Recent Publications by CFE Educators

BACKGROUND

Short-term estrogen administration improves vasodilation and has been shown to improve exercise capacity. However, it is unknown whether long-term estrogen replacement therapy is associated with improved exercise capacity in postmenopausal women without known coronary artery disease.

METHODS AND RESULTS

We studied 248 postmenopausal women without known coronary artery disease (mean age 63.5 years); 158 (64%) were current or past hormone replacement therapy (HRT) users and 108 (44%) were current users of HRT. Attributes potentially affecting exercise capacity and cardiac risk factors were carefully measured. These included duration of estrogen replacement therapy, all variables in the Framingham risk index, physical activity level, body mass index, waist-to-hip ratio, presence of osteoporosis, and family history of heart disease. We measured maximal oxygen uptake (MVO (2)) and anaerobic threshold as objective markers of exercise capacity. The relation between exercise capacity and use of HRT was analyzed with the use of logistic regression, controlling for confounding variables. We found that fitness, as measured by MVO (2) and anaerobic threshold, was significantly greater in women who had used HRT currently or in the past compared with women who had never used HRT. This difference in fitness was not confounded by age or physical activity level.

CONCLUSIONS

Estrogen replacement therapy is associated with increased exercise capacity as measured by MVO (2) and anaerobic threshold in postmenopausal women without coronary artery disease. This finding is consistent with the beneficial effect of short-term estrogen administration on improved endothelium-dependent and endothelium-independent vasodilation.

Hindpaw injection of dilute formalin produces brief (Phase 1) and persistent (Phase 2) nociceptive responses in the rat. We recently showed that systemically-administered remifentanil during Phase 1 interacted with peripheral opioid receptors to delay the onset and termination of Phase 2 (Taylor et al., 1997b). To test the hypothesis that opioid inhibition of proinflammatory events during Phase 1 contributed to this delay, we evaluated the effects of remifentanil on the time course of formalin-induced inflammation. We found that formalin increased paw thickness (edema), plasma extravasation and local blood flow within minutes of its injection, i.e. during Phase 1. Each of these responses was blocked during remifentanil administration (30 microg/kg i.v. bolus, followed 90 s later with a 15 microg/kg/min infusion for 13.5 min), indicating that opioids inhibit Phase 1 inflammation. Opioid blockade of the blood flow response could be reversed with a peripherally-acting opioid antagonist, naloxone methiodide, indicating that remifentanil acted upon peripheral opioid receptors. Although the administration of remifentanil during Phase 1 did not reduce the magnitude of inflammatory responses during Phase 2, it did delay the onset and termination of edema during Phase 2. As this corresponds to the effects of remifentanil on nociceptive responses during Phase 2, we suggest that opioid analgesics act upon peripheral sites to inhibit inflammation during Phase 1, leading to a delay in the temporal profile of inflammatory (and likely nociceptive) responses during Phase 2.

STUDY OBJECTIVE

Estimates of time intervals by bystanders are considered critical in cardiac arrest, and are often used in other disorders such as stroke and myocardial infarction. Because they have never been previously studied, we sought to determine their accuracy.

METHODS

This study was performed by prospective collection of bystander estimates (made at the time of the arrest) of the time from calling 911 to the arrival of urban fire department first responders, and comparison with actual measured response interval from computerized records, in all out-of-hospital cardiac arrests from January 1996 through June 1998.

RESULTS

The fire department responded to 1,015 patients in cardiac arrest during the study period. First responders arrived before advanced life support providers to 831 patients, who thus met study entry criteria. Bystander estimates were obtained in 497 of these 831 patients, who did not differ in key characteristics from those lacking estimates. The bystander's average estimated fire department response interval was 5.6 minutes (95% confidence interval [CI] 5.2 to 5.9 minutes) and the actual measured interval to the patient's side from computer records was 6.1 minutes (95% CI 5.9 to 6.4 minutes). However, the median error of the bystander estimate (1.3 minutes) was 32% of the median of the actual measured on-scene interval, and there was no correlation between the bystander estimates and the measured interval in individual cases (R

CONCLUSION

Although many diagnostic and research conclusions are based on interval estimates from laypersons, we found no correlation between estimates and actual measured intervals in cardiac arrest. Current methodology may not be developed well enough to provide reliable data for research or quality assurance, and other clinical time estimates by patients and bystanders may be equally unreliable.

OBJECTIVES

This study sought to determine the relationship of lipoprotein(a) (Lp(a)) and other cardiac risk factors to coronary atherosclerosis as measured by calcification of coronary arteries in asymptomatic postmenopausal women.

BACKGROUND

Lipoprotein(a) is considered a risk factor for coronary heart disease. Coronary calcium deposition is believed to be a useful noninvasive marker of coronary atherosclerosis in women. However, to our knowledge, there are no reports of the relationship of Lp(a) to coronary calcium in postmenopausal women.

METHODS

In 178 asymptomatic postmenopausal women (64 +/- 8 years), we measured Lp(a) and other cardiac risk factors: age, hypertension, diabetes, low-density lipoprotein cholesterol, smoking status, body mass index, physical activity level and duration of hormone replacement therapy. Electron-beam computed tomography was done to measure coronary calcium (calcium score). We analyzed the relationship between calcium score and cardiac risk factors using multivariate analysis.

RESULTS

Although calcium score correlated with traditional risk factors of age, diabetes, hypertension and smoking, it did not correlate with Lp(a) in the asymptomatic postmenopausal women. Similar multivariate analyses were done in the subjects age >60 years and in the subjects with significant coronary calcium deposit (calcium score > or =50). These analyses also have failed to show an association of levels of Lp(a) with coronary calcium deposits.

CONCLUSIONS

We conclude that in asymptomatic postmenopausal women, Lp(a) levels do not correlate with coronary atherosclerosis as measured by coronary calcium deposits.

Like many other complex biological phenomena, pain is starting to be studied at the level of the gene. Advances in molecular biological technology have allowed the cloning, mapping, and sequencing of genes, and also the ability to disrupt their function entirely (i.e. via transgenic knockouts). With these new tools at hand, pain researchers have begun in earnest the task of defining (a) which of the 70,000-150,000 mammalian genes are involved in the mediation of pain, and (b) which of the pain-relevant genes are polymorphic, contributing to both natural variation in responses and pathology. Although there are only a few known examples in which single gene mutations in humans are associated with pain conditions (e.g. an inherited form of migraine and congenital insensitivity to pain), it is likely that others will be identified. Concurrently, a variety of genes have been implicated in both the transmission and control of "pain" messages in animals. The present review summarizes current progress to these ends, focusing on both transgenic (gene-->behavior) and classical genetic (behavior-->gene) approaches in both humans and laboratory mice.

Intraplantar formalin injection produces early (Phase 1, 0- to 5-minute) and late (Phase 2, 15-plus minutes after injection) nociceptive responses, including painlike behavior and activation of primary afferents and dorsal horn neurons. Although we and others have reported that opioid analgesia or local anesthesia during Phase 1 does not reduce the overall magnitude of behavioral and/or neuronal responses during Phase 2, recent studies concluded that spinal sensitization during Phase 1 significantly contributes to the magnitude of painlike behavior during Phase 2. In this article, we provide additional evidence that Phase 1 and Phase 2 behaviors are independent. We found that remifentanil analgesia during Phase 1 does not reduce Phase 2, regardless of route of administration, duration of analgesia, types of behavior assessed, formalin concentration, concomitant use of general anesthesia, or concomitant administration of an N-methyl-D-aspartate (NMDA) antagonist. We suggest that Phase 1 behaviors compared with Phase 2 behaviors in the formalin test are not an appropriate model of spinal sensitization or preemptive opioid analgesia. Instead, early opioid administration delayed the onset of edema produced by formalin. Because the antiedema effect of remifentanil was reversed with a peripherally acting opioid receptor antagonist, we suggest that opioids interact with peripheral receptors to temporarily delay the onset and offset of formalin-induced edema.

Repeated administration of an opioid in the presence of specific environmental cues can induce tolerance specific to that setting (associative tolerance). Prolonged or repeated administration of an opioid without consistent contextual pairing yields non-associative tolerance. Here we demonstrate that cholecystokinin acting at the cholecystokinin-B receptor is required for associative but not non-associative morphine tolerance. Morphine given in the morphine-associated context increased Fos-like immunoreactivity in the lateral amygdala and hippocampal area CA1. Microinjection of the cholecystokinin B antagonist L-365,260 into the amygdala blocked associative tolerance. These results indicate that cholecystokinin acting in the amygdala is necessary for associative tolerance to morphine's analgesic effect.