Consistent with previous reports, sphingosine at a high concentration (5 microM) was cardiotoxic as evidenced by increased infarct size in response to ischemia/reperfusion in an ex vivo rat heart. Sphingosine 1-phosphate (S1P) at 5 microM was cardioprotective. However, at a physiologic concentration (0.4 microM) sphingosine as well as S1P was effective in protecting the heart from ischemia/reperfusion injury both when perfused prior to 40 min of ischemia (preconditioning) or when added to reperfusion media following ischemia (postconditioning). Protection by sphingosine and S1P was evidenced with both pre- and post-conditioning by a >75% recovery of left ventricular developed pressure during reperfusion and a decrease in infarct size from 45% of the risk area to less than 8%. When VPC23019, an S1P(1and3)G-protein coupled receptor antagonist, was added to the preconditioning or postconditioning medium along with S1P, it completely blocked S1P-induced protection. However, VPC 23019 did not affect the ability of 0.4 microM sphingosine to either precondition or postcondition hearts. Studies of preconditioning revealed that inhibition of protein kinase C with GF109203X blocked preconditioning by S1P. However, GF109203X did not affect preconditioning by 0.4 microM sphingosine. Likewise, cotreatment with the PI3 kinase inhibitor wortmanin blocked preconditioning by S1P but not by sphingosine. By contrast, inhibition of protein kinase G with KT5823 had no effect on S1P preconditioning but completely eliminated preconditioning by sphingosine. Also, the protein kinase A inhibitory peptide 14-22 amide blocked preconditioning by sphingosine but not S1P. These data reveal for the first time that sphingosine is not toxic at physiologic concentrations but rather is a potent cardioprotectant that utilizes a completely different mechanism than S1P; one that is independent of G-protein coupled receptors and utilizes cyclic nucleotide-dependent pathways.

Venous thromboembolic disease is a common disease associated with significant morbidity and mortality. Accurate and timely diagnosis should be guided by the use of validated clinical prediction rules. The mainstay of therapy is anticoagulation, although alternative approaches, such as use of concurrent thrombolysis or placement of vena caval filters, may be appropriate in selected patients. Determination of duration of anticoagulation requires a detailed assessment of the risk factors associated with the event allowing estimation of recurrence risk, and careful assessment of bleeding risk. Although extremely effective, anticoagulants have a narrow therapeutic window; systems should be in place to reduce risk of adverse events associated with these agents.

Interleukin (IL)-1beta has previously been shown to be among the most biologically active cytokines in the lungs of patients with acute lung injury (ALI). Furthermore, there is experimental evidence that lung vascular permeability increases after short-term exposure to IL-1 protein, although the exact mechanism is unknown. Therefore, the objective of this study was to determine the mechanisms of IL-1beta-mediated increase in lung vascular permeability and pulmonary edema following transient overexpression of this cytokine in the lungs by adenoviral gene transfer. Lung vascular permeability increased with intrapulmonary IL-1beta production with a maximal effect 7 days after instillation of the adenovirus. Furthermore, inhibition of the alphavbeta6 integrin and/or transforming growth factor-beta attenuated the IL-1beta-induced ALI. The results of in vitro studies indicated that IL-1beta caused the activation of transforming growth factor-beta via RhoA/alphavbeta6 integrin-dependent mechanisms and the inhibition of the alphavbeta6 integrin and/or transforming growth factor-beta signaling completely blocked the IL-1beta-mediated protein permeability across alveolar epithelial cell monolayers. In addition, IL-1beta increased protein permeability across lung endothelial cell monolayers via RhoA- and alphavbeta5 integrin-dependent mechanisms. The final series of in vivo experiments demonstrated that pretreatment with blocking antibodies to both the alphavbeta5 and alphavbeta6 integrins had an additive protective effect against IL-1beta-induced ALI. In summary, these results demonstrate a critical role for the alphavbeta5/beta6 integrins in mediating the IL-1beta-induced ALI and indicate that these integrins could be a potentially attractive therapeutic target in ALI.

The purpose of this study was to provide an analysis of gender-based disparities in hypertension and cardiovascular disease care in ambulatory practices across the United States. Using data from the 2005 National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey, we conducted a cross-sectional analysis of patient visits with their primary care providers and examined the association between gender and blood pressure control, use of any antihypertensive medication or initiation of new therapy for patients with uncontrolled hypertension, and receipt of recommended therapy for select cardiovascular conditions. Multivariable models were estimated to examine the association between gender and each outcome controlling for other variables. A total of 12 064 patient visits were identified (7786 women and 4278 men). Among patients with hypertension, women were less likely than men to meet blood pressure control targets (54.0% versus 58.7%; P<0.02). In multivariate analyses, women aged 65 to 80 years were less likely than men to have controlled hypertension (odds ratio: 0.62; 95% CI: 0.45 to 0.85). There was no association between gender and use of any antihypertensive medication or initiating a new therapy among patients with uncontrolled hypertension. In multivariate analyses, women were less likely than men to receive aspirin (odds ratio: 0.43; 95% CI: 0.27 to 0.67) and beta-blockers (odds ratio: 0.60; 95% CI: 0.36 to 0.99) for secondary prevention of cardiovascular disease. Our study highlights the persistent gender disparities in blood pressure control and cardiovascular disease management and also reveals the inadequate delivery of cardiovascular care to all patients.