Publications

The underlying mechanism for nerve growth factor (NGF) evoked pain and long-lasting mechanical hyperalgesia remains poorly understood. Using intrathecal antisense against the NGF receptor, receptor tyrosine kinase (TrkA), we found NGF to act at the primary afferent nociceptor directly in the Sprague-Dawley rat. Inhibitors of the three major pathways for TrkA receptor signalling, extracellular signal-related kinase (ERK)/mitogen-activated protein kinase kinase (MEK) (ERK/MEK), phosphatidylinositol 3-kinase (PI3K), and phospholipase Cgamma (PLCgamma) all attenuate NGF-induced hyperalgesia. Although inhibitors of kinases downstream of PI3K and PLCgamma[glycogen synthetase kinase 3 (GSK3), calmodulin-dependent protein kinase II (CAMII-K) or protein kinase C (PKC)] do not reduce mechanical hyperalgesia, hyperalgesia induced by activation of PI3K was blocked by ERK/MEK inhibitors, suggesting cross-talk from the PI3K to the ERK/MEK signalling pathway. As integrins have been shown to modulate epinephrine and prostaglandin E(2)-induced hyperalgesia, we also evaluated a role for integrins in NGF-induced mechanical hyperalgesia using beta(1)-integrin-specific antisense or antibodies.

Epinephrine produces sexually dimorphic beta(2)-adrenergic receptor-mediated mechanical hyperalgesia, with male rats exhibiting greater hyperalgesia. Because female rats have higher plasma epinephrine levels, and beta-adrenergic receptor sensitivity is affected by chronic exposure to agonists, we tested the hypothesis that this sexual dimorphism is due to epinephrine-induced desensitization of beta(2)-adrenergic receptors. Following gonadectomy, epinephrine hyperalgesia, as measured by the Randall-Selitto paw-withdrawal test, was unchanged in male rats while in females it was increased. Prepubertal male and female rats do not demonstrate sexual dimorphism in either plasma epinephrine level or epinephrine-induced hyperalgesia. Adrenal medullectomy and adrenal denervation both significantly enhanced epinephrine hyperalgesia, but only in females. In contrast, the sexually dimorphic hyperalgesia induced by prostaglandin E(2), another agent that acts directly to sensitize primary afferent nociceptors, was not enhanced by adrenal medullectomy or denervation. Chronic administration of epinephrine in male rats, to produce plasma levels similar to those of gonad-intact females, significantly attenuated epinephrine-induced hyperalgesia, making it similar to that in females. These results strongly support the suggestion that estrogen regulates plasma epinephrine in female rats and differential sensitivity to beta(2)-adrenergic agonists accounts for the sexual dimorphism in epinephrine-induced hyperalgesia. Unexpectedly, regulation of adrenal medullary function by estrogen was also found to modulate baseline nociceptive threshold such that females had a lower nociceptive threshold.

Pharmacogenetics and pharmacogenomics offer the potential of developing DNA-based tests to help maximize drug efficacy and enhance drug safety. Major scientific advances in this field have brought us to the point where such tests are poised to enter more widespread clinical use. However, many questions have been raised about whether such tests will be of significant value, and how to assess this. Here, we review the application of economics-based resource-allocation frameworks to assess the value of pharmacogenomics, and the findings so far. We then develop a resource-allocation framework for assessing the potential value of pharmacogenomic testing from a population perspective, and apply this framework to the example of testing for variant alleles of CYP2D6, an important drug-metabolizing enzyme. This review provides a framework for analysing the value of pharmacogenomic interventions, and suggests where further research and development could be most beneficial.

Decreasing response to stress has been one goal of interventions aimed at reducing relapse to substances of abuse. A laboratory stress test that can be repeated would be helpful in testing the efficacy of interventions in decreasing the response to stress before more extensive trials are begun. The effects of two types of psychological stress tests, the Trier Social Stress Test (TSST) and a stress imagery test, on psychological, physiological, and hormonal responses (salivary cortisol and DHEA) were examined when each test was given twice to cocaine- or methamphetamine-dependent human subjects, 24 of whom completed at least one session. The stress imagery test produced significant changes in several of the subjective response measures in both first and second sessions, including several measures of negative affect and a craving measure. The TSST produced significant changes only in the second session. The stress imagery protocol showed better replicability across two sessions. Cocaine users and methamphetamine users did not respond similarly in their craving responses. Reported craving for methamphetamine after stress testing showed decreases or much smaller increases compared to that for cocaine. Neither stress test significantly increased salivary cortisol or DHEA, and changes in hormone concentrations were not related to subjective responses. These results suggest that stress imagery testing procedures may be useful as provocative tests of stress-induced affect and stimulant drug craving. Although less convincing because of the heterogeneity of the subjects, they also suggest that HPA axis responsivity is not clearly linked to acute stress-induced stimulant craving or affective response.

BACKGROUND

Disturbances in rest-activity rhythm are prominent and disabling symptoms in Alzheimer's disease (AD). Nighttime sleep is severely fragmented and daytime activity is disrupted by multiple napping episodes. In most institutional environments, light levels are very low and may not be sufficient to enable the circadian clock to entrain to the 24-hour day. The purpose of this randomized, placebo-controlled, clinical trial was to test the effectiveness of morning bright light therapy in reducing rest-activity (circadian) disruption in institutionalized patients with severe AD.

METHOD

Subjects (n = 46, mean age 84 years) meeting the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke--the Alzheimer's Disease and Related Disorders Association) AD diagnostic criteria were recruited from two large, skilled nursing facilities in San Francisco, California. The experimental group received one hour (09:30-10:30) of bright light exposure (> or = 2500 lux in gaze direction) Monday through Friday for 10 weeks. The control group received usual indoor light (150-200 lux). Nighttime sleep efficiency, sleep time, wake time and number of awakenings and daytime wake time were assessed using actigraphy. Circadian rhythm parameters were also determined from the actigraphic data using cosinor analysis and nonparametric techniques. Repeated measures analysis of variance (ANOVA) was used to test the primary study hypotheses.

RESULTS AND CONCLUSION

Although significant improvements were found in subjects with aberrant timing of their rest-activity rhythm, morning bright light exposure did not induce an overall improvement in measures of sleep or the rest-activity in all treated as compared to control subjects. The results indicate that only subjects with the most impaired rest-activity rhythm respond significantly and positively to a brief (one hour) light intervention.

BACKGROUND

Accurate prognostication of the trajectory of an illness provides multiple benefits in end-of-life care. Prognostic information facilitates more realistic decision making regarding ongoing treatment, fosters risk-benefit considerations of specific interventions, and contributes to appropriate utilization of health care services.

OBJECTIVE

The Palliative Performance Scale (PPS) has been used as a tool for measurement of functional status in palliative care. This study explores the application of the PPS as a tool for projecting length of stay until death or discharge in a home-based hospice program.

METHODS

Records of 396 patients admitted to a large community-based hospice program between January 1, 2001, and March 31, 2001, were reviewed. PPS scores were evaluated for their predictive ability related to length of hospice survival and consideration for hospice discharge. Other variables analyzed included diagnosis, presence of comorbidities, and age.

RESULTS

PPS scores were associated with length of survival. Negative-change scores were predictive of patient decline toward death, while stable PPS ratings over time resulted in discharge consideration. The tool as used by this hospice was not highly discriminating between the 30% to 40% scores or the 50% to 70% scores.

CONCLUSION

The PPS scores are associated with patient length of survival in a hospice program and can be used in evaluating hospice appropriateness.