Isolated descending thoracic aortic aneurysm in Marfan's syndrome.
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Biomedical subjects
Publications and source records attributed to C E Green.
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Variation in hepatic metabolism between species may be an important factor in the differences observed in chemical carcinogenesis. We examined 6 chemicals representative of 4 chemical classes in the in vitro hepatocyte DNA repair assay using cells isolated from the Fischer-344 rat, B6C3F1 mouse, Syrian golden hamster, cynomolgus monkey and from human liver. Hepatocytes were isolated by in situ or biopsy liver perfusion and incubated with [3H]-thymidine and the test chemical. Unscheduled DNA synthesis (UDS) was measured as net grains/nucleus (NG) by quantitative autoradiography. Qualitative and quantitative differences in UDS responses were observed for every chemical. Liver cultures isolated from the rat, mouse, hamster, human, and monkey and treated with aflatoxin B1 or dimethylnitrosamine all yielded dose-related increases in NG. Human, rat, and hamster hepatocyte cultures yielded positive responses following exposure to the aromatic amines 2-acetylaminofluorene, 4-aminobiphenyl, and benzidine, whereas cultures isolated from the monkey and mouse yielded less than 0 NG. Treatment with benzo[a]pyrene (BAP) produced strong positive responses in monkey and human hepatocyte cultures, weak positive responses in hamster cultures, and equivocal or negative responses in rat and mouse hepatocyte cultures. Hepatocyte function was assessed by measurement of DNA content, glutathione content, BAP hydroxylase activity, p-nitroanisole-O-demethylase activity, p-nitrophenol conjugation, and urea synthesis rates. The functional capabilities of isolated hamster, monkey, and human hepatocyte cultures do not appear to correlate with UDS responses observed for any compound; however, they indicate that the cultures were metabolically competent at the time of chemical exposure. These studies suggest that rat hepatocytes are a suitable model for human hepatocytes, whereas mouse and male monkey hepatocytes may be insensitive to aromatic amines.
The results of cinefluoroscopic evaluation in 509 patients in whom there was no evidence of prosthetic mitral or aortic valve regurgitation were compared with those in 41 patients who had perivalvular aortic or mitral regurgitation. Rotational motion of the base ring of each prosthesis (base-ring tilt) was measured in at least two views. A base-ring tilt of 7 degrees or more for aortic prostheses or 11 degrees or more for mitral prostheses was associated with an increased incidence of significant perivalvular regurgitation. Likewise, in patients who had multiple studies, a change between studies in base-ring tilt of 4 degrees or more for aortic prostheses or 5 degrees or more for mitral prostheses was associated with significant perivalvular regurgitation. These data suggest that the presence of either an abnormal base-ring tilt or an abnormal increase in base-ring tilt is strong, supportive evidence of partial prosthetic valve dehiscence.
Emergency percutaneous transluminal coronary angioplasty (PTCA) is accepted as an important reperfusion intervention for acute myocardial infarction (AMI). Although its primary success rate is well documented, the frequency of restenosis after this procedure is unclear. The frequency of restenosis was determined in patients undergoing emergency PTCA at least 6 months after PTCA was performed during AMI. Of 66 consecutive patients undergoing emergency PTCA, 25 had a second, elective catheterization at an average of 22 months after AMI and 6 underwent repeat catheterization because of recurrent chest pain. Restenosis of the PTCA site was found in 10 of the 31 patients (32%) restudied. Also, 14 (45%) of these 31 patients showed progression of narrowing in the non-infarct-related coronary arteries. In summary, patients in whom AMI is treated by PTCA are at risk for restenosis and for progressive narrowing of the non-infarct artery.
Maximal myocardial salvage appears to be related to the severity of residual coronary arterial stenosis after thrombolysis. The degree of residual infarct vessel stenosis was assessed in 119 consecutive patients with patent arteries who received streptokinase during acute myocardial infarction. After administration of streptokinase, 99 of 119 patients (83%) had a residual stenosis 70% or more in diameter. Assuming that a residual diameter stenosis of at least 70% is flow limiting, the feasibility for percutaneous transluminal coronary angioplasty (PTCA) was determined by the following criteria: length less than 10 mm, no significant distal narrowing or left main stenosis, and an adequate-sized distal artery. In 81 of 99 patients (82%), arterial anatomy was suitable for PTCA. Thus, after therapy with streptokinase for acute myocardial infarction, most patients have a significant infarct arterial residual stenosis and are candidates for PTCA.
The limitation of infarct size by thrombolysis could potentially be improved by an early metabolic intervention. We therefore evaluated the effects of a 48-hour infusion of glucose-insulin-potassium (GIK) in patients with anterior infarctions. Seventeen patients were randomized to receive intravenous GIK (n = 10) or placebo (n = 7). All patients additionally received streptokinase. Changes in left ventricular function were assessed by comparing the global ejection fractions and the regional infarct area ejection fractions of the first ventriculogram with the 10-day second ventriculogram. There was a significantly greater improvement in the global ejection fraction of patients receiving GIK (increases 0.07 +/- 0.04) than in those randomized to placebo (decreases 0.08 +/- 0.04) (p less than 0.02). There was also a much greater improvement in the area ejection fractions of the group receiving GIK vs the group receiving placebo in the anterolateral (increases 0.24 +/- 0.07 vs decreases 0.02 +/- 0.04 [p less than 0.02]) and diaphragmatic (increases 0.08 +/- 0.08 vs decreases 0.17 +/- 0.05 [p less than 0.005]) segments. Thus in patients with anterior infarctions receiving streptokinase, GIK improves ventricular function and reduces the size of the segmental wall motion abnormality.
Continuous ST-segment Holter recordings were analyzed from 46 patients with acute myocardial infarction (AMI) receiving intracoronary streptokinase (SK) during the first 48 hours of hospitalization. Changes in ST deviation and the time periods of these changes were quantitated and correlated with angiographic evidence of reperfusion. Thirty-six patients had total occlusion of the infarct vessel and 10 had subtotal occlusion. Of the 36 vessels that were totally occluded, 19 were reperfused and 17 were not. In patients in whom reperfusion was successful, an ST steady state was achieved 55 +/- 32 minutes after SK administration. In patients in whom it was not successful, a steady state was achieved in 219 +/- 141 minutes (p less than 0.001). Achievement of steady state within 100 minutes after SK reperfusion indicated successful reperfusion with 89% sensitivity and 82% specificity. All patients with subtotal occlusion achieved an ST steady state before SK infusion. No patient with total occlusion achieved a steady state before SK. Achievement of ST steady state before SK infusion was 100% sensitive and 100% specific for subtotal occlusion at initial angiography. Continuous, quantitative ST-segment analysis is a sensitive and specific noninvasive technique for following coronary artery patency during AMI.
We describe an unusual case of aortic dissection causing spinal cord infarction. The dissection arose from an intimal tear at the suture line of a coronary artery bypass graft. CT was used to diagnose the dissection and to demonstrate its extension to the aortoiliac bifurcation and innominate artery and its rupture into the left pleural cavity. The most common causes of intimal tears following cardiac bypass surgery are aortic cross-clamping, aortic cannulation, and injury during suturing of the graft to the aorta. An underlying disease of the aorta such as atherosclerosis, cystic medial necrosis, or aortitis is commonly present. CT is an accurate and safe means of detecting aortic dissections following cardiac surgery, and is also useful in assessing the extent of the dissection and identifying its rupture into the pleural or pericardial cavity.
Accelerated idioventricular rhythm has been used as a marker for coronary reperfusion. The incidence of accelerated idioventricular rhythm and ventricular tachycardia was evaluated in 52 consecutive patients undergoing thrombolysis with intracoronary streptokinase during acute myocardial infarction. Complete 12-hour Holter recordings during and after intracoronary streptokinase were obtained in 39 patients. Reperfusion was documented in 17 patients (44%), no reperfusion in 14 (36%), and subtotal occlusion in eight (20%). Accelerated idioventricular rhythm occurred in 83%, 57%, and 63% of patients by group, respectively (p greater than 0.05). Ventricular tachycardia occurred in 100%, 71%, and 100% of patients by group, respectively (p less than 0.05). These data demonstrate that accelerated idioventricular rhythm is not specific for reperfusion and cannot be used as a marker for this event, and that ventricular tachycardia is more common with reperfusion and subtotal occlusion.
"Stunned" myocardium prevents the assessment of myocardial salvage after streptokinase. In order to unmask "stunning," we sought to evaluate left ventricular inotropic contractile reserve of patients after streptokinase. Radionuclide ventriculograms were obtained in 75 consecutive patients 2 weeks after myocardial infarction, at rest and during intravenous isoproterenol infusion. Resting and isoproterenol-stressed ejection fractions were compared in the patent and closed-infarct vessel groups. Although there was no difference in the resting ejection fractions between the patent group (0.48 +/- 0.02) and the closed group (0.48 +/- 0.02), isoproterenol increased the ejection fractions in the patent group (increase 0.14 +/- 0.01) significantly more than in the closed group (increase 0.06 +/- 0.01) (p less than 0.0001). Thus, despite identical resting ventricular function, the greater inotropic contractile reserve in the patent infarct vessel group suggests that restoration of blood flow in acute myocardial infarction salvages myocardium.
Timing of coronary artery bypass grafting after acute myocardial infarction (MI) is controversial, especially if myocardial function is depressed. Early coronary artery bypass grafting may result in reperfusion injury causing cardiac failure. Delay, however, may risk a second ischemic event. This study was performed to determine if four preoperative factors--time after MI, ejection fraction, ischemia (need for intravenous administration of nitroglycerin), and failure (need for inotropic support)--independently predict postoperative cardiac failure. Postoperative failure was defined as the need for inotropic support or intraaortic balloon pumping. The study group consisted of 145 patients who underwent isolated coronary artery bypass grafting between January, 1980, and July, 1985, within 4 weeks of an acute MI. Postoperatively 38 patients (26%) had cardiac failure. Five patients, all of whom had postoperative cardiac failure, died. Univariate and stepwise logistic regression analyses showed preoperative failure (p = .0001), ejection fraction less than 45% (p = .002), and preoperative ischemia (p = .02) were predictors of postoperative cardiac failure. Time after MI was not found to be an independent predictor (p = .96). We conclude that if ischemia or threatening coronary anatomy is present early after MI and clinical improvement is not occurring, operative intervention should be strongly considered at that time, as it does not appear that delay itself reduces the risk of cardiac failure and may risk a second ischemic event.
Emergency cardiac catheterization and angiography in patients have resulted in an appreciation of the pathogenesis of AMI and the efficacy of thrombolytic therapy. Simple reperfusion of the infarcted myocardium, however, does not necessarily guarantee myocardial salvage, and preliminary studies have been somewhat confusing as to its beneficial effects. Metabolic support of the ventricle during early reperfusion may enhance left ventricular performance. Although the potential effects of thrombolytic therapy are still unclear, the routine administration of these agents has resulted in more frequent performance of early coronary angiography, with the result that appropriate therapeutic decisions can be made immediately regarding medical treatment, coronary angioplasty, or complete myocardial revascularization. In fact, in prolonged chest pain syndromes, emergency angiography may play a very important role in establishing appropriate initial therapy early in the course of hospitalization, potentially lowering mortality, morbidity, and cost. These issues will be answered ultimately only by carefully designed long-term randomized trials.
Isolated hepatocyte suspensions from rat, rabbit, dog, squirrel monkey and human livers were used to study the metabolism of amphetamine (AMP), a drug for which species-dependent differences in metabolism have been demonstrated in vivo. Hepatocytes were isolated by perfusion of the whole liver or of biopsy specimens. In general, the metabolite profile of hepatocytes from each species corresponded to the profile of urinary metabolites identified previously. Rat hepatocytes primarily metabolized AMP by aromatic hydroxylation to p-hydroxyamphetamine. Rabbit hepatocytes converted AMP almost exclusively to products of the oxidative deamination pathway. Metabolism by hepatocytes from the other three species was mixed, but oxidative deamination was somewhat more active than aromatic hydroxylation in dog, squirrel monkey and human hepatocytes. The overall rate of AMP metabolism differed significantly among the species; the half-life in the hepatocyte suspensions varied about 70-fold, with rabbit less than rat less than dog less than squirrel monkey = human. Metabolism of AMP by human hepatocytes mare closely resembled metabolism by squirrel monkey liver cells than the other species in terms of metabolite profile and rate. However, the disposition of phenylacetone, a product of oxidative deamination of AMP, varied in hepatocytes from the two primate species. Thus, the metabolism of AMP by isolated hepatocytes was unique for each species examined. These studies demonstrate the applicability of isolated hepatocytes to the study of interspecies differences in hepatic xenobiotic metabolism, providing an in vitro technique that can be readily adapted to human liver tissue.
Although thrombolytic therapy can result in lysis of a coronary artery thrombus, salvage of myocardium as measured by enzymatic, electrocardiographic and regional wall motion evaluation has not been clearly documented. Many patients after successful reperfusion continue to experience recurrent chest pain. The presence of recurrent chest pain suggests salvaged myocardium. Controlled reocclusion of the infarct vessel with the use of coronary angioplasty may support evidence for myocardial salvage. Experience in 50 patients who underwent angioplasty was reviewed retrospectively. Sixteen of the 50 patients had electrocardiographic or clinical evidence of ischemia at the time of balloon inflation. Prospectively, all patients who underwent angioplasty after they had received streptokinase were evaluated, and 5 of 5 patients had chest pain and ST-segment elevation during balloon inflation. The development of ischemic changes during balloon catheter inflation suggests the presence of persistently viable, salvaged myocardium after successful thrombolysis.
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Acetaminophen (APAP) disposition was studied in vitro using hepatocytes isolated from rats, hamsters, rabbits, and dogs, species that vary markedly in susceptibility to the hepatotoxicity of this drug. Metabolism was assessed by concurrent measurements of glutathione depletion and protein adduct formation (activation pathway) and of total aqueous metabolite production (detoxication pathways). Cytotoxicity was monitored by cell count and by lactate dehydrogenase (LDH) release to culture medium. In agreement with whole animal studies, hepatocytes from hamsters were very susceptible to APAP-induced toxicity whereas rat and rabbit hepatocytes were resistant. In vivo data were unavailable for the dog, but dog hepatocytes were also relatively resistant. Parameters of APAP metabolism generally correlated with the species susceptibility ranking; however, no single parameter was an ideal index of the sensitivity observed. As predicted by the cytotoxicity data, hamster hepatocytes produced more covalent adducts of APAP, were depleted of GSH more rapidly, and detoxified APAP by formation of polar metabolites at a slower rate than rat hepatocytes. On the other hand, rabbit hepatocytes had no detectable covalent adducts, retained higher amounts of GSH, and metabolized more APAP to polar conjugates than the other species. Dog hepatocytes formed low amounts of both covalent adducts and conjugates. These studies indicate that interspecies comparisons using isolated hepatocytes to study xenobiotic metabolism and the resulting cytotoxicity are feasible, but for a clear understanding of observed differences, it is necessary to study the interrelationships between the toxication and detoxication pathways of metabolism.