Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice.

Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA-binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1ß and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein-protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.

Detection of abnormal left ventricular wall movement during isovolumic contraction and early relaxation. Comparison of echo- and angiocardiography.

Abnormal left ventricular wall movement during isovolumic contraction and early relaxation was assessed from simultaneous apex and echocardiograms in 50 patients with ischaemic heart disease, and compared with estimates from the corresponding digitised left ventriculograms. During isovolumic contraction, a normal angiogram was accompanied by normal apex-dimension relations in 13 out of 14 cases. In 19 cases, there was angiographic evidence of discrete outward wall movement during isovolumic contraction which was associated with abnormal apex-dimension relations in 15. During isovolumic relaxation, of 14 cases who were normal angiographically, apex-dimension relations were normal also in 11, which in 36 patients with abnormal wall movement on angiogram, apex-dimension relations were abnormal in 30. Correlation was less good between echocardiographic and angiographic estimates of left ventricular minor dimension (r = 0.75), and was absent between those of peak rates of dimension change during systole and diastole. Asynchronous onset of inward wall movement and the distribution of regional abnormalities of overall wall movement amplitude were unrelated to apex-dimension relations. The apex-dimension relation is thus a sensitive and specific means of detecting abnormalities of left ventricular wall movement during isovolumic contraction and early relaxation, unaffected by other manifestation

Regional abnormalities of left ventricular wall movement during isovolumic relaxation in patients with ischemic heart disease.

In order to study events during isovolumic relaxation, left ventricular angiograms of 120 patients with ischemic heart disease were digitized frame by frame, and compared with those of 15 normal subjects. In patients with ischemic heart disease, abnormal inward movement of endocardium occurred in areas supplied by narrowed coronary arteries. When these involved the free wall, they were due to abnormal wall thickening rather than to inward movement of epicardium. Since the volume of the ventricle was constant, they were accompanied by compensatory outward movement of endocardium elsewhere, due to premature thinning. Identical abnormalities were demonstrated in 80 patients by M-mode echocardiography, and in individual patients, agreement with angiography was good. These abnormalities were aggravated by TNT administration, and were unaffected by isometric stress. In approximately half, they were associated with abnormalities of isovolumic contraction. They appear to represent the behavior of regions of the left ventricle with partial loss of function due to previous ischemic injury.