Recent Publications by CFE Educators

Bacterial endotoxin (LPS) elicits dramatic responses in the host including elevated plasma lipid levels due to the increased synthesis and secretion of triglyceride (TG)-rich lipoproteins by the liver, and the inhibition of lipoprotein lipase. This cytokine-induced hyperlipoproteinemia, clinically termed the "lipemia of sepsis", was customarily thought to represent the mobilization of lipid stores to fuel the host response to infection. However, since lipoproteins can also bind and neutralize LPS, we hypothesize that TG-rich lipoproteins (VLDL and chylomicrons) are also components of an innate, non-adaptive host immune response to infection. Herein we review data demonstrating the capacity of lipoproteins to bind LPS, protect against LPS-induced toxicity, and modulate the overall host response to this bacterial toxin. Lastly, we propose a pathway whereby lipoprotein-bound LPS may represent a novel, endogenous mechanism for regulating the hepatic acute phase response.

Marked reductions in cardiovascular mortality have been reported over the last 2 decades as a result of therapeutic advances in ischemic heart disease. Despite medical advances, case fatality rates are higher for women than men. A critical step toward improving outcomes is early diagnosis of coronary artery disease by noninvasive evaluation. The use of noninvasive testing in women has been controversial because of a perception of diminished accuracy, limited female representation, and compromise of efficacy of testing because of technical limitations (eg, thallium-201 breast artifact). Recent meta analysis and large observational series report marked improvements in the accuracy of results for women undergoing exercise treadmill, echocardiography, and nuclear testing. Exercise treadmill testing has an improved accuracy when multiple risk parameters (eg, ST deviation, chest pain, exercise time) are included in the test interpretation. For women, a low-risk Duke treadmill score is associated with a 97% 5-year survival, with 80% of these patients having no obstructive disease. Multivessel disease (70%) is common for those with a high-risk treadmill score with a 5-year survival of 90%. The diagnostic accuracy of electron beam computed tomography reveals a sensitivity and specificity of 88% and 49%. For exercise echocardiography, test diagnostic sensitivity and specificity are 86% and 79%. For nuclear imaging, 3-year cardiac survival ranged from 99% to 85% for 0 to 3 vascular territories with perfusion abnormalities. A sufficient body of evidence supports the use of noninvasive testing for intermediate-risk, symptomatic women. Diagnostic certainty may be effectively guided by the evaluation of global and regional wall motion, eg, with echocardiography. Risk assessment may be more precise with the evaluation of myocardial perfusion, eg, with stress nuclear imaging. With the use of updated evidence, informed test selection for women may result in improved diagnostic and therapeutic decision-making, with the use of available noninvasive testing modalities.

Although opioids can reduce stimulus-evoked efflux of Substance P (SP) from nociceptive primary afferents, the consequences of this reduction on spinal cord nociceptive processing has not been studied. Rather than assaying SP release, in the present study we examined the effect of opioids on two postsynaptic measures of SP release, Fos expression and neurokinin-1 (NK-1) receptor internalization, in the rat. The functional significance of the latter was first established in in vitro studies that showed that SP-induced Ca(2+) mobilization is highly correlated with the magnitude of SP-induced NK-1 receptor internalization in dorsal horn neurons. Using an in vivo analysis, we found that morphine had little effect on noxious stimulus-evoked internalization of the NK-1 receptor in lamina I neurons. However, internalization was reduced when we coadministered morphine with a dose of an NK-1 receptor antagonist that by itself was without effect. Thus, although opioids may modulate SP release, the residual release is sufficient to exert maximal effects on the target NK-1 receptors. Morphine significantly reduced noxious stimulus-induced Fos expression in lamina I, but the Fos inhibition was less pronounced in neurons that expressed the NK-1 receptor. Taken together, these results suggest that opioid analgesia predominantly involves postsynaptic inhibitory mechanisms and/or presynaptic control of non-SP-containing primary afferent nociceptors.

Epileptic seizures are associated with increases in hippocampal excitability, but the mechanisms that render the hippocampus hyperexcitable chronically (in epilepsy) or acutely (in status epilepticus) are poorly understood. Recent evidence suggests that substance P (SP), a peptide that has been implicated in cardiovascular function, inflammatory responses, and nociception, also contributes to hippocampal excitability and status epilepticus, in part by enhancing glutamate release. Here we report that mice with disruption of the preprotachykinin A gene, which encodes SP and neurokinin A, are resistant to kainate excitoxicity. The mice show a reduction in the duration and severity of seizures induced by kainate or pentylenetetrazole, and both necrosis and apoptosis of hippocampal neurons are prevented. Although kainate induced the expression of bax and caspase 3 in the hippocampus of wild-type mice, these critical intracellular mediators of cell death pathways were not altered by kainate injection in the mutant mice. These results indicate that the reduction of seizure activity and the neuroprotection observed in preprotachykinin A null mice are caused by the extinction of a SP/neurokinin A-mediated signaling pathway that is activated by seizures. They suggest that these neurokinins are critical to the control of hippocampal excitability, hippocampal seizures, and hippocampal vulnerability.