessels (BFP-labeled human aortic smooth muscle cells and GFP-labeled human umbilical cord vein endothelial cells without foam cells). Additionally, perfusion with circulating THP-1 monocytes was performed to observe cell extravasation and recruitment., Results: The resulting vessels displayed early lesion morphology, with a layered composition including an endothelium and media, and foam cells accumulating in the subendothelial space. The layered wall composition of both atherosclerotic and healthy vessels remained stable under perfusion. Circulating THP-1 monocytes demonstrated cell extravasation into the atherosclerotic vessel wall and recruitment to the foam cell core. The qPCR analysis indicated increased expression of atherosclerosis markers in the atherosclerotic vessels and adaptation of vascular smooth muscle cell migration in response to flow and the plaque microenvironment, compared with control vessels., Conclusions: The human 3-dimensional atherosclerosis model demonstrated stability under perfusion and allowed for the observation of immune cell behavior, providing a valuable tool for the atherosclerosis research field.

Mechanical forces are translated into biochemical stimuli by mechanotransduction channels, such as the mechanically activated cation channel Piezo2. Lung Piezo2 expression has recently been shown to be restricted to endothelial cells. Hence, we aimed to investigate the role of Piezo2 in regulation of pulmonary vascular function and structure, as well as its contribution to development of pulmonary arterial hypertension (PAH). The expression of Piezo2 was significantly reduced in pulmonary microvascular endothelial cells (MVECs) from patients with PAH, in lung tissue from mice with a Bmpr2 +/R899X knock-in mutation commonly found in patients with pulmonary hypertension, and in lung tissue of monocrotaline (MCT) and sugen-hypoxia-induced PH (SuHx) PAH rat models, as well as from a swine model with pulmonary vein banding. In MVECs, Piezo2 expression was reduced in response to abnormal shear stress, hypoxia, and TGFβ stimulation. Functional studies in MVECs exposed to shear stress illustrated that siRNA-mediated Piezo2 knockdown impaired endothelial alignment, calcium influx, phosphorylation of AKT, and nitric oxide production. In addition, siPiezo2 reduced the expression of the endothelial marker PECAM-1 and increased the expression of vascular smooth muscle markers ACTA2, SM22a, and calponin. Thus, Piezo2 acts as a mechanotransduction channel in pulmonary MVECs, stimulating shear-induced production of nitric oxide and is essentially involved in preventing endothelial to mesenchymal transition. Its blunted expression in pulmonary hypertension could impair the vasodilator capacity and stimulate vascular remodeling, indicating that Piezo2 might be an interesting therapeutic target to attenuate progression of the disease. NEW & NOTEWORTHY The mechanosensory ion channel Piezo2 is exclusively expressed in lung microvascular endothelial cells (MVECs). Patient MVECs as well as animal models of pulmonary (arterial) hypertension showed lower expression of Piezo2 in the lung. Mechanistically, Piezo2 is required for calcium influx and NO production in response to shear stress, whereas stimuli known to induce endothelial to mesenchymal transition (EndMT) reduce Piezo2 expression in MVECs, and Piezo2 knockdown induces a gene and protein expression pattern consistent with EndMT.

Fibrosis is a major cause of mortality worldwide, characterized by myofibroblast activation and excessive extracellular matrix deposition. Systemic sclerosis is a prototypic fibrotic disease in which CXCL4 is increased and strongly correlates with skin and lung fibrosis. Here we aim to elucidate the role of CXCL4 in fibrosis development. CXCL4 levels are increased in multiple inflammatory and fibrotic mouse models, and, using CXCL4-deficient mice, we demonstrate the essential role of CXCL4 in promoting fibrotic events in the skin, lungs, and heart. Overexpressing human CXCL4 in mice aggravates, whereas blocking CXCL4 reduces, bleomycin-induced fibrosis. Single-cell ligand-receptor analysis predicts CXCL4 to affect endothelial cells and fibroblasts. In vitro, we confirm that CXCL4 directly induces myofibroblast differentiation and collagen synthesis in different precursor cells, including endothelial cells, by stimulating endothelial-to-mesenchymal transition. Our findings identify a pivotal role of CXCL4 in fibrosis, further substantiating the potential role of neutralizing CXCL4 as a therapeutic strategy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The coronary microvasculature plays a key role in regulating the tight coupling between myocardial perfusion and myocardial oxygen demand across a wide range of cardiac activity. Short-term regulation of coronary blood flow in response to metabolic stimuli is achieved via adjustment of vascular diameter in different segments of the microvasculature in conjunction with mechanical forces eliciting myogenic and flow-mediated vasodilation. In contrast, chronic adjustments in flow regulation also involve microvascular structural modifications, termed remodeling. Vascular remodeling encompasses changes in microvascular diameter and/or density being largely modulated by mechanical forces acting on the endothelium and vascular smooth muscle cells. Whereas in recent years, substantial knowledge has been gathered regarding the molecular mechanisms controlling microvascular tone and how these are altered in various diseases, the structural adaptations in response to pathologic situations are less well understood. In this article, we review the factors involved in coronary microvascular functional and structural alterations in obstructive and non-obstructive coronary artery disease and the molecular mechanisms involved therein with a focus on mechanobiology. Cardiovascular risk factors including metabolic dysregulation, hypercholesterolemia, hypertension and aging have been shown to induce microvascular (endothelial) dysfunction and vascular remodeling. Additionally, alterations in biomechanical forces produced by a coronary artery stenosis are associated with microvascular functional and structural alterations. Future studies should be directed at further unraveling the mechanisms underlying the coronary microvascular functional and structural alterations in disease; a deeper understanding of these mechanisms is critical for the identification of potential new targets for the treatment of ischemic heart disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Brandt, Cheng, Merkus, Duncker and Sorop.)

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are pivotal regulators of extracellular matrix (ECM) composition and could, due to their dynamic activity, function as prognostic tools for fibrosis and cardiac function in left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF). We conducted a systematic review on experimental animal models of LVDD and HFpEF published in MEDLINE or Embase. Twenty-three studies were included with a total of 36 comparisons that reported established LVDD, quantification of cardiac fibrosis and cardiac MMP or TIMP expression or activity. LVDD/HFpEF models were divided based on underlying pathology: hemodynamic overload (17 comparisons), metabolic alteration (16 comparisons) or ageing (3 comparisons). Meta-analysis showed that echocardiographic parameters were not consistently altered in LVDD/HFpEF with invasive hemodynamic measurements better representing LVDD. Increased myocardial fibrotic area indicated comparable characteristics between hemodynamic and metabolic models. Regarding MMPs and TIMPs; MMP2 and MMP9 activity and protein and TIMP1 protein levels were mainly enhanced in hemodynamic models. In most cases only mRNA was assessed and there were no correlations between cardiac tissue and plasma levels. Female gender, a known risk factor for LVDD and HFpEF, was underrepresented. Novel studies should detail relevant model characteristics and focus on MMP and TIMP protein expression and activity to identify predictive circulating markers in cardiac ECM remodeling.

Background: Venous thromboembolism (VTE) remains a serious complication for trauma patients. While early VTE prophylaxis has gained traction, the timing of prophylaxis remains uncertain. We hypothesized that VTE prophylaxis within 24 hours of admission would have lower VTE rates and similar rates of adverse events in seriously injured patients., Methods: Trauma patients were included from 32 American College of Surgeons verified Level 1 and 2 trauma centers over a 10-year period. Patients with injury severity score (ISS) <15, death or discharge within 48 hours of arrival, or who received no prophylaxis were excluded., Results: 14 096 patients received VTE prophylaxis with an ISS of ≥15. Patients given prophylaxis at <24 hours had fewer VTE events and trended toward fewer serious in-hospital complications. Mortality and return to the operating room were similar across groups. Hospital and intensive care unit length of stay in the <24 hours prophylaxis group was significantly shorter when VTE prophylaxis was initiated earlier., Conclusions: In severely injured trauma patients with ISS >15, early VTE prophylaxis within 24 hours significantly reduced the risk of VTE as compared with delayed prophylaxis. Early chemoprophylaxis was found to be efficacious in reducing the incidence of VTE; however, the safety of this practice should be evaluated by future prospective studies.

Microfluidic organ-on-a-chip designs are used to mimic human tissues, including the vasculature. Here we present a novel microfluidic device that allows the interaction of endothelial cells (ECs) with pericytes and the extracellular matrix (ECM) in full bio-matrix encased 3D vessel structures (neovessels) that can be subjected to continuous, unidirectional flow and perfusion with circulating immune cells. We designed a polydimethylsiloxane (PDMS) device with a reservoir for a 3D fibrinogen gel with pericytes. Open channels were created for ECs to form a monolayer. Controlled, continuous, and unidirectional flow was introduced via a pump system while the design facilitated 3D confocal imaging. In this vessel-on-a-chip system, ECs interact with pericytes to create a human cell derived blood vessel which maintains a perfusable lumen for up to 7 days. Dextran diffusion verified endothelial barrier function while demonstrating the beneficial role of supporting pericytes. Increased permeability after thrombin stimulation showed the capacity of the neovessels to show natural vascular response. Perfusion of neovessels with circulating THP-1 cells demonstrated this system as a valuable platform for assessing interaction between the endothelium and immune cells in response to TNFα. In conclusion: we created a novel vascular microfluidic device that facilitates the fabrication of an array of parallel soft-channel structures in ECM gel that develop into biologically functional neovessels without hard-scaffold support. This model provides a unique tool to conduct live in vitro imaging of the human vasculature during perfusion with circulating cells to mimic (disease) environments in a highly systematic but freely configurable manner.

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts. Additionally, we aimed to investigate whether differences exist in disease progression in obese male and female ZSF1 rats. Therefore, male and female ZSF1 rats, lean as well as obese (N = 6-9/subgroup), were used. Every two weeks, from 12 to 26 weeks of age, systolic blood pressure and echocardiographic measurements were performed, and venous blood was sampled. Female obese ZSF1 rats, as compared to female lean ZSF1 rats, developed diastolic dysfunction with cardiac hypertrophy and fibrosis in the presence of severe dyslipidemia, increased plasma growth differentiation factor 15 and mild hypertension, and preservation of systolic function. Although obese female ZSF1 rats did not develop hyperglycemia, their diastolic dysfunction was as severe as in the obese males. Taken together, the results from the present study suggest that the female obese ZSF1 rat is a relevant animal model for HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions., Competing Interests: The authors have declared that no competing interests exist.

A common feature of tumorigenesis is the upregulation of angiogenesis pathways in order to supply nutrients via the blood for the growing tumor. Understanding how cells promote angiogenesis and how to control these processes pharmaceutically are of great clinical interest. Clear cell renal cell carcinoma (ccRCC) is the most common form of sporadic and inherited kidney cancer which is associated with excess neovascularization. ccRCC is highly associated with biallelic mutations in the von Hippel-Lindau (VHL) tumor suppressor gene. Although upregulation of the miR-212/132 family and disturbed VHL signaling have both been linked with angiogenesis, no evidence of a possible connection between the two has yet been made. We show that miRNA-212/132 levels are increased after loss of functional pVHL, the protein product of the VHL gene, in vivo and in vitro. Furthermore, we show that blocking miRNA-212/132 with anti-miRs can significantly alleviate the excessive vascular branching phenotype characteristic of vhl -/- mutant zebrafish. Moreover, using human umbilical vascular endothelial cells (HUVECs) and an endothelial cell/pericyte coculture system, we observed that VHL knockdown promotes endothelial cells neovascularization capacity in vitro, an effect which can be inhibited by anti-miR-212/132 treatment. Taken together, our results demonstrate an important role for miRNA-212/132 in angiogenesis induced by loss of VHL. Intriguingly, this also presents a possibility for the pharmaceutical manipulation of angiogenesis by modulating levels of MiR212/132.

Microvascular homeostasis is strictly regulated, requiring close interaction between endothelial cells and pericytes. Here, we aimed to improve our understanding of how microvascular crosstalk affects pericytes. Human-derived pericytes, cultured in absence, or presence of human endothelial cells, were studied by RNA sequencing. Compared with mono-cultured pericytes, a total of 6704 genes were differentially expressed in co-cultured pericytes. Direct endothelial contact induced transcriptome profiles associated with pericyte maturation, suppression of extracellular matrix production, proliferation, and morphological adaptation. In vitro studies confirmed enhanced pericyte proliferation mediated by endothelial-derived PDGFB and pericyte-derived HB-EGF and FGF2. Endothelial-induced PLXNA2 and ACTR3 upregulation also triggered pericyte morphological adaptation. Pathway analysis predicted a key role for TGFβ signaling in endothelial-induced pericyte differentiation, whereas the effect of signaling via gap- and adherens junctions was limited. We demonstrate that endothelial cells have a major impact on the transcriptional profile of pericytes, regulating endothelial-induced maturation, proliferation, and suppression of ECM production.

Obesity and hypertension are prevalent comorbidities in heart failure with preserved ejection fraction. To clarify if and how interaction between these comorbidities contributes to development of diastolic dysfunction, lean and obese ZSF1 rats were treated with deoxycorticosterone acetate implants and a high-salt diet (DS) to induce severe hypertension, or with placebo. In addition to echocardiographic, metabolic and hemodynamic analyses, immunohistochemistry and RNAseq were performed on left ventricular tissue. Obesity negatively affected cardiac output, led to an elevated E/e' ratio and mildly reduced ejection fraction. DS-induced hypertension did not affect cardiac output and minimally elevated E/e' ratio. Diastolic derangements in placebo-treated obese rats developed in absence of inflammation and fibrosis, yet in presence of oxidative stress and hypertrophic remodelling. In contrast, hypertension triggered apoptosis, inflammation and fibrosis, with limited synergy of the comorbidities observed for inflammation and fibrosis. Transcriptional data suggested that these comorbidities exerted opposite effects on mitochondrial function. In placebo-treated obese rats, genes involved in fatty acid metabolism were up-regulated, whereas DS-induced a down-regulation of genes involved in oxidative phosphorylation. Overall, limited interaction was observed between these comorbidities in development of diastolic dysfunction. Importantly, differences in obesity- and hypertension-induced cardiac remodelling emphasize the necessity for comorbidity-specific phenotypical characterization., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Purpose: The study assesses the safety of high-dose intravenous (i.v.) labetalol in adults., Methods: This is a retrospective administrative record review of 28 hospitals in one health care system, from October 2010 through October 2015. Patients were included if they received 300 mg of i.v. labetalol within a 24-hour period. Vital signs, adverse events and cumulative medication doses were obtained for up to 24 hours while on labetalol. Adverse events were defined as any systolic blood pressure measurement less than 90 mm Hg or heart rate less than 60 beats per minute., Results: We analyzed the records of 188 patients who received i.v. labetalol at higher than the maximum recommended dose of 300 mg. The mean dose of labetalol was 996 mg (range 300 to 4465 mg). The cumulative labetalol dose was not associated with adverse safety outcomes (p = 0.428), although eighty-one patients (44.3%) experienced adverse events. Sixty-six patients (36.5%) developed bradycardia and 34 patients (18.6%) developed hypotension. Only five patients (2.7%) required a rescue agent for refractory adverse events., Conclusion: A retrospective review of high-dose i.v. labetalol hydrochloride with doses greater than 300 mg in 24 hours observed a high rate of bradycardia and hypotension, but the study found that these events rarely caused clinically significant hemodynamic compromise and was not statistically associated with adverse events.

Vascular endothelial (VE) cadherin is a key component of endothelial adherens junctions (AJs) and plays an important role in maintaining vascular integrity. Endocytosis of VE-cadherin regulates junctional strength and a decrease of surface VE-cadherin reduces vascular stability. However, disruption of AJs is also a requirement for vascular sprouting. Identifying novel regulators of endothelial endocytosis could enhance our understanding of angiogenesis. Here, we evaluated the angiogenic potential of (CKLF-like MARVEL transmembrane domain 4) CMTM4 and assessed in which molecular pathway CMTM4 is involved during angiogenesis. Using a 3D vascular assay composed of GFP-labeled HUVECs and dsRED-labeled pericytes, we demonstrated in vitro that siRNA-mediated CMTM4 silencing impairs vascular sprouting. In vivo, CMTM4 silencing by morpholino injection in zebrafish larvae inhibits intersomitic vessel growth. Intracellular staining revealed that CMTM4 colocalizes with Rab4 + and Rab7 + vesicles, both markers of the endocytic trafficking pathway. CMTM4 colocalizes with both membrane-bound and internalized VE-cadherin. Adenovirus-mediated CMTM4 overexpression enhances the endothelial endocytic pathway, in particular the rapid recycling pathway, shown by an increase in early endosomal antigen-1 positive (EEA1 + ), Rab4 + , Rab11 +  , and Rab7 +  vesicles. CMTM4 overexpression enhances membrane-bound VE-cadherin internalization, whereas CMTM4 knockdown decreases internalization of VE-cadherin. CMTM4 overexpression promotes endothelial barrier function, shown by an increase in recovery of transendothelial electrical resistance (TEER) after thrombin stimulation. We have identified in this study a novel regulatory function for CMTM4 in angiogenesis. CMTM4 plays an important role in the turnover of membrane-bound VE-cadherin at AJs, mediating endothelial barrier function and controlling vascular sprouting.

Aims: Formation of a functional vascular system is essential and its formation is a highly regulated process initiated during embryogenesis, which continues to play important roles throughout life in both health and disease. In previous studies, Fzd5 was shown to be critically involved in this process and here we investigated the molecular mechanism by which endothelial loss of this receptor attenuates angiogenesis., Methods and Results: Using short interference RNA-mediated loss-of-function assays, the function and mechanism of signaling via Fzd5 was studied in human endothelial cells (ECs). Our findings indicate that Fzd5 signaling promotes neovessel formation in vitro in a collagen matrix-based 3D co-culture of primary vascular cells. Silencing of Fzd5 reduced EC proliferation, as a result of G 0 /G 1 cell cycle arrest, and decreased cell migration. Furthermore, Fzd5 knockdown resulted in enhanced expression of the factors Angpt2 and Flt1, which are mainly known for their destabilizing effects on the vasculature. In Fzd5-silenced ECs, Angpt2 and Flt1 upregulation was induced by enhanced PKC signaling, without the involvement of canonical Wnt signaling, non-canonical Wnt/Ca 2+ -mediated activation of NFAT, and non-canonical Wnt/PCP-mediated activation of JNK. We demonstrated that PKC-induced transcription of Angpt2 and Flt1 involved the transcription factor Ets1., Conclusions: The current study demonstrates a pro-angiogenic role of Fzd5, which was shown to be involved in endothelial tubule formation, cell cycle progression and migration, and partly does so by repression of PKC/Ets1-mediated transcription of Flt1 and Angpt2.

Purpose: This study is aimed to adapt a three-dimensional (3-D) in vitro angiogenesis model to the ophthalmology field using retinal endothelial cells (REC). This system is applied to assess the angiogenic capacity of aqueous humor (AH) from patients with ocular disorders, and to test the effect of VEGF inhibitor (aflibercept) on induced angiogenesis., Methods: Human REC and umbilical vein endothelial cells (HUVEC) and pericytes were co-cultured in a gel matrix with 25-200 ng/ml pro-angiogenic growth factors (GF). AH from patients with cataract, glaucoma or proliferative diabetic retinopathy (PDR) was tested in the REC-pericyte co-culture. Aflibercept was then introduced to the co-culture containing PDR AH. The surface area and total tubule length were measured using Image J., Results: Optimal GF concentrations at 200 ng/ml induced angiogenesis by REC as well as HUVEC, while vessel formation by both cell types was strongly reduced using 25-50 ng/ml GF. Addition of AH from the PDR patient triggered tubule formation by REC at low GF concentration. Aflibercept, however, significantly inhibited angiogenesis induced by PDR AH, but showed no significant influence on other conditions., Conclusion: REC can be applied efficiently in the 3-D in vitro angiogenesis model as a diagnostic tool to assess the AH angiogenic status and to validate new anti-angiogenic therapeutic compounds prior to clinical trial.

Genome-wide association studies (GWASs) have identified many genetic risk factors for CKD. However, linking common variants to genes that are causal for CKD etiology remains challenging. By adapting self-transcribing active regulatory region sequencing, we evaluated the effect of genetic variation on DNA regulatory elements (DREs). Variants in linkage with the CKD-associated single-nucleotide polymorphism rs11959928 were shown to affect DRE function, illustrating that genes regulated by DREs colocalizing with CKD-associated variation can be dysregulated and therefore, considered as CKD candidate genes. To identify target genes of these DREs, we used circular chromosome conformation capture (4C) sequencing on glomerular endothelial cells and renal tubular epithelial cells. Our 4C analyses revealed interactions of CKD-associated susceptibility regions with the transcriptional start sites of 304 target genes. Overlap with multiple databases confirmed that many of these target genes are involved in kidney homeostasis. Expression quantitative trait loci analysis revealed that mRNA levels of many target genes are genotype dependent. Pathway analyses showed that target genes were enriched in processes crucial for renal function, identifying dysregulated geranylgeranyl diphosphate biosynthesis as a potential disease mechanism. Overall, our data annotated multiple genes to previously reported CKD-associated single-nucleotide polymorphisms and provided evidence for interaction between these loci and target genes. This pipeline provides a novel technique for hypothesis generation and complements classic GWAS interpretation. Future studies are required to specify the implications of our dataset and further reveal the complex roles that common variants have in complex diseases, such as CKD., (Copyright © 2018 by the American Society of Nephrology.)

Aims: The formation of cell-cell and cell-extra cellular matrix (ECM) contacts by endothelial cells (ECs) is crucial for the stability and integrity of a vascular network. We previously identified cingulin-like 1 (Cgnl1) in a transcriptomic screen for new angiogenic modulators. Here we aim to study the function of the cell-cell junction associated protein Cgnl1 during vessel formation., Methods and Results: Unlike family member cingulin, Cgnl1 expression is enriched in ECs during vascular growth. Cgnl1 is important for the formation of multicellular tubule structures, as shown in vitro using loss-of function assays in a 3D matrix co-culture system that uses primary human ECs and supporting mural cells. Further studies revealed that Cgnl1 regulates vascular growth by promoting Ve-cadherin association with the actin cytoskeleton, thereby stabilizing adherens junctions. Cgnl1 also regulates focal adhesion assembly in response to ECM contact, promoting vinculin and paxillin recruitment and focal adhesion kinase signalling. In vivo, we demonstrate in a postnatal retinal vascular development model in mice that Cgnl1 function is crucial for sustaining neovascular growth and stability., Conclusions: Our data demonstrate a functional relevance for Cgnl1 as a defining factor in new vessel formation both in vitro and in vivo., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.)

The use of doxorubicin (DOXO) as a chemotherapeutic drug has been hampered by cardiotoxicity leading to cardiomyopathy and heart failure. Folic acid (FA) is a modulator of endothelial nitric oxide (NO) synthase (eNOS), which in turn is an important player in diseases associated with NO insufficiency or NOS dysregulation, such as pressure overload and myocardial infarction. However, the role of FA in DOXO-induced cardiomyopathy is poorly understood. The aim of this study was to test the hypothesis that FA prevents DOXO-induced cardiomyopathy by modulating eNOS and mitochondrial structure and function. Male C57BL/6 mice were randomized to a single dose of DOXO (20 mg/kg intraperitoneal) or sham. FA supplementation (10 mg/day per oral) was started 7 days before DOXO injection and continued thereafter. DOXO resulted in 70% mortality after 10 days, with the surviving mice demonstrating a 30% reduction in stroke volume compared with sham groups. Pre-treatment with FA reduced mortality to 45% and improved stroke volume (both P < 0.05 versus DOXO). These effects of FA were underlain by blunting of DOXO-induced cardiomyocyte atrophy, apoptosis, interstitial fibrosis and impairment of mitochondrial function. Mechanistically, pre-treatment with FA prevented DOXO-induced increases in superoxide anion production by reducing the eNOS monomer:dimer ratio and eNOS S-glutathionylation, and attenuated DOXO-induced decreases in superoxide dismutase, eNOS phosphorylation and NO production. Enhancing eNOS function by restoring its coupling and subsequently reducing oxidative stress with FA may be a novel therapeutic approach to attenuate DOXO-induced cardiomyopathy., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Strangulated gastric prolapse through a percutaneous endoscopic gastrostomy tract is a rare and potentially life-threatening complication that requires surgical intervention. We describe a case of a 74-year-old woman who was debilitated and ventilator-dependent and who presented with acute gastric prolapse with resultant ischaemic necrosis. The patient underwent an emergent exploratory laparotomy, partial gastrectomy, repair of gastrostomy defect and placement of a gastrojejunostomy feeding tube remote to the previous location. Literature on gastric prolapse in adult patients is sparse, and therefore treatment is not standardised. In this patient with strangulated tissue, the principles of management included the assessment of gastric mucosa viability, resection of ischaemic tissue and closure of the gastrostomy defect., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: As genome-wide association efforts, such as CARDIoGRAM and METASTROKE, are ongoing to reveal susceptibility loci for their underlying disease-atherosclerotic disease-identification of candidate genes explaining the associations of these loci has proven the main challenge. Many disease susceptibility loci colocalize with DNA regulatory elements, which influence gene expression through chromatin interactions. Therefore, the target genes of these regulatory elements can be considered candidate genes. Applying these biological principles, we used an alternative approach to annotate susceptibility loci and identify candidate genes for human atherosclerotic disease based on circular chromosome conformation capture followed by sequencing., Methods and Results: In human monocytes and coronary endothelial cells, we generated 63 chromatin interaction data sets for 37 active DNA regulatory elements that colocalize with known susceptibility loci for coronary artery disease (CARDIoGRAMplusC4D) and large artery stroke (METASTROKE). By circular chromosome conformation capture followed by sequencing, we identified a physical 3-dimensional interaction with 326 candidate genes expressed in at least 1 of these cell types, of which 294 have not been reported before. We highlight 16 genes based on expression quantitative trait loci., Conclusions: Our findings provide additional candidate-gene annotation for 37 disease susceptibility loci for human atherosclerotic disease that are of potential interest to better understand the complex pathophysiology of cardiovascular diseases., (© 2017 American Heart Association, Inc.)

Aims: Impairment of the endothelial barrier leads to microvascular breakdown in cardiovascular disease and is involved in intraplaque haemorrhaging and the progression of advanced atherosclerotic lesions that are vulnerable to rupture. The exact mechanism that regulates vascular integrity requires further definition. Using a microarray screen for angiogenesis-associated genes during murine embryogenesis, we identified thrombospondin type I domain 1 (THSD1) as a new putative angiopotent factor with unknown biological function. We sought to characterize the role of THSD1 in endothelial cells during vascular development and cardiovascular disease., Methods and Results: Functional knockdown of Thsd1 in zebrafish embryos and in a murine retina vascularization model induced severe haemorrhaging without affecting neovascular growth. In human carotid endarterectomy specimens, THSD1 expression by endothelial cells was detected in advanced atherosclerotic lesions with intraplaque haemorrhaging, but was absent in stable lesions, implying involvement of THSD1 in neovascular bleeding. In vitro, stimulation with pro-atherogenic factors (3% O2 and TNFα) decreased THSD1 expression in human endothelial cells, whereas stimulation with an anti-atherogenic factor (IL10) showed opposite effect. Therapeutic evaluation in a murine advanced atherosclerosis model showed that Thsd1 overexpression decreased plaque vulnerability by attenuating intraplaque vascular leakage, subsequently reducing macrophage accumulation and necrotic core size. Mechanistic studies in human endothelial cells demonstrated that THSD1 activates FAK-PI3K, leading to Rac1-mediated actin cytoskeleton regulation of adherens junctions and focal adhesion assembly., Conclusion: THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Arteriogenesis is a complicated process induced by increased local shear-and radial wall-stress, leading to an increase in arterial diameter. This process is enhanced by growth factors secreted by both inflammatory and endothelial cells in response to physical stress. Although therapeutic promotion of arteriogenesis is of great interest for ischaemic diseases, little is known about the modulation of the signalling cascades via microRNAs. We observed that miR-132/212 expression was significantly upregulated after occlusion of the femoral artery. miR-132/212 knockout (KO) mice display a slower perfusion recovery after hind-limb ischaemia compared to wildtype (WT) mice. Immunohistochemical analysis demonstrates a clear trend towards smaller collateral arteries in KO mice. Although Ex vivo aortic ring assays score similar number of branches in miR-132/212 KO mice compared to WT, it can be stimulated with exogenous miR-132, a dominant member of the miR-132/212 family. Moreover, in in vitro pericyte-endothelial co-culture cell assays, overexpression of miR-132 and mir-212 in endothelial cells results in enhanced vascularization, as shown by an increase in tubular structures and junctions. Our results suggested that miR-132/212 may exert their effects by enhancing the Ras-Mitogen-activated protein kinases MAPK signalling pathway through direct inhibition of Rasa1, and Spred1. The miR-132/212 cluster promotes arteriogenesis by modulating Ras-MAPK signalling via direct targeting of its inhibitors Rasa1 and Spred1., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objective: In arteriogenesis, pre-existing anastomoses undergo enlargement to restore blood flow in ischemic tissues. Chemokine (C-X-C motif) ligand 10 (CXCL10) is secreted after Toll-like receptor activation. Toll-like receptors are involved in arteriogenesis; however, the role of CXCL10 is still unclear. In this study, we investigated the role for CXCL10 in a murine hindlimb ischemia model., Approach and Results: Unilateral femoral artery ligation was performed in wild-type (WT) and CXCL10(-/-) knockout (KO) mice and perfusion recovery was measured using laser-Doppler perfusion analysis. Perfusion recovery was significantly lower in KO mice compared with WT at days 4 and 7 after surgery (KO versus WT: 28±5% versus 81±13% at day 4; P=0.003 and 57±12% versus 107±8% at day 7; P=0.003). Vessel measurements of α-smooth muscle actin-positive vessels revealed increasing numbers in time after surgery, which was significantly higher in WT when compared with that in KO. Furthermore, α-smooth muscle actin-positive vessels were significantly larger in WT when compared with those in KO at day 7 (wall thickness, P<0.001; lumen area, P=0.003). Local inflammation was assessed in hindlimb muscles, but this did not differ between WT and KO. Chimerization experiments analyzing perfusion recovery and histology revealed an equal contribution for bone marrow-derived and circulating CXCL10. Migration assays showed a stimulating role for both intrinsic and extrinsic CXCL10 in vascular smooth muscle cell migration., Conclusions: CXCL10 plays a causal role in arteriogenesis. Bone marrow-derived CXCL10 and tissue-derived CXCL10 play a critical role in accelerating perfusion recovery after arterial occlusion in mice probably by promoting vascular smooth muscle cell recruitment and maturation of pre-existing anastomoses.

Purpose: Peripheral tissue oxygen saturation (Sto2) has shown promise as an early indicator of tissue hypoperfusion and as a risk stratification tool in various forms of shock. The purpose of this study was to determine if Sto2 would predict admission to an intensive (ICU) or progressive care unit in patients with early signs of sepsis., Methods: In this prospective observational study, a rapid response team measured Sto2 levels in patients screening positive for sepsis. Using a logistic regression model, the value of Sto2 as a predictor for ICU admission within 72 hours of the initial assessment was determined., Results: The 31 (47%) of 66 patients who required ICU admission within 72 hours of evaluation had a significantly lower Sto2 value (median, 78% vs 81%; P = .05). All patients with Sto2 less than 70% required ICU admission. A 1-point increase in Sto2 was associated with a 7% decrease in the odds of requiring ICU admission, and the area under the curve for Sto2 was 0.64 (0.51-0.77, P = .01)., Conclusions: Low Sto2 levels in patients screening positive for sepsis are associated with an increased risk of ICU admission, but their reliability as a predictor is rather low. An Sto2 below 70% might be an interesting cutoff value for further study., (© 2013.)

Rare disorders are scarcely represented in international classifications and therefore invisible in information systems. One of the major needs in health information systems and for research is to share and/or to integrate data coming from heterogeneous sources with diverse reference terminologies. ORPHANET (www.orpha.net) is a multilingual information portal on rare diseases and orphan drugs. Orphanet information system is supported by a relational database built around the concept of rare disorders. Representation of rare diseases in Orphanet encompasses levels of increasing complexity: lexical (multilingual terminology), nosological (multihierarchical classifications), relational (annotations-epidemiological data-and classes of objects-genes, manifestations, and orphan drugs-integrated in a relational database), and interoperational (semantic interoperability). Rare disorders are mapped to International Classification of Diseases (10th version), SNOMED CT, MeSH, MedDRA, and UMLS. Genes are cross-referenced with HGNC, UniProt, OMIM, and Genatlas. A suite of tools allow for extraction of massive datasets giving different views that can be used in bioinformatics to answer complex questions, intended to serve the needs of researchers and the pharmaceutical industry in developing medicinal products for rare diseases. An ontology is under development. The Orphanet nomenclature is at the crossroads of scientific data repositories and of clinical terminology standards, and is suitable to be used as a standard terminology., (© 2012 Wiley Periodicals, Inc.)

Unlabelled: While clinicians' management of severe sepsis and septic shock has been positively influenced by a number of clinical research studies in the last decade, challenges remain regarding early hemodynamic optimization as envisioned in the Surviving Sepsis Campaign's (SSC) resuscitation bundle (RB). We examined the impact of a hospital-wide continuous quality improvement (CQI) initiative on patients presenting with severe sepsis and septic shock, and the impact of the sepsis RB on patient outcomes when completed beyond the 6-hour recommendation period. The study was an 18-month, prospective cohort study enrolling patients who met the definition of severe sepsis or septic shock. Compliance with the hemodynamic components of the sepsis RB was defined as achieving goal mean arterial pressure (MAP) ≥ 65 mm Hg, central venous pressure (CVP) ≥ 8 mm Hg, and central venous oxygen saturation (ScvO₂) ≥ 70%. Compliance was assessed at 6 hours and 18 hours after diagnosis of severe sepsis or septic shock. In all, 498 patients with severe sepsis and/or septic shock were evaluated to determine the upper limit of the range of hours that compliance with the RB would still improve outcomes. Using 18 hours as a marker, Compliers at 18 hrs and Non-Compliers at 18 hrs were compared. There were 202 patients who had the RB completed in less than or equal to 18 hours. There were 296 patients who did not complete the RB at 18 hours. The Compliers at 18 hrs had a significant 10.2% lower hospital mortality 37.1% (22% relative reduction) compared to the Non-Compliers at 18 hrs hospital mortality of 47.3% (P < .03). When the two groups were adjusted for differences in baseline illness severity, the Compliers at 18 hrs had a greater reduction in predicted mortality of 26.8% versus 9.4%, P < 0.01., Conclusions: Initiating the sepsis RB for patients with severe sepsis and/or septic shock decreased mortality. A CQI initiative that monitored the implementation in real-time allowed for improvement in compliance and efficacy of the bundle on outcomes. Multiple studies have shown that compliance to the RB within 6 hours lowers hospital mortality. This study uniquely shows that when bundle completion is extended to 18 hours, the mortality reduction remains significant., (© SAGE Publications 2011.)

Background: Our institution initiated the implementation of the Surviving Sepsis Campaign guidelines in 2006. We hypothesize that the addition of a surgical intensivist improved results more than the implementation of the guidelines alone., Methods: We collected data on 273 patients who were admitted to the surgical intensive care unit for sepsis. The groups were divided into pre-bundle, n = 19; bundle, n = 186; and bundle-plus, n = 68, to denote the method by which the patients were treated for sepsis., Results: There was no difference in age or sex between groups. There was a statistically significant decrease in length of stay (LOS) between the 3 groups, and in mortality between the bundle and bundle-plus treatment groups (P < .01). In addition, there was an average cost savings between each group., Conclusions: Implementation of evidence-based guidelines decreased LOS and decreased cost in our surgical intensive care unit. By adding the expertise of a surgical intensivist, we reduced LOS, cost, and relative risk of death even further than using the guidelines alone., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: In 2002, tight glycemic control (TGC) was mandated at Henry Ford Hospital (Detroit) to reduce surgical site infections (SSIs). THE FIVE STEPS FOR IMPROVEMENT: The TGC initiative was developed in terms of the five primary steps of the Institute for Healthcare Improvement (IHI) framework for leadership for improvement to drive practice change and maintain continuous improvement. In terms of Steps 1-3 (set direction, establish the foundation, and build will), in April 2002 the chief executive officer of the Henry Ford Hospital (Detroit) announced a hospitalwide initiative to reduce SSIs. For steps 4 and 5 (generate ideas and execute change), the 40-bed surgical intensive care unit (SICU) was designated the practice-change setting. TGC protocols were implemented in cardiothoracic patients, followed by all SICU patients, with target glucose ranges moving from the initial < 150 mg/dL to 80-110 mg/dL. Results showed decreases in SSIs and mortality. The project's success led initiation of hospitalwide TGC in the next two years. RESPONDING TO A CHANGING EVIDENCE BASE: In 2009, as studies began to show that the recommended glucose target of 80-110 mg/dL was not associated with clinical improvement in ICU patients and perhaps may cause harm (increased mortality), the target ranges were modified., Lessons Learned: Barriers to adoption of new practice change must be integrated into the planning process. Leadership champions are required across multiple levels of the organization to drive change to the bedside for effective and lasting improvement., Conclusions: A universal TGC protocol continues to be used throughout the hospital, with modifications and next-generation improvements occurring as evidence arises.

Background: In 2000, we implemented an evidence-based guideline in the surgical intensive care unit (SICU) using a transfusion threshold of hemoglobin <8 g/dL. We hypothesized that continual education on the transfusion protocol would decrease transfusions., Methods: We analyzed 2-month samples of admissions in even-numbered years from 1998 to 2006. Any infusion of packed red blood cells (PRBCs) was included., Results: We analyzed data from 2,138 patients resulting in 5,130 transfusions. Thirty-six patients received >20 U of blood. The only difference between groups occurred in 2006 when renal failure increased. Transfusions decreased from 3.2 +/- 0.34 (SE) to 1.7 +/- 0.2. The number of patients who received blood also decreased. Mortality and length of stay (LOS) were not different among the groups. Every unit of blood transfused increased the mortality risk by 14%., Conclusions: Implementation of an evidence-based transfusion guideline reduced the number of infused units and patients transfused without an increase in mortality.

Background: Universal agreement on criteria for acute renal failure (ARF) is lacking. The purpose of the current study was to determine which of 6 definitions for ARF best predicted clinical outcomes in postoperative cardiothoracic surgery (CTS) patients., Methods: Criteria for ARF were retrospectively applied to 1,085 CTS patients. General linear models analyzed length of stay (LOS) and ventilator days with logistic regression for mortality., Results: Thirty-seven percent of patients met at least 1 of 6 definitions of ARF. For each 1-mg/dL increase from the initial creatinine, LOS increased by 6.96 days, ventilator days increased by 3.58 days, and mortality increased by 2.23 times (P < .0001)., Conclusions: One definition that best predicted ARF was not found. ARF was a significant independent predictor of increased mortality, LOS, and ventilator days. Even small increases in creatinine correlate with clinically significant worsening of expected outcomes.

Background: Hyperbilirubinemia in intensive care unit (ICU) patients is common. We hypothesized that hyperbilirubinemia in the surgical ICU predisposes patients to infection., Methods: Patients with bilirubin < or = 3 mg/dL were compared to patients with bilirubin > 3 mg/dL. We then compared the low bilirubin patients to high bilirubin patients who developed infection after their hyperbilirubinemia., Results: There were 1,620 infections in 5,712 patients with low bilirubin (28%), compared with 284 in 409 patients in the high bilirubin group (69%, P < .001). After removing the patients in whom hyperbilirubinemia developed after infection, we found infection in 156 of 281 remaining patients (56%, P < .001). This group had a 3-fold increased risk of infection compared with low bilirubin (odds ratio [OR] 3.17, 95% confidence interval [CI] 2.48-4.03, P < .001)., Conclusions: There is an increased susceptibility to infection among jaundiced surgical ICU (SICU) patients that persists even when sepsis-related hyperbilirubinemia patients are excluded.

The negative impact of mild to moderate renal dysfunction on patient outcome is often under-estimated. Any amount of renal dysfunction is deleterious in the surgical intensive care unit (SICU). We evaluated all surgery patients admitted to our SICU. We identified two groups of patients: no renal failure and acute renal failure. A total of 5152 patients were included in this study. There were 1259 patients in the acute renal failure group. The average number of ventilator days increased by 2.2 for every increase of creatinine by 1.0. Patients who required dialysis stayed an average of 11 days longer than patients who did not have any renal failure. For every increase of creatinine by 1.0, average cost increased by $23,048. Only 7 per cent of the patients with acute renal failure required dialysis (n = 85). The odds ratio for mortality compared with those patients without renal failure was 7.06 (confidence interval, 3.91-12.76) regardless of the definition of renal failure. This study demonstrates that even mild to moderate renal failure increases mortality. Moreover, we demonstrated that even a mild decline in renal function increases length of stay, ventilator days, and cost in patients in the SICU. Aggressive vigilance in the prevention of any loss of renal function is warranted in the SICU.

Background: Acute renal failure (ARF) is a devastating complication in critically ill patients. There is a paucity of data that describes the impact of ARF on the outcome of trauma patients admitted to the intensive care unit., Methods: We studied trauma patients admitted to the surgical intensive care unit to determine the effect of increases in serum creatinine on the number of ventilator days, length of stay, mortality, and cost. We used the administrative database of the hospital and the trauma registry. Renal failure (RF) was defined as one or more of the following: creatinine >1.5 mg/dL, increase in creatinine of >50%, or increase of creatinine by 0.5 mg/dL., Results: We obtained data on 1,033 patients. Two hundred and forty-six (23.8%) patients met at least one criterion for RF. Only 25 of these patients had one or more episodes of renal replacement therapy. The RF group had mortality of 24.4% compared with 2.3% in the no renal failure group (p < 0.0001). For each 1 mg/dL increase from the initial creatinine, length of stay increased by 2.21 days, ventilator days increased by 1.09 days, and the mortality risk increased by 1.83 times (CI, 1.47-2.29; p < 0.0001). For any diagnosis of renal dysfunction, the average cost increase was $3,088.00 and increased mortality risk was 7.19 times (CI, 4.11-12.58)., Conclusion: Vigilance in preventing creatinine increases and ameliorating or removing potential causes should occur as soon as creatinine begins to rise to avoid worsening renal function, to reduce cost, and to improve patient outcome.

Cattle (n = 995 steers and 757 heifers) were randomly selected from a commercial abattoir (Emporia, KS) to determine the relationships between USDA quality and yield grade characteristics and serum concentrations of leptin, IGF-I, and GH. Animals were randomly selected postexsanguination on the slaughter line on 4 occasions (March, May, August, and January). Blood was collected at exsanguination and transported to the University of Missouri for analysis. Sex and hide color were recorded. Carcass data included HCW, 12th-rib fat thickness, KPH, LM area, and marbling score, which were collected from each carcass approximately 24 h postmortem. Average serum leptin concentrations were greater (P = 0.008) for heifers (11.9 ng/mL) than steers (10.9 ng/mL). Heifers had lighter carcasses (331.9 vs. 352.2 kg, P < 0.001), greater 12th-rib fat measurements (1.3 vs. 1.1 cm, P < 0.001), greater KPH (2.5 vs. 2.4%, P < 0.001), and more marbling (Small(40) vs. Small(10), P < 0.001) than steers. Positive correlations (P < 0.01) existed between leptin concentration and marbling score (r = 0.28), 12th-rib fat depth (r = 0.37), KPH (r = 0.23), and USDA yield grade (r = 0.32). Negative correlations were found between leptin and IGF-I (r = -0.11; P < 0.001) and leptin and GH (r = -0.32; P < 0.001). Negative correlations (P < 0.01) were observed for IGF-I and KPH (r = -0.23) and marbling score (r = -0.20), whereas GH was most highly negatively correlated with KPH (r = -0.23; P < 0.001). Leptin concentration accounted for variation (P < 0.001) in a model separating least squares means across USDA quality grade, separating USDA standard (8.5 ng/mL), select (10.3 ng/mL), low choice (12.2 ng/mL), and upper 2/3 choice/prime (>12.9 ng/mL) carcasses. There was no difference (P = 0.31) observed in leptin concentrations between the upper 2/3 choice and prime carcasses (12.9 and 14.2 ng/mL, respectively). Relationships within endocrine profiles and between endocrine concentrations and carcass quality characteristics may prove to be a useful tool for the prediction of beef carcass composition.

Background: Nonoperative management (NOM) of blunt liver injuries (BLIs) is common, but little data exist on the management of complications related to NOM. Furthermore, bile leaks are emerging as frequent complications of NOM. The goal of this study was to determine which BLI patients are at greatest risk for bile leaks and how to manage this complication., Methods: Patients treated with NOM, including angiographic embolization (AE) and observation, were compared with those undergoing operation (OR). Mortality, hospital length of stay, liver-related complications, and severity of liver injury were compared among the groups., Results: Two hundred eighty-one patients sustained a BLI from 1997 through 2004. The Injury Severity Score and age of the groups were similar. The mortality rate of the OR patients was higher (P = .02). All bile leaks occurred in patients with a liver Abbreviated Injury Score (AIS) of > or = 4. For survivors of more than 4 days, 71% of OR, 50% of AE, and 17% of observed patients developed bile leaks. For the OR and AE groups, HIDA scanning detected all leaks, leading to earlier drainage procedures. Detection of a bile leak in NOM patients before 5 days of hospitalization led to shorter HLOS, P = .02. No patient with a negative HIDA scan developed a subsequent bile leak., Conclusions: NOM of BLIs is associated with lower mortality, but significant complications. Bile leaks are more common in patients with higher liver AIS, and in this study presented in only those with liver AIS > or = 4. HIDA scanning successfully diagnosed all patients with bile leaks and led to less invasive drainage procedures over time and shorter HLOS.

Thermal injury historically constitutes approximately 5% to 20% of conventional warfare casualties. This article reviews medical planning for burn care during war in Iraq and experience with burns during the war at the US Army Burn Center; aboard the USNS Comfort hospital ship; and at Combat Support Hospitals in Iraq and in Afghanistan. Two burn surgeons were deployed to the military hospital in Landstuhl, Germany, and to the Gulf Region to assist with triage and patient care. During March 2003 to May 2004, 109 burn casualties from the war have been hospitalized at the US Army Burn Center in San Antonio, Texas, and US Army Burn Flight Teams have moved 51 critically ill burn casualties to the Burn Center. Ten Iraqi burn patients underwent surgery and were hospitalized for up to 1 month aboard the Comfort, including six with massive wounds. Eighty-six burn casualties were hospitalized at the 28th Combat Support Hospital for up to 53 days. This experience highlights the importance of anticipating the burn care needs of both combatants and the local civilian population during war.

Ventilator-associated pneumonia (VAP) remains a major cause of morbidity and mortality for patients with burns. In nonburn populations, bronchoalveolar lavage (BAL) excludes other pathology such as systemic inflammatory response syndrome. We hypothesized that BAL would decrease our false-positive VAP rate. All ventilated patients with burn injury who were admitted to our institution from July 2000 through June 2003 were included. After June 2001, BAL was used to make the diagnosis of VAP, with > or =10(4) organisms considered a positive result. Fifty patients met criteria for VAP, 21 in the pre-BAL period and 29 in the BAL period. Six patients (21%) in the BAL group had quantitative cultures <10(4) and were not treated. The outcomes for these patients were not different than those treated for VAP. There were no differences in age, TBSA size, antibiotic use, or ventilator days for the pre-BAL or BAL groups, although the pneumonia rate was lower for the BAL time period. The use of BAL eliminated the unnecessary antibiotic treatment of 21% of patients in the BAL time period and was associated with a lower rate of VAP.

Background: We hypothesize that data collected from computed tomographic (CT) scans obtained for workup of chest or abdominal injuries provide data that are sufficient to screen for spinal fractures and will decrease the cost and time of spine evaluation after trauma., Methods: We reviewed plain radiographs from 55 selected trauma patients who also underwent CT scanning of the chest, abdomen, and pelvis. We also timed the radiologic workup of 50 consecutive trauma patients to determine the time required to complete radiographic spine evaluation., Results: Forty-seven patients had thoracolumbar fractures. Thirteen patients were found to have 33 thoracolumbar spine fractures identified by CT scan but not plain radiography. Fractures were found on initial trauma CT scans of the chest, abdomen, and pelvis obtained to evaluate for visceral injuries. No injuries seen on plain film were missed on CT scan., Conclusion: We recommend using the data acquired from CT scans to evaluate the spine, supplementing them with additional studies only when needed for further clarification.

Background: There is no direct evidence that beta-blockers improve mortality in burn victims. Beta-blockers attenuate hypermetabolic states in burned children, and perioperative use in elective adult cases has beneficial effects, which suggests that beta-blockers may also improve burn outcomes. However, beta-blockers decrease cardiac output and may decrease oxygen delivery, and theoretically may increase mortality. What is the effect of beta-blockers on healing time and mortality in burn patients?, Methods: This was a retrospective cohort study. We identified three cohorts of adult burn patients between 1996 and 2001: all who were on beta-blockers (BB) before their injury (PMH BB); all who were initiated on BB during their hospitalization for management of hypertension or tachyarrhythmia (HOSP BB); and control, who were never treated with beta-blockers. For each patient in the PMH BB and HOSP BB groups, two patients were placed in the control cohort by matching age and total body surface area burn. Premorbid conditions such as diabetes, hypertension, cardiac disease, renal insufficiency, and diuretic and calcium channel blocker use were analyzed. Multivariate regression models were used to identify independent modifiers., Results: There were 21 PMH BB, 22 HOSP BB, and 86 control patients. All PMH BB patients remained on their BB regimen in the hospital. HOSP BB patients were initiated on beta-blockers at a mean of 8.8 days postinjury. There were no differences in age (mean, 58 +/- 17 years), total body surface area burned (mean, 14 +/- 12%), or mechanism of injury among the cohorts. The mortality rate was 5% for the PMH BB cohort, 27% for the HOSP BB cohort, and 13% for controls. The mean healing times were 51 +/- 29 days for PMH BB patients, 79 +/- 54 days for HOSP BB patients, and 60 +/- 39 for controls. In multivariate analyses, PMH BB was associated with a significant decrease in fatal outcome and healing time (p < or = 0.05 compared with control)., Conclusion: Beta-blockers have the potential to improve adult burn outcomes. Postinjury treatment should be studied in a randomized, clinical trial.

Background: Blunt thoracic aortic injury (BTAI) is a severe injury that traditionally has mandated immediate surgical repair. Delaying operative intervention for BTAI can allow other life-threatening injuries to be managed first, but potentially increases the risk of aortic rupture and death. The objective of this study was to evaluate the outcome of delayed repair (DR) compared with early repair (ER) for BTAI and to assess the effectiveness of a protocol for medical control of systolic blood pressure and heart rate in those patients whose repairs were delayed., Methods: This study is a retrospective review of University of Michigan Health System (UMHS) data from January 1, 1992, through March 1, 2003. ER was defined as operative repair within 16 hours from the time of injury. A similar analysis was conducted for patients with BTAI selected from the National Trauma Data Bank., Results: For the UMHS data, there were 45 patients in the DR group and 33 patients in the ER group. Mortality in the ER group versus the DR group was 9% versus 20%. Multivariate analysis adjusting for age, Injury Severity Score, abdominal Abbreviated Injury Scale score, Glasgow Coma Scale score, and intubation status demonstrated an odds ratio for death from ER compared with DR of 1.72 (p = 0.57). Patients undergoing DR had an absolute increase in hospital length of stay (33.1 vs. 20.9 days) and complication rate (2.1 vs. 1.5 incidents per patient). A similar result was obtained for multivariate analysis of the National Trauma Data Bank data, with an odds ratio of 1.40 (p = 0.51) for death from ER versus DR. UMHS patients whose repairs were delayed achieved target systolic blood pressure and heart rate for 76% and 74% of the hourly measurements recorded, respectively., Conclusion: Patients with BTAI can safely undergo delayed aortic repair if other injuries warrant a higher treatment priority without increasing their overall risk of mortality. Delayed repair is, however, associated with a higher complication rate.