Expansion of atherosclerotic abdominal aortic aneurysm (AAA) has been attributed to remodeling of the extracellular matrix by active proteolysis. We used in situ hybridization to analyze the expression of fibrinolytic genes in aneurysm wall from eight AAA patients. All specimens exhibited specific areas of inflammatory infiltrates with macrophagelike cells expressing urokinase-type plasminogen activator (u-PA) and tissue-type PA (t-PA) mRNA. Type 1 PA inhibitor (PAM-) mRNA was expressed at the base of the necrotic atheroma of all specimens and also within some of the inflammatory infiltrates where it frequently colocalized in regions contining u-PA and t-PA mRNA expressing cells.However, in these areas, the cellular distribution of the transcripts for t-PA and u-PA extended far beyond the areas of PAT-i expression. These observations suggest a local ongoing proteolytic process, one which is only partially counteracted by the more restricted expression of PAT-i mRNA. An abundance of capillaries was also obvious in all inflammatory infiltrates and may reflect local angiogenesis in response to active pericellular fibrinolysis. The increased fibrinolytic capacity in AAA wall may promote angiogenesis and contribute to local proteolytic degradation of the aortic wall leading to physical weakening and active expansion of the aneurysm. (J. Clin. Invest. 1995. 96:639-645.)

Thirty-four cardiac patients, treated with nifedipine (Adalat, Procardia) during a period of 1 year or more, developed slight to severe gingival epithelial hyperplasia, and five cases presented nodular overgrowth of the gingiva. In terms of histopathologic and clinical morphology, nifedipine-induced gingival hyperplasia is similar to that known to be caused by phenytoin (Dilantin). Both drugs have the ability to alter calcium metabolism. We believe that the hyperplastic condition is related to calcium imbalance.

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Kaposi's sarcoma of the gingiva and skin developed in an HIV-negative renal transplant patient while he was receiving cyclosporine therapy. The Kaposi's sarcoma developed shortly after the patient had an acute infection with cytomegalovirus (CMV). Electron microscopy of the tumor's established cell line showed two types of virus-like particles. CMV DNA was identifiable in the cell line whereas infectious CMV could be isolated only after repeated passages (only after 3 months of culture). The other virus could not be identified, but did not appear to be either HIV or papilloma virus. The patient's tumor regressed after the discontinuation of cyclosporine therapy and the recovery from the acute CMV infection.

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BackgroundUnstable carotid plaques cause cerebral emboli. Leptin promotes atherosclerosis and vessel wall remodeling. We hypothesized that carotid atherosclerotic lesion instability is associated with local leptin synthesis.Methods and ResultsCarotid endarterectomy plaques from symptomatic (n=40) and asymptomatic patients with progressive stenosis (n=38) were analyzed for local expression of leptin, tumor necrosis factor (TNF)-α, and plasminogen activator inhibitor type 1. All lesions exhibited advanced atherosclerosis inclusive of thick- and thin-cap fibroatheromas or lesion rupture. Symptomatic lesions exhibited more plaque ruptures and macrophage infiltration (P=0.001 and P=0.05, respectively). Symptomatic plaques showed preferential leptin, TNF-α, and plasminogen activator inhibitor type 1 transcript (P=0.03, P=0.04, and P=0.05, respectively). Leptin mRNA and antigen in macrophages and smooth muscle cells were confirmed by in situ hybridization and immunohistochemistry. Plasma leptin levels were not significantly different between groups (P=1.0), whereas TNF-α was significantly increased in symptomatic patients (P=0.006). Human aortic smooth muscle cell culture stimulated by TNF-α, lipopolysaccharide, or lipoteichoic acid revealed 6-, 6.7-, and 6-fold increased secreted leptin antigen, respectively, at 72 hours (P<0.05).ConclusionsNeurologically symptomatic patients overexpress leptin mRNA and synthesize leptin protein in carotid plaque macrophages and smooth muscle cells. Local leptin induction, presumably by TNF-α, could exert paracrine or autocrine effects, thereby contributing to the pathogenesis of lesion instability.Clinical Trial RegistrationURL: www.Clinicaltrials.gov. Unique identifier: NCT00449306.

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The pharmacokinetics of theophylline were studied in 6 healthy volunteers at rest, during light and moderate exercise and during exercise in a hot environment. Exercise was performed between 2 and 4 h after oral ingestion of theophylline in solution at a dose of 200 mg/m² body surface. Significant prolongations of the half-life (t_½) of the drug and reductions in its body clearance were observed during exercise to 30% of VO_{2 max} both at 22 and 40 °C, as well as during exercise to 50% of VO_{2, max} at 22 °C. t_½ was (mean ± SEM) 8.5 ± 0.8, 8.0 ± 1.0 and 7.2 ± 1.0 h at the three exercise sessions, respectively, compared with 6.4 ± 0.9 h at rest. Plasma clearances at the three exercise sessions were 0.70 ± 0.09, 0.62 ± 0.1 and 0.75 ± 0.09 ml/min/kg, respectively, compared with 0.99 ± 0.13 ml/min/kg at rest. The apparent volumes of drug distribution (V_d) decreased significantly at the 50% and the 30% exercise in the heat, suggestive of some dehydration. The areas under the concentration-time curves (AUC_0-∞) and the elimination rate constants (K_el) also changed significantly under the different experimental conditions. It is suggested that appropriate dose adjustments may have to be made in moderately active patients who are treated with theophylline.