Severe sepsis is one of the leading causes of death worldwide. High mortality rates in sepsis are frequently associated with neutropenia. Despite the central role of neutrophils in innate immunity, the mechanisms causing neutropenia during sepsis remain elusive. Here, we show that neutropenia is caused in part by apoptosis and is sustained by a block of hematopoietic stem cell (
Objective-Homeostasis of the hematopoietic compartment is challenged and maintained during conditions of stress by mechanisms that are poorly defined. To understand how the bone marrow (BM) microenvironment influences hematopoiesis, we explored the role of Notch signaling and bone marrow endothelial cells in providing microenvironmental cues to hematopoietic cells in the presence of inflammatory stimuli.Methods-The human BM endothelial cell line BMEC and primary human BM endothelial cells were analyzed for expression of Notch ligands and the ability to expand hematopoietic progenitors in an in vitro co-culture system. In vivo experiments were carried out to identify modulation of Notch signaling in BM endothelial and hematopoietic cells in mice challenged with TNFα or LPS, or in Tie2-tmTNFα transgenic mice characterized by constitutive TNFα activation.Results-BM endothelial cells were found to express Jagged ligands and to greatly support progenitor's colony-forming ability. This effect was markedly decreased by Notch antagonists and augmented by increasing levels of Jagged2. Physiologic upregulation of Jagged2 expression on BMEC was observed upon TNFα activation. Injection of TNFα or LPS upregulated 3 to 4 fold Jagged2 expression on murine BM endothelial cells in vivo and resulted in increased Notch
Ground-level falls (GLFs) are the leading cause of nonfatal hospitalized injuries in the US. We hypothesized that risk-adjusted mortality would not vary between levels of trauma center verification if regional triage functioned appropriately. Data were collected from our regional trauma registry for the years 2001 through 2009. A multilevel mixed-effects logistic regression model was developed to compare risk-adjusted mortality rates by trauma center level and by year. GLF patients numbered 8202 over 9 years with 2.1% mortality. Mean age was 74.5 years and mean probability of death was 0.021 (95% confidence interval [CI], 0.020-0.021). The level I center-treated patients had the highest probability of death (0.033) compared to levels II and III/IV patients (0.023 and 0.018, respectively; P < 0.001), with the highest mortality (6.0%, 3.1%, and 1.1% for levels I, II, and III/IV; P < 0.001). The adjusted odds ratio of mortality was lowest at the level I center (0.71; 95% CI, 0.56-0.91), while no difference existed between level II (1.17; 95% CI, 0.90-1.51) and level III/IV centers (1.22; 95% CI, 0.90-1.66). The 95% CIs for risk-adjusted mortality by year overlapped the 1.0 reference line for each year from 2002 to 2009. In conclusion, regional risk-adjusted mortality for GLF has varied little since 2002. More study is warranted to understand the lower risk-adjusted GLF mortality at the level I center for this growing patient population.
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