Recent Publications by CFE Educators

Intraplantar injection of dilute formalin evokes brief (Phase 1) and persistent (Phase 2) increases in primary afferent activity, pain behavior, and cardiovascular responses, and induces spinal cord Fos-like immunoreactivity (Fos-LI). Although previous studies demonstrated that the destruction of small diameter primary afferents with neonatal capsaicin treatment decrease formalin-evoked nociception, these studies only evaluated behavioral responses, and did not distinguish between Phase 1 and 2. To address these questions, we simultaneously evaluated formalin-evoked pain behavior (flinching of the afflicted paw), cardiovascular responses (heart rate and mean arterial pressure), and lumbar spinal cord Fos expression in control rats and in rats treated with capsaicin (100 mg/kg) one day postpartum. We found that neonatal capsaicin-treated rats, compared to controls, exhibited similar cardiovascular responses and slightly less flinching behavior during Phase 1. During Phase 2, however, capsaicin-treated rats exhibited 59% less flinching and 45% smaller heart rate responses. Also, in capsaicin-treated rats, we counted 59% fewer Fos-labeled neurons in the spinal cord. These results indicate that capsaicin-sensitive afferents contribute to formalin-evoked behavioral and cardiovascular responses and to spinal cord neuronal responses. The differential effect of neonatal capsaicin on nociception during Phase 1 and Phase 2 suggests that sensitization mechanisms during Phase 1 do not contribute to the magnitude of nociceptive responses during Phase 2.

Severe or prolonged tissue or nerve injury can induce hyperexcitability of dorsal horn neurons of the spinal cord, resulting in persistent pain, an exacerbated response to noxious stimuli (hyperalgesia), and a lowered pain threshold (allodynia). These changes are mediated by NMDA (N-methyl-D-aspartate)-type glutamate receptors in the spinal cord. Here we report that activation of the NMDA receptor causes release of substance P, a peptide neurotransmitter made by small-diameter, primary, sensory 'pain' fibres. Injection of NMDA in the cerebrospinal fluid of the rat spinal cord mimicked the changes that occur with persistent injury, and produced not only pain, but also a large-scale internalization of the substance P receptor into dorsal horn neurons, as well as structural changes in their dendrites. Both the pain and the morphological changes produced by NMDA were significantly reduced by substance P-receptor antagonists or by elimination of substance P-containing primary afferent fibres with the neurotoxin capsaicin. We suggest that presynaptic NMDA receptors located on the terminals of small-diameter pain fibres facilitate and prolong the transmission of nociceptive messages, through the release of substance P and glutamate. Therapies directed at the presynaptic NMDA receptor could therefore ameliorate injury-evoked persistent pain states.

Substance P is involved in cardiovascular control at the spinal cord level, where it acts through neurokinin-1 receptors. In this study we used immunocytochemistry and retrograde tracing to investigate the presence of the neurokinin-1 receptor and its ultrastructural localization in rat sympathetic preganglionic neurons that project to the superior cervical ganglion or the adrenal medulla. Immunofluorescence for the neurokinin-1 receptor outlined the somatic and dendritic surfaces of neurons in autonomic subnuclei of spinal cord segments T1-T12, whereas immunofluorescence for the tracer, cholera toxin B subunit, filled retrogradely labelled cells. There was a significant difference in the proportion of neurokinin-1 receptor-immunoreactive sympathetic preganglionic neurons supplying the superior cervical ganglion and the adrenal medulla. Thirty-eight percent of the neurons that projected to the superior cervical ganglion were immunoreactive for the neurokinin-1 receptor compared to 70% of neurons innervating the adrenal medulla. Of neurons projecting to the superior cervical ganglion, significantly different proportions showed neurokinin-1 receptor immunoreactivity in spinal cord segment T1 (15%) versus segments T2 T6 (45%). At the ultrastructural level, neurokinin-1 receptor staining occurred predominantly on the inner leaflets of the plasma membranes of retrogradely labelled sympathetic preganglionic neurons. Deposits of intracellular label were often observed in dendrites and in the rough endoplasmic reticulum and Golgi apparatus of cell bodies. Neurokinin-1 receptor immunoreactivity was present at many, but not all, synapses as well as at non-synaptic sites, and occurred at synapses with substance P-positive as well as substance P-negative nerve fibres. Only 37% of the substance P synapses occurred on neurokinin-1-immunoreactive neurons in the intermediolateral cell column. These results show that presence of the neurokinin-1 receptor in sympathetic preganglionic neurons is related to their target. The ultrastructural localization of the receptor suggests that sympathetic preganglionic neurons may be affected (i) by substance P released at neurokinin-1 receptor-immunoreactive synapses, (ii) by other tachykinins (e.g., neurokinin A), which co-localize in substance P fibres in the intermediolateral cell column, acting through other neurokinin receptors, and (iii) by substance P that diffuses to neurokinin-1 receptors from distant sites.

BACKGROUND AND OBJECTIVES

Based on prior research and current public policy needs, this article identifies five areas that should receive priority in future research on faculty development: 1) To conduct research, greater clarity is needed about the components, competencies, and strategies of faculty development. 2) A stronger link needs to be created between assessment and outcomes of faculty development programs. 3) As faculty roles and career paths change, greater understanding of the nature of professional development is needed. Strategies for promoting teaching, research, and leadership skills require further study. 4) Organizational culture and structure require greater description and illumination as contributors to organizational vitality. 5) Information and instructional technology offer new opportunities for faculty development, but research is needed to determine appropriate uses. Since research takes place in a broader context of societal needs and resources, we conclude with public policy recommendations. We strongly recommend that government, foundations, and universities work together to support fundamental research on faculty development.

Gold-induced pulmonary disease is difficult to diagnose, especially, in the case in which interstitial pneumonia appears in the course of gold therapy for rheumatoid arthritis. We analyzed the literature to define the clinical features and prognosis of gold-induced pulmonary disease, and to identify those features that distinguish gold-induced pulmonary disease from pulmonary disease secondary to the underlying disease process of rheumatoid arthritis. Relevant articles from the medical literature were identified using a Mediline search, and the bibliographies of the articles were retrieved. These works were critically reviewed for information on the clinical, physiologic, radiographic, pathologic, and bronchoalveolar lavage (BAL) findings. A total of 140 cases of gold-induced pulmonary disease were identified from 110 reports. In 81% of the patients, gold was being used to treat rheumatoid arthritis, bronchial asthma (6%), pemphigus (5%), or other processes (9%). Side effects other than pulmonary toxicity were common, and included skin rash (38%), peripheral eosinophilia (38%), liver dysfunction (15%), and proteinuria (22%). Only the presence of pemphigus or liver dysfunction correlated with a bad prognosis. Gold-induced pulmonary disease most often followed improvement in rheumatoid arthritis, presumably induced by gold therapy. BAL lymphocytosis and computed tomography (CT) scan findings are useful in making a diagnosis of gold-induced pulmonary disease in an appropriate clinical setting. Features that distinguish gold-induced pulmonary disease from rheumatoid lung disease include female predominance, presence of fever or skin rash, absence of subcutaneous nodules or finger clubbing, low titers of rheumatoid factor at onset of lung disease, lymphocytosis in bronchoalveolar lavage fluid (BALF), and alveolar opacities along the bronchovascular bundles on chest CT scan. Gold-induced lung disease is a distinct entity that can be distinguished from rheumatoid lung disease. It usually improves with cessation of therapy or treatment with corticosteriods.

Diffuse alveolar hemorrhage (DAH) resulting from pulmonary capillaritis typically accompanies the systemic vasculitides and collagen vascular diseases. Isolated pulmonary capillaritis and DAH without systemic disease occurs in patients with antineutrophil cytoplasmic antibodies. However, isolated pulmonary capillaritis and DAH is not described for patients without clinical or serologic evidence for an underlying systemic disease. To describe such patients, we undertook a retrospective chart review of 29 patients with DAH and biopsy-proven pulmonary capillaritis from seven Denver hospitals. Eight (28%) were diagnosed with isolated pulmonary capillaritis without clinical, serologic, or histologic evidence of an associated illness. Their median age was 30 yr. No association with occupational or drug exposures was identified. All had lower respiratory tract symptoms; seven had upper respiratory tract symptoms. None demonstrated systemic disease or evidence of glomerulonephritis. All were antineutrophil cytoplasmic antibody negative. Other serologies were not significant where measured. Direct immunofluorescence studies of lung tissue were negative in five. Six presented with acute respiratory failure, four requiring mechanical ventilation. One died during initial hospitalization; seven survived. Median follow-up is 43 mo (7 to 73 mo). Five remain in remission. Two experienced multiple recurrences of DAH but without development of systemic disease while on therapy. Herein we characterize DAH and isolated pulmonary capillaritis in the absence of clinical, serologic, or histologic evidence indicating an accompanying systemic illness. The prognosis for this group appears favorable.

The pontomedullary raphe magnus (RM) contains two physiologically defined types of neurons that participate in the opioid-induced modulation of dorsal horn nociceptive messages: OFF cells, which decrease, and ON cells, which increase their discharge rates when reflex behavior is evoked by noxious pinch or heat. Because both types of neuron have inhibitory inputs and because there is evidence that gamma-aminobutyric acid (GABA) inhibitory mechanisms within RM contribute to the antinociceptive action of opioids, we have sought anatomical evidence for a direct GABAergic input to OFF and ON cells. In this study, cells of each type located in the RM were electrophysiologically defined and intracellularly filled with horseradish peroxidase or Neurobiotin. One cell of each type was labeled in the cat, and 2-3 cells of each type were labeled in the rat. Thin sections were labeled by a postembedding immunogold procedure by using an antibody directed against glutaraldehyde-conjugated GABA. GABA-immunoreactive (GABA-ir) boutons contained small, round, clear vesicles and made symmetrical synapses with identified dendrites. GABA-ir boutons were apposed to soma and to proximal and distal dendrites of both cell types in both species. These findings demonstrate direct GABAergic input to identified OFF and ON cells in the RM. J. Comp. Neurol. 378:196-204, 1997.