Recent Publications by CFE Educators

An expanding knowledge of neuropeptides and their function has led to a profound change in our view of how the PAN contributes to pain. In addition to their expected direct action on postsynaptic cells in the dorsal horn, neuropeptides can modify transmitter release from nearby terminals of other PANs and/or diffuse to act on dorsal horn neurons at a considerable distance from their site of release (Fig. 2). Contrary to early expectations and despite the evidence that several neuropeptides excite central nociceptive neurons, there is no clear correspondence between neuropeptide content and physiologically defined classes of small-diameter primary afferents. There is, however, a tendency for populations of afferents innervating different organs to differ consistently in their peptide content. In fact, the peptide content of primary afferents is, in part, determined by specific factors in the tissues that they innervate. Furthermore, peptide content can change dramatically in response to certain prolonged stimuli or nerve damage. The lack of correspondence of peptide content and physiological response pattern, the plasticity of peptide content, its tissue specificity, and the possibility for action at a distance from the site of their release from central PAN terminals strongly suggest that PAN peptides have functions that are fundamentally different from those of the short-range actions of amino acid neurotransmitters that are also found in the PAN. Finally, nowhere is the plasticity of function of the PAN more evident than at its peripheral terminals. Long-term changes are produced in these terminals by a host of peptides that derive from a variety of cell types. The complexity of this transduction process is augmented by the activity-induced release of peripherally active neuropeptides from the PAN itself. In addition to the variety of fundamental neurobiological issues that recent studies of PANs have raised, they have also generated a great deal of clinical interest, in view of the role of the PAN in inflammation and its accessibility for study and for therapeutic intervention.

Over the past decade, the evaluation of teaching has increased in importance in US medical schools. In this review, research on student ratings, teaching portfolios, and peer review of teaching is presented in the context of instructional scholarship. Five principles for designing a comprehensive system to evaluate teaching are discussed, along with the impact of such systems on teaching improvement and academic promotions.

Recent evidence suggests that left atrial (LA) appendage velocities may provide clues to the thrombogenic potential of this structure. Pulsed Doppler evaluation of LA appendage flow during transesophageal echocardiography was performed in 109 patients to evaluate the effects of rhythm, mitral regurgitation, and spontaneous contrast. During sinus rhythm, there was a forward LA appendage contraction wave of 46 +/- 18 cm/sec followed by a retrograde filling wave of 46 +/- 17 cm/sec. In 40% of the patients in sinus rhythm, additional forward and retrograde velocities of 23 +/- 10 and 22 +/- 11 cm/sec, respectively, were seen. In contrast, atrial fibrillation was associated with reduced forward and retrograde flows in an irregularly irregular pattern. In sinus rhythm moderate to severe mitral regurgitation did not appear to affect the LA appendage velocities. Last, although forward LA appendage velocities were found to be significantly reduced in patients with spontaneous contrast by univariate analysis, multivariate analysis demonstrated that only the presence of atrial fibrillation was a significant predictor for spontaneous contrast.

Recent studies have demonstrated an important contribution of the A5 noradrenergic cell group of the rostral medulla in the regulation of nociceptive messages at the level of the spinal cord. These noradrenergic controls parallel those arising from the serotonin-containing neurons of the nucleus raphe magnus. In the present study, we used postembedding immunogold staining to identify GABA-immunoreactive terminals that synapse upon identified spinally projecting noradrenergic neurons of the A5 cell group in the rat. A5 projection neurons were identified by Fluoro-Gold transport from the spinal cord; sections containing retrogradely labelled cells were then immunoreacted for tyrosine hydroxylase (TH) to identify the catecholamine-containing, presumed noradrenergic, neurons. Double-labelled A5 cells were intracellularly filled with Lucifer Yellow (LY) and then the LY was photo-oxidized to an electron-dense product. Seven intracellularly filled TH-immunoreactive projection neurons were studied with postembedding immunocytochemistry. Each A5 neuron received a significant GABA-immunoreactive terminal input. Out of a pooled total of 151 terminal profiles found in apposition to intracellularly labelled somatic and dendritic profiles, 31 (20.5%) were GABA-immunoreactive. The proportion of GABA-immunoreactive terminals that contacted somatic profiles (12/72; 17%) was similar to the proportion that contacted TH-labelled dendritic profiles (19/79; 24%). There was a discernible synaptic specialization in about 50% of the labelled terminals that contacted the TH projection neuron. Both symmetric and asymmetric synaptic specializations were found. Labelled terminals contained round or pleiomorphic vesicles, but not flat vesicles; many also contained dense-core vesicles. Our results indicate that noradrenergic neurons of the A5 cell group, which contribute to both antinociceptive and cardiovascular controls through their projection to the spinal cord, are regulated by local GABAergic, presumably inhibitory, mechanisms. Whether the initiation of A5 neuron activity results from a lifting of tonic GABAergic inhibitory control, as has been proposed for the neurons of the nucleus raphe magnus, remains to be determined.

BACKGROUND

Although angiotensin converting enzyme (ACE) inhibitors have been reported to increase coronary blood flow, the effect of selective angiotensin II (AT1)-receptor antagonism on the coronary circulation has not been defined.

METHODS AND RESULTS

We examined the effects of the AT1-receptor antagonist Losartan (DuP 753, 0.2-3.2 mg/kg) on coronary arteries in vivo in 11 dogs, using a combination of intravascular two-dimensional and Doppler ultrasound. In six dogs, a 30-MHz, 4.3F ultrasound imaging catheter was placed in the midsegment of the circumflex coronary artery to measure cross-sectional area (CSA), and a 0.018-in. Doppler wire was placed alongside to measure coronary flow velocity. At peak effect (1.6 mg/kg), Losartan increased mean coronary CSA from 7.9 +/- 0.5 to 9.5 +/- 0.8 mm2 and average peak velocity (APV) from 32 +/- 10 to 56 +/- 18 cm/sec, resulting in an increase in coronary blood flow from 74 +/- 19 to 151 +/- 36 mL/min. The maximal effect of the ACE inhibitor enalaprilat (5 mg) was an increase in CSA from 7.7 +/- 0.7 to 8.4 +/- 0.8 mm2 and an increase in APV from 36 +/- 10 to 53 +/- 20 cm/sec, with an increase in coronary blood flow from 82 +/- 25 to 122 +/- 41 mL/min. Relative to maximal hyperemia with adenosine (6 mg i.c.), the magnitude of flow increase from baseline was 0.37 with the AT1-receptor antagonist and 0.19 with the ACE inhibitor (p 0.05). These effects were seen without changes in heart rate or systemic arterial pressure. In an additional five dogs, the ultrasound imaging catheter was introduced directly over a 0.014-in. Doppler wire, and the effects of indomethacin, propranolol, and N omega-nitro-L-arginine methylester (L-NAME) on the vasodilator effect of Losartan (1.6 mg/kg) were examined. Indomethacin and propranolol had no effect on Losartan-induced vasodilation, suggesting that it was not mediated via prostaglandins or beta-adrenoceptors. However, Losartan-induced epicardial vasodilation was partially inhibited by L-NAME, suggesting an action partly dependent on endothelial release of nitric oxide.

CONCLUSIONS

Thus, these acute studies in anesthetized dogs suggest that inhibition of AT1-receptors in the coronary circulation results in vasodilator responses greater in magnitude than ACE inhibition and partly endothelium dependent. The exact role for AT1-receptors in human coronary physiology and pathology remains to be defined.

In the present experiments, we studied the effect of i.t. nicotine on synovial bradykinin-induced plasma extravasation (BK-PE), assessed by measurement of extravasation of Evan's blue dye into the rat knee joint. We report that in normal rats, i.t. nicotine dose-dependently inhibited BK-PE; the dose required was 100 times greater than the effective s.c. dose. In adrenal medullectomized rats, i.t. nicotine inhibited BK-PE at doses 10(6) times smaller than in rats with intact adrenal medullae. A similar leftward shift in the i.t. nicotine dose-response curve was seen in normal rats after blocking peripheral nicotinic receptors by hexamethonium or after bilateral denervation of the adrenal medulla. Intra-articular infusion of the knee joint in normal rats with knee joint perfusate collected from donor rats that had received i.t. nicotine decreased BK-PE significantly. Denervation of the sciatic nerves in the donor rat did not affect this action of i.t. nicotine. Perfusate collected from adrenal medullectomized donor rats that had received i.t. nicotine resulted in a greater decrease of BK-PE compared to the decrease produced by perfusate from normal donor rats that received i.t. nicotine. Intra-articular pretreatment of recipient rats with different receptor antagonists [phentolamine (alpha adrenoceptors), ICI-118,551 (beta 2 adrenoceptors), methysergide (serotoninergic S1/2 receptors) or naloxone (opioid receptors)] did not affect the BK-PE response produced by this perfusate. Nicotine, when administered i.t., can inhibit synovial BK-PE, but this effect is expressed only at high doses in the presence of an intact adrenal medulla.(ABSTRACT TRUNCATED AT 250 WORDS)

Polymorphonuclear leukocytes (PMN) contribute to epithelial injury at sites of inflammation, but their mechanisms of action are incompletely understood. PMN can injure target tissues by oxidative and nonoxidative mechanisms. Included in the nonoxidative mechanisms are defensins (DEF), small (3.5 to 4.0 kD), arginine- and cysteine-rich polypeptides. DEF are bactericidal, fungicidal, viricidal, and tumoricidal, but their ability to contribute to inflammatory injury has not been extensively evaluated. One marker of inflammatory injury is disrupted epithelial barrier integrity. Using Madin-Darby canine kidney (MDCK) epithelial monolayers, we measured the effect of both human and rabbit DEF on barrier integrity using mannitol permeability (Pmann) and transepithelial electrical resistance (Rt). Human DEF (HNP1-3, 2:2:1 molar ratio) increased Pmann in a time- and concentration-dependent manner and Rt fell progressively over a 48-h period after exposure of monolayers to HNP1-3. Rabbit DEF peptide 1 (NP-1) also increased Pmann, but rabbit peptide 5 (NP-5) had no effect on Pmann. To investigate the role of charge, HNP1-3 was added to the monolayers with the polyanions heparin or sulfated dextran. Heparin and sulfated dextran only partially inhibited the increase in Pmann. Fetal bovine serum (FBS), however, completely inhibited the effect of HNP1-3, but this protection was only partially explained by the anionic protein, albumin. The FBS protection was time dependent and was present when FBS was added up to 16 h after exposure to HNP1-3. While both HNP1-3 and NP-1 increased epithelial permeability, neither were cytolytic to MDCK cells as measured by lactate dehydrogenase release.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVES

The aim of this study was to test the hypothesis that atherosclerotic plaque in the thoracic aorta detected by transesophageal echocardiography is a marker for coronary artery disease.

BACKGROUND

Previous pathologic and roentgenographic studies have suggested a relation between aortic plaque and coronary artery disease but have lacked clinical utility.

METHODS

We performed transesophageal echocardiography on 61 patients (30 women and 31 men aged 22 to 83 years [mean 60 +/- 14]) who had previously undergone cardiac catheterization with coronary angiography. The clinical indications for angiography were angina (n = 26), valvular heart disease (n = 17), positive noninvasive evaluation for ischemia without angina (n = 6), postmyocardial infarction (n = 5), familial hypercholesterolemia (n = 4), coronary cameral fistula (n = 1), atrial myxoma (n = 1) and suspected aortic dissection (n = 1). All patients underwent transesophageal echocardiography with imaging of the thoracic aorta. The criteria used to diagnose atherosclerotic plaque on transesophageal echocardiography were the presence of linear or focal increased echo-density with lumen irregularity and thickening or calcification of the aortic intima.

RESULTS

In 41 of the 61 patients, obstructive coronary artery disease was detected by angiography in at least one vessel (> 50% left main coronary artery stenosis or > 70% stenosis in the left anterior descending, right coronary or left circumflex artery distribution). In 37 of the 41, atherosclerotic plaque was detected in the thoracic aorta by transesophageal echocardiography. Twenty of the 61 patients had normal coronary angiographic findings or nonobstructive lumen irregularities. In 2 of these 20 patients, plaque was detected in the thoracic aorta on transesophageal echocardiography. The presence of aortic plaque on transesophageal study had a sensitivity of 90% and a specificity of 90% for angiographically proved obstructive coronary artery disease. The positive predictive value of aortic plaque for obstructive coronary artery disease was 95% and the negative predictive value was 82%.

CONCLUSIONS

The detection of atherosclerotic plaque in the thoracic aorta by transesophageal echocardiography appears to be a marker for the identification of obstructive coronary artery disease and deserves further investigation.

Sarcoidosis is a multisystem disease of unknown etiology characterized by the presence of noncaseating granulomas in involved tissues. To investigate a potential role for gamma/delta T cells in the pathogenesis of pulmonary sarcoidosis, we studied lung and blood T cells from patients for preferential expression of particular gamma/delta T cell receptors. An abnormally high percentage of gamma/delta cells was found in the blood of some patients. However, the increased percentage did not reflect an increase in absolute number, and appeared to be secondary to a decrease in T cells expressing alpha/beta receptors. Furthermore, as in normals, the circulating gamma/delta cells in patients predominantly expressed V gamma 9/V delta 2 receptors, a subset that was not enriched at the site of disease. In contrast, in the lung, an increased percentage of gamma/delta cells expressing V delta 1 was found in a subset of patients. Importantly, these cells demonstrated evidence of prior activation by selectively expanding in vitro in the presence of interleukin 2. Furthermore, an analysis of junctional region sequences revealed their clonal nature. These clonal expansions of V delta 1+ cells in pulmonary sarcoidosis provide evidence for a disease process that involves specific recognition of a local antigen by T cells, and contributes new information regarding the nature of the as yet undefined antigenic stimulus.