Cancers are believed to arise from cancer stem cells (CSCs), but it is not known if these cells remain dependent upon the niche microenvironments that regulate normal stem cells. We show that endothelial cells interact closely with self-renewing brain tumor cells and secrete factors that maintain these cells in a stem cell-like state. Increasing the number of endothelial cells or blood vessels in orthotopic brain tumor xenografts expanded the fraction of self-renewing cells and accelerated the initiation and growth of tumors. Conversely, depletion of blood vessels from xenografts ablated self-renewing cells from tumors and arrested tumor growth. We propose that brain CSCs are maintained within vascular niches that are important targets for therapeutic approaches.

Background — Inflammation and infection may initiate and promote atherosclerosis or its complications by adverse effects on the vascular endothelium. The mechanisms by which aspirin reduces cardiovascular risk might involve anti-inflammatory actions or direct effects on the endothelium in addition to its antiplatelet action. We investigated the role of aspirin in modulating endothelial dysfunction induced by an experimental inflammatory stimulus. Methods and Results — An inflammatory response was generated in healthy volunteers by Salmonella typhi vaccination. Venous occlusion plethysmography was used to assess resistance vessel responses (16 hours before and 8 hours after vaccination) to the endothelium-dependent dilator bradykinin (BK) and the endothelium-independent dilator glyceryl-trinitrate (GTN). Twelve subjects were randomized to receive either aspirin 1.2 g orally or placebo 2 hours before vaccination. After vaccination alone there was suppression of the response to BK in the placebo group ( P =0.01), with no change in response to GTN. In the aspirin group there was no change in the response to either BK or GTN after vaccination. Aspirin treatment prevented vaccine-induced elevation of interleukin-1 receptor antagonist but enhanced the generation of tumor necrosis factor-α compared with placebo. In an additional 5 individuals, local intrabrachial aspirin (10 mg/min for 15 minutes) failed to restore responses to BK after vaccination. Conclusions — Experimental inflammation produces endothelial dysfunction, which can be prevented by pretreatment with aspirin. Locally administered aspirin does not reverse vaccine-induced endothelial dysfunction once established. The protective effects of aspirin on inflammation-induced endothelial dysfunction may be through modulation of the cytokine cascade.

Immediately following cardiac surgery, many children become relatively refractory to lipopolysaccharide stimulation. This immunoparalysis appears to be related in part to high circulating levels of interleukin-10 and places these patients at increased risk of postoperative complications. Interleukin-10 genotype may be a risk factor for immunoparalysis.

BackgroundAs a conceptual review, this paper will debate relevant learning theories to inform the development, design and delivery of an effective educational programme for simulated team training relevant to health professionals.DiscussionKolb’s experiential learning theory is used as the main conceptual framework to define the sequence of activities. Dewey’s theory of reflective thought and action, Jarvis modification of Kolb’s learning cycle and Schön’s reflection-on-action serve as a model to design scenarios for optimal concrete experience and debriefing for challenging participants’ beliefs and habits. Bandura’s theory of self-efficacy and newer socio-cultural learning models outline that for efficient team training, it is mandatory to introduce the social-cultural context of a team.SummaryThe ideal simulated team training programme needs a scenario for concrete experience, followed by a debriefing with a critical reflexive observation and abstract conceptualisation phase, and ending with a second scenario for active experimentation. Let them re-experiment to optimise the effect of a simulated training session. Challenge them to the edge: The scenario needs to challenge participants to generate failures and feelings of inadequacy to drive and motivate team members to critical reflect and learn. Not experience itself but the inadequacy and contradictions of habitual experience serve as basis for reflection. Facilitate critical reflection: Facilitators and group members must guide and motivate individual participants through the debriefing session, inciting and empowering learners to challenge their own beliefs and habits. To do this, learners need to feel psychological safe. Let the group talk and critical explore. Motivate with reality and context: Training with multidisciplinary team members, with different levels of expertise, acting in their usual environment (in-situ simulation) on physiological variables is mandatory to introduce cultural context and social conditions to the learning experience. Embedding in situ team training sessions into a teaching programme to enable repeated training and to assess regularly team performance is mandatory for a cultural change of sustained improvement of team performance and patient safety.

Patients with decreased HLA-DR in the early postoperative period represent a subpopulation at greatly increased risk of later sepsis/SIRS. Such patients may benefit from strategies aimed to reduce this risk.

There is a 6- to 12-month learning curve in the implementation of an embedded multidisciplinary team training programme. Repeated exposure to simulation is most beneficial to crisis resource management training and single, isolated exposure may not be sufficient.

: Many factors other than tissue hypoxia may contribute to hyperlactemia in critical illness. Although the presence of hyperlactemia on admission appears to be associated with intensive care unit mortality and morbidity in some retrospective analyses, significant overlap between survivors and nonsurvivors means that nonsurvivors cannot be predicted from admission lactate measurement. Persistently elevated postoperative lactate is associated with increased morbidity and mortality in the pediatric cardiac population. To date there is no randomized control trial of goal-directed therapy in adult or pediatric cardiac care that includes normalization of lactate as a target. Overall equivalent time measurements of base excess, anion gap, and pH have a low predictive value for morbidity and mortality in children after cardiac surgery. Lactate is one of a cluster of markers of cellular perfusion and oxygen delivery. Alone, as a single measurement, it has minimal predictive value and is nondiscriminatory for survival.

Our data support the concept that fetal exposure to inflammation before preterm delivery leads to subsequent endotoxin hyporesponsiveness (immunoparalysis), which increases the risk of subsequent sepsis and associated organ dysfunction.