Recent Publications by CFE Educators

Insulin-like growth factor-I (IGF-I) has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) through its ability to stimulate fibroblast proliferation and collagen synthesis. However, although alveolar macrophages (AM) have been shown to express this growth factor, it is likely to also have other cellular sources. We sought to determine the distribution of cells expressing IGF-I in lung tissues obtained from 10 patients with IPF and 10 control subjects. We evaluated the levels of IGF-I and of a macrophage/monocyte-specific marker, CD68, by immunocytochemistry and quantified by morphometry. In control subjects, IGF-I was localized principally to AM. In contrast, in IPF patients IGF-I was localized to AM, interstitial macrophages, alveolar epithelial cells, and ciliated columnar epithelial cells. The normalized volume density (Vv) of IGF-I-positive (IGF-I+) interstitial macrophages (Vv of IGF-I+ interstitial macrophages/Vv of lung x 100) was increased in patients with IPF as compared with control subjects, and the ratio of Vv of IGF-I+ to CD68(+) interstitial macrophages correlated with: (1) the degree of clinical impairment in patients with IPF as measured by their clinical-radiologic-physiologic (CRP) score; and (2) the degree of collagen deposition in the interstitium. These findings support a role for interstitial macrophages as a source of IGF-I in IPF.

Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells (IDHPNC) is a clinicopathological entity characterized by a diffuse hyperplasia of neuroendocrine cells involving distal bronchi and bronchioles. The pathogenesis of this syndrome remains unknown. The hyperplastic neuroendocrine (NE) cells contain multiple neuropeptides, including the bombesinlike peptides (BLP), which are likely important in the pathogenesis of the disorder by stimulating proliferation of fibroblasts in a paracrine fashion and the NE cells themselves in an autocrine manner. Neutral endopeptidase (NEP) is a cell-surface enzyme that hydrolyzes BLP and other bioactive peptides. Low or undetectable NEP is present in many primary lung cancers and cell lines. Low NEP expression could increase neuropeptide-induced autocrine effects by increasing local levels of neuropeptides. We hypothesized that IDHPNC was associated with low or absent NEP expression. NEP expression was assayed in patients with IDHPNC (n = 3) and was compared with expression in patients with idiopathic pulmonary fibrosis (n = 5), hypersensitivity pneumonitis (n = 5), and normal lung (n = 4) using immunohistochemistry, ELISA, activity assay, and Western blot analysis. By these assays, NEP expression was highest in lungs affected by IDHPNC. NEP mRNA, as assessed in IDHPNC lung tissue by RT-PCR, was the expected size and free of mutation between bp 238-2437. Therefore, IDHPNC is unlikely to be the result of a defect in NEP expression. The apparent increase in NEP expression in lung tissue from patients with IDHPNC may reflect a compensatory increase that partly counteracts abundant neuropeptides, including BLP, present in this disorder.

Coronary artery disease kills more women than all cancers combined, yet the clinical picture in women is different enough from men that the diagnosis can be missed or delayed. A cardiologist highlights these gender-based differences and explains why certain diagnostic tests are better than others at identifying CAD in women. Coronary artery disease (CAD) is the leading killer of women in the US. After menopause, mortality rates from CAD in women nearly equal those of men. Yet the clinical picture in women is different enough from that in men that it can obscure the correct diagnosis. Women are 10 years older than men, on average, when presenting with CAD, possibly due to delayed diagnosis or presentation. Differences in symptomatology between men and women are important to note. For example, other diseases, such as arthritis or osteoporosis, can obscure CAD symptoms. Further, compared with men, women's chest pain is more often associated with abdominal pain, dyspnea, nausea, and fatigue. More women than men with CAD have diabetes, hypertension, hypercholesterolemia, and a family history of CAD. Clinicians need to know how to assess the gender-specific pretest likelihood of CAD in women, starting with a careful review of the patient's chest pain history. Other risk factors, including smoking, abdominal obesity, and certain comorbidities, should be taken into consideration. The diagnostic accuracy of exercise testing is slightly lower for women than men. Certain diagnostic tests, particularly exercise echocardiography and exercise thallium/sestamibi testing, offer more prognostic information than traditional exercise electrocardiographic studies without imaging. Mortality associated with interventional procedures--such as angioplasty and coronary artery bypass grafting (CABG)--is slightly higher in women, although long-term survival rates are similar for both sexes. Detection of CAD at an earlier stage in women may result in earlier referrals for CABG, with the benefit of lower associated mortality rates.

Transection of the sciatic nerve leads to sprouting of sympathetic efferent, noradrenergic axons and terminals around large cell bodies in the dorsal root ganglion. Here we examined whether injury to unmyelinated afferents contributes to the sprouting. Neonatal treatment with the C-fiber neurotoxin capsaicin increased sprouting after nerve injury. We conclude that injury to large, rather than small diameter fibers, triggers the sprouting of sympathetic efferents after nerve injury.

Capsaicin, the main pungent ingredient in "hot" chili peppers, elicits buming pain by activating specific (vanilloid) receptors on sensory nerve endings. The cloned vanilloid receptor (VR1) is a cation channel that is also activated by noxious heat. Here, analysis of heat-evoked single channel currents in excised membrane patches suggests that heat gates VR1 directly. We also show that protons decrease the temperature threshold for VR1 activation such that even moderately acidic conditions (pH or = 5.9) activate VR1 at room temperature. VR1 can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit pain. Immunocytochemical analysis indicates that the receptor is located in a neurochemically heterogeneous population of small diameter primary afferent fibers. A role for VR1 in injury-induced hypersensitivity at the level of the sensory neuron is presented.

Tissue or nerve injury can dramatically alter the transmission of sensory stimuli by spinal cord neurons, so that a light touch produces pain. The discovery that peptide products of prepronociceptin processing either facilitate or inhibit these mechanisms suggests novel approaches to treating these conditions.

Efforts to redesign education in ambulatory settings are hampered by a lack of rigorous and coherent research on the learning process in these settings and the desired outcomes of the educational experiences. The authors present 13 priority research topics and 51 important research questions concerning education in ambulatory settings that were defined by a distinguished group of medical educators, clinicians, and policymakers who attended an invitational conference on education in ambulatory settings in 1996. The need to establish valid and reliable measures of quality and outcomes of educational programs and instructional interventions stood out as the major prerequisite for conducting research on education in ambulatory settings. Issues of theory building, research priorities, and research design are discussed, and policy recommendations are made for the development of valid measures of educational outcomes. The creation of a "Medical Education Outcomes Commission" is proposed to act as a repository for measures and instruments, and to provide the field with mechanism to validate instruments and uniform recommendations to conduct studies of quality. The authors urge funding agencies with missions that support medical education to invest in basic research on the outcomes of education in ambulatory settings.