Accuracy of Doppler methods for estimating peak-to-peak and peak instantaneous gradients across coarctation of the aorta: An In vitro study.

Although data exist that address the attempt to correlate noninvasive Doppler-derived pressure gradients with invasive catheter pressure gradients in patients with coarctation of the aorta, few data exist about stiffness of the proximal descending aorta (precoarctation) and its relation to these pressure measurements. In this study, an in vitro flow model of a simulated neonatal aorta with a coarctation was developed. Three proximal descending aortas of different stiffnesses were used. The stiffness index of the proximal descending aorta was calculated as beta = ln [systolic pressure/diastolic pressure/(systolic diameter - diastolic diameter)]. We evaluated pressure gradients obtained by continuous wave Doppler and standard catheter methods and looked at acceleration of flow velocity determined by pulsed wave Doppler in the 3 precoarctation segments of differing stiffnesses. Pressures in the proximal descending aorta (precoarctation) increased with increasing stiffness, ranging from 105 mm Hg (soft) to greater than 300 mm Hg (stiff). Continuous wave Doppler instantaneous pressure gradients overestimated the catheter instantaneous pressure gradients substantially (mean 41% +/- 19%). The stiffer the precoarctation segment, the more the degree of overestimation: soft, 0% to 63% (= 3.47); medium, 13% to 54% (beta = 4.42); and stiff, 43% to 66% (beta = 5.91). Inclusion of the precoarctation velocity [V1] component in the Bernoulli equation did not significantly improve the correlation or the agreement. An additional observation was that pullback catheter peak-to-peak gradients were higher than simultaneous peak-to-peak gradients. In the stiff aorta, this difference could be greater than 22 mm Hg (>19%). Acceleration of flow velocity toward the coarctation was evident by pulsed wave Doppler interrogation. Increasing the stiffness of the precoarctation segment also increased the degree of acceleration within this proximal segment: soft, 0.4 to 0.8 m/s; medium, 0.5 to 1. 4 m/s; and stiff, 0.7 to 1.5 m/s. These data suggest that increasing stiffness of the proximal descending aorta can alter the continuous wave detected Doppler gradient and although the gradient itself has increased, it may not predict accurately the true severity of the localized, most severely obstructed segment.

The dorsomedial hypothalamus mediates stress-induced hyperalgesia and is the source of the pronociceptive peptide cholecystokinin in the rostral ventromedial medulla.

While intense or highly arousing stressors have long been known to suppress pain, relatively mild or chronic stress can enhance pain. The mechanisms underlying stress-induced hyperalgesia (SIH) are only now being defined. The physiological and neuroendocrine effects of mild stress are mediated by the dorsomedial hypothalamus (DMH), which has documented connections with the rostral ventromedial medulla (RVM), a brainstem region capable of facilitating nociception. We hypothesized that stress engages both the DMH and the RVM to produce hyperalgesia. Direct pharmacological activation of the DMH increased sensitivity to mechanical stimulation in awake animals, confirming that the DMH can mediate behavioral hyperalgesia. A behavioral model of mild stress also produced mechanical hyperalgesia, which was blocked by inactivation of either the DMH or the RVM. The neuropeptide cholecystokinin (CCK) acts in the RVM to enhance nociception and is abundant in the DMH. Using a retrograde tracer and immunohistochemical labeling, we determined that CCK-expressing neurons in the DMH are the only significant supraspinal source of CCK in the RVM. However, not all neurons projecting from the DMH to the RVM contained CCK, and microinjection of the CCK2 receptor antagonist YM022 in the RVM did not interfere with SIH, suggesting that transmitters in addition to CCK play a significant role in this connection during acute stress. While the RVM has a well-established role in facilitation of nociception, the DMH, with its well-documented role in stress, may also be engaged in a number of chronic or abnormal pain states. Taken as a whole, these findings establish an anatomical and functional connection between the DMH and RVM by which stress can facilitate pain.

High-performance liquid chromatography (HPLC) assay for ribavirin and comparison of the HPLC assay with radioimmunoassay.

The use of high-performance liquid chromatography (HPLC) to measure ribavirin in serum and other biological fluids has been limited by endogenous interfering substances. We report an HPLC procedure based on the extraction of ribavirin from serum, plasma, or cerebrospinal fluid with a boronate affinity gel, which uses a 3-methylcytidine internal standard. This assay is sensitive (to 0.4 microM), specific (no interference with 34 commonly prescribed drugs), reproducible (coefficients of variation from 5.4 to 22.4%), and linear (r = 0.999) over the range of clinically relevant concentrations in serum (from 0.5 to 50.0 microM). It also correlates well with the ribavirin radioimmunoassay (r = 0.992). This HPLC assay should be useful for measuring ribavirin in serum and other body fluids during clinical trials.