Potentiation of the vasospastic response to angioplasty by pretreatment with fluoxetine. A study in the atherosclerotic rabbit.

There is evidence that angioplasty-induced vasospasm is mediated by serotonin (5-hydroxytryptamine [5-HT]) release from platelets. We tested the hypothesis that pretreatment of the atherosclerotic rabbit with fluoxetine, a platelet-uptake inhibitor of 5-HT, would reduce vasospasm after balloon angioplasty. Short-term administration of fluoxetine reduced platelet 5-HT uptake to 4% of baseline. Daily administration of fluoxetine for 7 days reduced whole-blood 5-HT levels to 28% of baseline. Thus, fluoxetine inhibited platelet 5-HT uptake in this model as predicted. Contrary to our expectations and despite the substantial reduction in whole-blood 5-HT levels, pretreatment with fluoxetine for 1 week resulted in augmentation of angioplasty-induced vasospasm in atherosclerotic rabbits. Intraperitoneal administration of fluoxetine produced vasoconstriction in normal rabbits that was augmented by 5-HT and not reversed with LY53857, a specific serotonin receptor antagonist. We postulate that this new observation is probably a result of the inhibition of the clearance mechanism for serotonin, with resultant enhancement of the effect of serotonin released by the activated platelets that are deposited on the vessel wall surface at the time of angioplasty. A direct effect of fluoxetine on serotonergic receptors is a second possible mechanism for the observed effect.

Reproducibility of quantitative planar thallium-201 scintigraphy: quantitative criteria for reversibility of myocardial perfusion defects.

Fifty-two paired stress/delayed planar 201TI studies (27 exercise studies, 25 dipyridamole studies) were processed twice by seven technologists to assess inter- and intraobserver variability. The reproducibility was inversely related to the size of 201TI perfusion abnormalities. Intraobserver variability was not different between exercise and dipyridamole studies for lesions of similar size. Based upon intraobserver variability, objective quantitative criteria for reversibility of perfusion abnormalities were defined. These objective criteria were tested prospectively in a separate group of 35 201TI studies and compared with the subjective interpretation of quantitative circumferential profiles. Overall, exact agreement existed in 78% of images (kappa statistic k = 0.66). We conclude that quantification of planar 201TI scans is highly reproducible, with acceptable inter- and intraobserver variability. Objective criteria for lesion reversibility correlated well with analysis by experienced observers.

Effects of serotonin-receptor blockade on angioplasty-induced vasospasm in an atherosclerotic rabbit model.

Vasospasm occurs both in patients and animal models after angioplasty and may be associated with early closure of the dilated vessel. To investigate the mechanism of angioplasty-induced vasospasm, the effect of serotonin-receptor blockade with two serotonin2 (S2) antagonists, LY53857 and sergolexole, was examined in rabbits with focal femoral artery atherosclerosis. In preliminary studies, local infusion of 1-100 micrograms serotonin caused significant femoral artery vasoconstriction (p less than 0.05) in both normal and atherosclerotic rabbits. There was no significant difference in the degree of vasoconstriction induced by equal doses of serotonin in normal and atherosclerotic animals. Infusion of 10 micrograms serotonin produced a 23 +/- 5% decrease in luminal diameter in atherosclerotic femoral arteries. This was blocked by pretreatment with both S2 inhibitors given separately in different animals before serotonin infusion (p less than 0.002). In contrast, LY53857 (sergolexole was not tested) had no significant effect on phenylephrine-induced vasoconstriction, confirming its specificity as an S2-receptor antagonist. Balloon angioplasty of atherosclerotic vessels caused a significant increase in vessel diameter at the angioplasty site (45% increase from baseline diameter, p less than 0.05). This was associated with significant luminal narrowing both proximal (21% reduction from baseline, p less than 0.05) and distal (17% reduction from baseline, p less than 0.03) to the angioplasty site. These proximal and distal changes are most likely due to vasospasm, as there was no histological evidence of thrombus or dissection at these sites to explain the luminal narrowing. Pretreatment of animals with 10 mg LY53857 or 20 mg sergolexole blocked the proximal vasospasm (2.6 +/- 0.4 before versus 2.2 +/- 0.1mm after angioplasty for LY53857, 2.1 +/- 0.4 before versus 2.1 +/- 0.4 mm after angioplasty for sergolexole; p = NS). Treatment with 20 mg LY53857 inhibited both proximal (2.3 +/- 0.1 before versus 2.2 +/- 0.2 mm after angioplasty, p = NS) and distal (1.7 +/- 0.1 before versus 1.6 +/- 0.2 mm after angioplasty, p = NS) vasospasm after angioplasty. Proximal (2.3 +/- 0.5 before versus 2.5 +/- 0.3 mm after) and distal (1.7 +/- 0.2 before versus 1.7 +/- 0.4 mm after) vasospasm was also prevented by pretreatment with 40 mg sergolexole.(ABSTRACT TRUNCATED AT 400 WORDS)

Pulmonary embolism presenting as exercise-induced hypotension.

A 68-year-old man with remote history of previous myocardial infarction presented with a four-week history of intermittent dyspnea. After developing hypotension during an exercise tolerance test, he underwent cardiac catheterization, revealing significant pulmonary hypertension and two-vessel coronary artery disease. Pulmonary angiography confirmed the presence of pulmonary emboli which partially resolved after thrombolytic therapy. Subsequent treadmill testing confirmed the absence of exercise-induced hypotension two months following treatment. This case underscores the importance of considering pulmonary embolism as a potential cause of exercise-induced hypotension, since it can be successfully treated with thrombolytic agents weeks after the initial onset of symptoms.

Vascular reactivity after balloon angioplasty in an atherosclerotic rabbit.

Alterations in vessel wall reactivity (VR) at or adjacent to the dilation site after balloon angioplasty (BA) may vary according to the inflation protocol and the time after angioplasty and may influence outcome. In 64 atherosclerotic rabbit femoral arteries, we evaluated VR after BA with intravenous ergonovine (ERGO) (40 micrograms/min for 5 minutes) and intra-arterial nitroglycerin (NTG) (2,500 micrograms single bolus) 24-72 hours and 28 days after BA. Comparisons were made with atherosclerotic, nonangioplastied, age-matched controls. BA was standardized to three 1-minute inflations, each 1 minute apart. For each balloon size, 2.5- (appropriate size) or 3.0-mm (oversized) vessels were allocated to either 5 or 10 atm inflation pressure. For the analysis, four groups were compared: Group 1, 3.0/5; group 2, 3.0/10; group 3, 2.5/5, and group 4, 2.5 mm/10 atm. Angiographic diameters were measured at, proximal, and distal to the lesion at baseline, 10 minutes after ERGO, and 5 minutes after NTG. Angiograms were measured with electronic calipers by two blinded observers. All segments of control vessels vasoconstricted to ERGO and vasodilated to NTG (p less than 0.05 versus baseline), indicating a normal response. At 24-72 hours after dilatation, the angioplasty sites for all inflation pressure/balloon size combinations were not responsive to either ERGO or NTG. All segments distal to the dilatation sites vasoconstricted to ERGO and dilated to NTG (p less than 0.05 versus baseline), indicating a normal response. Proximal segments of vessels dilated with a 2.5-mm balloon (appropriate size) responded positively to both stimuli (p less than 0.05). Those vessels dilated with a large balloon (3.0 mm) were nonreactive in the segment proximal to the angioplasty site. Twenty-eight days later angioplasty sites dilated with a 2.5-mm balloon (appropriately sized) regained reactivity; however, segments dilated with a large balloon (3.0 mm) remained unresponsive. All proximal segments, including those from vessels dilated with a large balloon, reacted positively. All distal segments reacted appropriately. Restenosis rates were not different between the over- and appropriately sized balloon groups. These data demonstrate that immediately after angioplasty, vessels lose reactivity at the dilatation site. Those vessels dilated with the smaller-size balloon (2.5 mm) regained reactivity. For large balloons, reactivity is not regained at 28 days. For segments proximal to the site of dilatation, transient loss of reactivity is seen only when a large balloon is used. Thus, acute closure originating at the site of dilatation is not a result of spasm.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of inflation pressure and balloon size on the development of intimal hyperplasia after balloon angioplasty. A study in the atherosclerotic rabbit.

To evaluate the effect of balloon size and inflation pressure on acute and subsequent outcome following balloon angioplasty (BA), 70 New Zealand White rabbits with bilateral femoral atherosclerosis were assigned to four groups: group 1, oversized balloon, low inflation pressure (n = 35 vessels; balloon size, 3.0 mm/inflation pressure, 5 atm); group 2, oversized balloon, high inflation pressure (n = 36; 3.0 mm/10 atm); group 3, appropriate size, low inflation pressure (n = 17; 2.5 mm/5 atm); and group 4, appropriate size balloon, high inflation pressure (n = 19; 2.5 mm/10 atm). Angiograms were obtained before, 10 minutes after, and 28 days after BA and read by two blinded observers using electronic calipers. The in vivo balloon-to-vessel ratio was measured for each group. There were eight non-BA controls. Rabbits were sacrificed either immediately (n = 34) or at 28 days after BA (n = 36), with the femoral vessels pressure perfused for histologic and morphometric analysis. The latter was performed at 28 days only. Absolute angiographic diameters increased in all groups immediately after BA (p less than 0.01). Acute angiographic success, defined as greater than 20% increase in luminal diameter, was higher using high inflation pressure (group 2, 32/36 [89%] and group 4, 16/19 [84%] vs. group 1, 23/35 [66%] and group 3, 9/17 [53%]; p less than 0.05). A 3.0-mm balloon resulted in significant oversizing irrespective of inflation pressure (balloon-to-vessel ratio, 1.5 +/- 0.1 vs. 1.1 +/- 0.1 to 1, for the 2.5-mm balloon). Vessels exposed to high inflation pressure had a significantly higher incidence of mural thrombus, dissection (p less than 0.01), and medial necrosis versus low pressure (p less than 0.05). At 28 days, the rates of restenosis (defined as greater than 50% loss of initial gain) were 14/20 (70%), 11/16 (69%), 5/10 (50%), and 5/10 (50%) for groups 1 through 4 (p = NS; a trend in favor of the groups using an oversized balloon). There was an increase in the degree of intimal hyperplasia by morphometric analysis in all groups, being most marked in group 2 (oversized balloon and high inflation pressure, 1.7 +/- 0.9 vs. 0.5 +/- 0.2 mm for controls, p less than 0.001). We reached two conclusions. First, all protocols resulted in a significant increase in luminal diameter immediately after angioplasty with the highest success rate in vessels subjected to high pressure dilatation.(ABSTRACT TRUNCATED AT 400 WORDS)

Liver disease associated with occupational exposure to the solvent dimethylformamide.

STUDY OBJECTIVE: to characterize an outbreak of liver disease among workers in a fabric coating factory; and to determine the outbreak's cause and natural history and strategies for clinical recognition, treatment, and prevention. DESIGN: clinical-epidemiological investigation. SETTING: academic medical center, Occupational Medicine Clinic, and worksite. PATIENTS: fifty-eight of sixty-six workers participated in the study. All had standard liver function tests at least once. Forty-six workers completed a questionnaire; 27 had more extensive clinical evaluation for recognized liver abnormalities. RESULTS: a plant-wide outbreak of liver disease was recognized after a new employee presented with signs and symptoms of hepatitis. Evaluation of the worksite showed that dimethylformamide, a widely used industrial solvent and known hepatotoxin, was being used to coat fabric in poorly ventilated areas without appropriate skin protection. No other major hepatotoxic exposure was identified. Overall, 36 of 58 (62%) workers tested had elevations of either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels. Enzyme abnormalities occurred almost exclusively in production workers (35 of 46 were abnormal), whereas only 1 of 12 nonproduction workers showed any elevations in enzyme levels (P less than 0.0001). Serologic tests excluded known infectious causes of hepatitis in all but 2 workers and changes characteristic of toxic liver injury were confirmed by histologic examinations of biopsy specimens from 4 workers. The ratio of AST to ALT levels was one or less in all but 1 worker. After modification of work practices and removal of workers most severely affected from exposure, improvement in liver enzyme abnormalities and symptoms in most patients were seen, although some patients showed persistent elevations of enzyme levels. CONCLUSIONS: an outbreak of toxic liver disease has been associated with exposure to dimethylformamide in the workplace. The diagnosis of toxic liver disease was established by the clinical histories, negative viral serologies, an enzyme pattern of ALT levels being greater than AST levels, epidemiologic data on coworkers, and liver biopsy specimens. The high prevalence of unsuspected liver enzyme abnormalities in these workers suggests that occupational liver disease may occur more frequently than is generally recognized.

Studies on the production of endogenous pyrogen by rabbit monocytes: the role of calcium and cyclic nucleotides.

Rabbit monocytes stimulated with endotoxin produced endogenous pyrogen, even under conditions of high or low extracellular calcium concentrations. Maximal production occurred when the concentration was in the near-physiological range. Prolonged incubation of cells with a calcium chelator prevented subsequent activation with endotoxin, an effect which was rapidly reversible by re-addition of calcium but not other cations. Addition of small amounts of lanthanum, which acts as a calcium channel blocker, prevented the restoration of pyrogen production, indicating that entry of the added calcium into the monocyte was required. Incorporation of a calcium ionophore into the cell membrane did not stimulate pyrogen production, and no measurable influx or efflux of calcium occurred during stimulation with endotoxin. These observations suggest that a slowly exchangeable calcium pool is necessary for the production of endogenous pyrogen, but that a rise in intracellular calcium is not by itself a necessary or sufficient stimulus. This stands in contrast to other biological systems in which Ca2+ directly couples stimulus and hormone secretion. Incubation of cells with agents shown to increase cyclic 3',5' AMP or cyclic 3',5' GMP levels in monocytes similarly did not stimulate pyrogen production or modulate its production by endotoxin stimulation. Thus, cyclic nucleotides also did not play a detectable role as intracellular messengers in this system. Future work is required to define more clearly the mechanism for the production of endogenous pyrogen, given its marked effects on the immune system through lymphocyte activation and temperature regulation.

Fever, rash, and blindness in a previously healthy young male.

A 31-year-old male presented to the emergency room with a sudden onset of blindness and a rash after a five-day history of myalgia, abdominal pain, and fever. The diagnostic approach and the patient's clinical course are presented. Indications for surgical intervention in staphyloccal endocarditis are discussed. Surgical and autopsy findings are reviewed.

Adult respiratory distress syndrome in a previously healthy young male.

Infection with pneumocystis carinii and cytomegalovirus was found in a young male suspected of having miliary tuberculosis. Problems of diagnosis and predisposing factors for these infections in the patient are discussed. The patient's clinical course and management are reviewed. Autopsy findings are presented. Alternative modes of therapy are considered.

Fever theory in the seventeenth century: building toward a comprehensive physiology.

Physicians in the seventeenth century developed several theories to explain the causes and cures of fever. These theories relied heavily upon the most important physiological discovery of the period, the circulation of blood throughout the human body. In addition, physicians, increasingly emphasized careful observation of their patients' symptoms, in order to develop empirically effective methods of treatment.