Recent Publications by CFE Educators

Exposure to acute stressors activates both the hypothalamic-pituitary-adrenal (HPA) and cardiovascular systems. Prior chronic stress enhances HPA responses to novel, acute stressors, but whether it alters cardiovascular responsivity to novel, acute stress is unknown. In the present study, we examined mean arterial blood pressure (MAP) and heart rate (HR) to two distinct stimuli, restraint and formalin, following prior exposure to 7 days of intermittent cold. In two sets of control and chronically stressed animals, we measured MAP and HR for 60 min following onset of 30 min restraint and MAP, HR and behavioral responses to intraplantar injection of formalin. Chronic stress raised MAP and HR under resting conditions and elevated HR during, but not following termination of, restraint. These increases in HR during restraint were due to the differences in resting levels of HR, since both control and chronically stressed animals exhibited similar increases from resting levels in HR during restraint. Conversely, chronically stressed animals exhibited lower changes in MAP and HR from resting levels following termination of restraint. Formalin produced the characteristic biphasic pattern of cardiovascular and behavioral responses. Prior chronic stress did not alter behavior, but increased MAP and HR in Interphase and only MAP in Phase 2. The increases in MAP during Interphase and Phase 2 were a result of the elevations in resting levels of MAP, but even when differences in resting levels were taken into account, HR remained elevated in the Interphase in chronically stressed animals. Together, these data demonstrate that prior chronic intermittent cold stress modifies cardiovascular function both under resting conditions and, in very specific ways, under stimulated conditions produced by restraint and formalin. We propose that these modifications are produced by brain regions that are known to regulate cardiovascular function and which are activated by chronic stress.

We previously reported that withdrawal from morphine induces the expression of Fos, a marker of neuronal activity, in spinal cord neurons, particularly in laminae I and II of the superficial dorsal horn, and that the magnitude of Fos expression is increased in rats with a midthoracic spinal transection. We suggested that loss of withdrawal-associated increases in descending inhibitory controls that arise in the brainstem underlie the increased Fos expression after spinal transection. Here, we addressed the origin of the supraspinal inhibition. We injected rats intracerebroventricularly with saline or anti-dopamine-beta-hydroxylase-saporin, a toxin that destroys noradrenergic neurons of the locus coeruleus. Eleven days later, we implanted rats with morphine or placebo pellets, and after 4 d, we precipitated withdrawal with naltrexone. One hour later, the rats were killed, their brains and spinal cords were removed, and transverse sections of the brains and spinal cords were immunoreacted with an antibody to Fos. In placebo-pelleted rats, the toxin injection did not alter behavior and did not induce expression of the Fos protein. However, compared with saline-injected withdrawing rats, the toxin-treated rats that underwent withdrawal demonstrated an intense withdrawal behavior rarely seen in the absence of toxin, namely forepaw fluttering. The rats also had significantly increased Fos-like immunoreactivity in all laminae of the cervical cord and in laminae I and II and the ventral horn of the lumbar cord. No differences were recorded in the sacral cord. We conclude that the effects of spinal transection in rats that withdraw from morphine in part reflect a loss of coeruleospinal noradrenergic inhibitory controls.

Although glucocorticoids inhibit inflammation and are used to treat painful inflammatory rheumatic diseases, the contribution, if any, of endogenous pituitary-adrenocortical activity to the control of pain remains unclear. We report that injection of dilute formalin into the hindpaw not only evokes inflammation and pain-related behavior, but it also increases ACTH and corticosterone to a greater extent than restraint and saline injection alone. This difference was particularly robust during the final periods of pain-related behavior in the formalin test, when the ACTH and corticosterone (B) levels in the restraint/saline control group had returned to normal. These results indicate that formalin-evoked increases in ACTH and B reflect nociceptive input, rather than the stress associated with handling. To test the hypothesis that the formalin-induced increase in corticosterone reduces pain and inflammation, we next evaluated the effect of adrenalectomy (to prevent activation of glucocorticoid receptors) or high-dose dexamethasone (to saturate glucocorticoid receptors) on nociceptive processing in the formalin test. Neither adrenalectomy nor dexamethasone changed behavioral or cardiovascular nociceptive responses. Furthermore, the increases in blood pressure and heart rate produced by formalin may not be mediated by adrenomedullary catecholamine release. In addition, we conclude that the nociceptive component of the formalin stimulus is sufficient to activate the pituitary-adrenocortical system in the awake rat, but that the resulting release of corticosterone does not feed back and reduce nociceptive processing.

The generation of knock-out and transgenic mice offers a promising approach to the identification of novel biochemical factors that contribute to persistent pain conditions. To take advantage of these mice, however, it is important to demonstrate that the traditional models of persistent pain, which were largely developed for studies in the rat, can be used in the mouse. Here, we combined behavioral and anatomical methods to characterize the pathophysiology of a partial nerve injury-evoked pain condition in the 'normal' mouse. In male C57BL6 mice we tied a tight ligature around 1/3 to 1/2 of the diameter of the sciatic nerve and evaluated the time-course and magnitude of the ensuing mechanical and thermal allodynia. We also used immunocytochemistry to analyze nerve injury-induced changes in substance P (SP) and NK-1 (SP) receptor expression in the spinal cord. As in the rat, partial nerve injury markedly decreased paw withdrawal thresholds to both mechanical and thermal stimuli on the injured side. We detected threshold changes one day after the injury. The thermal allodynia resolved by 49 days, but the mechanical allodynia persisted for the duration of the study (70 days). We found no changes contralateral to the nerve injury. Sympatholytic treatment with guanethidine significantly reduced both the thermal and mechanical allodynia. We observed a reduction of SP immunoreactivity in the superficial dorsal horn on the injured side at 7 and 14, but not at 3 or 70 days after the nerve injury, and we observed an increase of NK-1 receptor expression at 3, 7, 14 and 42, but not at 70 days after the injury. We conclude that partial injury to the sciatic nerve produces a comparable allodynia and neurochemical plasticity in the rat and mouse. These results establish a valuable model for future studies of the biochemical basis of neuropathic pain in mice with specific gene modifications.

The nonreceptor tyrosine kinase Src is expressed at a high level in cells that are specialized for regulated secretion, such as the neuron, and is concentrated on secretory vesicles or at the site of exocytosis. To investigate the possibility that Src may play a role in regulating membrane traffic, we searched for neuronal proteins that will interact with Src. The SH3 domain of Src, but not that of the splice variant N-Src, bound to three proteins from mouse synaptosomes or PC12 cells: dynamin, synapsin Ia, and synapsin Ib. Dynamin and the synapsins coprecipitated with Src from PC12 cell extracts, and they colocalized with a subset of Src in the PC12 cell by immunofluorescence. Neither dynamin nor the synapsins were phosphorylated by Src, suggesting that the interaction of these proteins serves to direct the kinase activity of Src toward other proteins in the vesicle population. In immunoprecipitates containing Src and dynamin, the clathrin adaptor protein alpha-adaptin was also found. The association of Src and synapsin suggests a role for Src in the life cycle of the synaptic vesicle. The identification of a complex containing Src, dynamin, and alpha-adaptin indicates that Src may play a more general role in membrane traffic as well.

Medical school faculty members are being asked to assume new academic duties for which they have received no formal training. These include time-efficient ambulatory care teaching, case-based tutorials, and new computer-based instructional programs. In order to succeed at these new teaching tasks, faculty development is essential. It is a tool for improving the educational vitality of academic institutions through attention to the competencies needed by individual teachers, and to the institutional policies required to promote academic excellence. Over the past three decades, strategies to improve teaching have been influenced by the prevailing theories of learning and research on instruction, which are described. Research on these strategies suggests that workshops and students' ratings of instruction, coupled with consultation and intensive fellowships, are effective strategies for changing teachers' actions. A comprehensive faculty development program should be built upon (1) professional development (new faculty members should be oriented to the university and to their various faculty roles); (2) instructional development (all faculty members should have access to teaching-improvement workshops, peer coaching, mentoring, and/or consultations); (3) leadership development (academic programs depend upon effective leaders and well-designed curricula; these leaders should develop the skills of scholarship to effectively evaluate and advance medical education); (4) organizational development (empowering faculty members to excel in their roles as educators requires organizational policies and procedures that encourage and reward teaching and continual learning). Comprehensive faculty development, which is more important today than ever before, empowers faculty members to excel as educators and to create vibrant academic communities that value teaching and learning.

The excitatory neurotransmitter glutamate coexists with the peptide known as substance P in primary afferents that respond to painful stimulation. Because blockers of glutamate receptors reliably reduce pain behaviour, it is assumed that 'pain' messages are mediated by glutamate action on dorsal horn neurons. The contribution of substance P, however, is still unclear. We have now disrupted the mouse preprotachykinin A gene (PPT-A), which encodes substance P and a related tachykinin, neurokinin A. We find that although the behavioural response to mildly painful stimuli is intact in these mice, the response to moderate to intense pain is significantly reduced. Neurogenic inflammation, which results from peripheral release of substance P and neurokinin A, is almost absent in the mutant mice. We conclude that the release of tachykinins from primary afferent pain-sensing receptors (nociceptors) is required to produce moderate to intense pain.

Prebeta-1 HDL is a molecular species of plasma HDL of approximately 67 kDa mass that contains apolipoprotein A-I, phospholipids, and unesterified cholesterol. It participates in a cyclic process involved in the retrieval of cholesterol from peripheral tissues. In this cycle, unesterified cholesterol from cells is incorporated into prebeta-1 HDL, providing a substrate for esterification of cholesterol by lecithin:cholesterol acyltransferase. Prebeta-1 HDL then becomes incorporated into larger HDL species of alpha mobility as esterification proceeds and is regenerated during the transfer of cholesteryl esters from alpha HDL particles to acceptor lipoproteins. Thus the steady state level of prebeta-1 HDL in plasma reflects the relative efficiencies of the major metabolic processes involved in its generation and removal. We have used an isotope dilution technique to measure prebeta-1 HDL levels in the plasmas of 136 normolipidemic individuals (46 M, 90 F). The mean absolute concentration of prebeta-1 HDL as apolipoprotein A-I was 68 +/- 40 microg/ml for women, and 84 +/- 49 m/ml for men. Prebeta-1 HDL represented 5.5 +/- 3.3% of total apolipoprotein A-I in women, and 7.2 +/- 4.0% in men. The distributions of both absolute and percent prebeta-1 HDL are highly asymmetric, with skew toward higher values. However, the skew appears not to be attributable to either plasma cholesterol or triglyceride levels which are also skewed in population samples. The percent prebeta-1 HDL was negatively correlated with HDL cholesterol levels (P 0.0001), whereas absolute levels of prebeta-1 HDL were positively correlated with apolipoprotein A-I and negatively correlated with HDL cholesterol (P, for both, 0.0001). Multiple linear regression analysis revealed effects of age and gender, but no association with lipoprotein fractions other than HDL. Lower levels of prebeta-1 HDL were associated with female gender in all models.

The authors reviewed the literature published from 1966 to 1996 to identify enrichment programs for underrepresented minority precollege students sponsored by medical schools and affiliated programs, finding 19 articles describing 27 programs. The authors categorized the reported programs according to the components they contained. Most programs contained more than one component type. Twenty-four programs had an academic enhancement component. Two thirds had a motivational component to encourage students to consider medical and other health careers. Two programs set up mentoring relationship between students and health professionals. There were four research apprenticeships and three academic partnerships between medical schools and local school districts. Twelve of the 27 programs were evaluated in the literature. Eight evaluations focused on identifying the numbers of students who continued their education into college and professional schools. Five programs reported participant satisfaction or identified other short-term outcomes such as gains on standardized tests. While the percentage of participants completing college and entering health care careers is impressive, the authors do not believe that the educational success of participants can be attributed to involvement in these programs. The authors recommend ways to improve the quality and interpretability of enrichment program evaluations. Evaluators should adopt common terminology for activities and outcomes. Participants' economic and educational disadvantages should be described. Programs' theoretical underpinnings should be identified and related to evaluation. Measures should include immediate effects as well as long-term outcomes. Where possible, data from comparison groups should be reported to support conclusions. Adequate funding needs to be available to design and complete reasonable evaluations.