The effects of 25-hydroxycholesterol (25-OHC), a potent inhibitor of sterol synthesis, on the growth, viability, and sterol content of C-6 rat glioma cells have been studied. Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and sterol synthesis in cells that were proliferating in medium supplemented with lipoprotein-poor fetal calf serum caused an arrest of growth after 24 hr. Prolonged incubation of serum-supplemented cells with 25-OHC resulted in a loss of morphological integrity and an 80% decline in cell viability, determined by trypan blue dye exclusion. In contrast, C-6 cells that were induced to enter a quiescent state by removal of serum from the medium remained viable and morphologically differentiated in the presence of 25-OHC. Following the addition of whole fetal calf serum to the medium, serum-free cells that had been incubated with 25-OHC for 3 days were able to resume proliferation. the selective killing of proliferating C-6 glioma cells by 25-OHC was correlated with a 45 to 50% decline in the sterol/phospholipid molar ratio, whereas the sterol/phospholipid ratio in the quiescent cells was not affected by 25-OHC. The results suggest that inhibitors of sterol synthesis may have potential as agents that might selectively decrease the growth and viability of glioma cells in the central nervous system without detriment to the normal nondividing neural cells.

Animals↗

PubMed1981

Translocation of the aortic valve for prosthetic valve endocarditis.

Aortic prosthetic valve endocarditis is frequently associated with a perivalvular ring abscess which destroys the normal annulus, so that it is difficult to seat a new prosthesis. Between November, 1974, and January, 1980, we treated four patients with aortic prosthetic endocarditis by translocation of the aortic valve, closure of the native coronary artery ostia, and placement of saphenous vein bypass grafts to the coronary arteries. In each case operation was undertaken because of progressive congestive heart failure resulting from aortic regurgitation; two patients had systemic emboli, and two patients had uncontrolled infection. Infection was due to Enterococcus in three instances and to an unknown organism in one. Total ischemic times averaged 2 hours, 15 minutes; a 25 mm Dacron graft containing a porcine valve was used to replace the ascending aorta and aortic valve, and two or three saphenous vein grafts were placed to distal coronary arteries. One patient died 40 days postoperatively of renal failure and Pseudomonas pneumonia with an intact repair. The other three patients were hospital survivors, with one doing well until dying of chronic active hepatitis 12 months postoperatively. The other two patients are alive at 4 months and 18 months with satisfactory hemodynamic function and are free of infection. Translocation of the aortic valve for prosthetic valve endocarditis is a useful alternative when conventional replacement techniques cannot be utilized.

Adult↗

PubMed1981

Postinfarction ventricular septal defect: an argument for early operation.

We reviewed our experience with 43 consecutive patients who underwent operations for postinfarction ventricular septal defect to determine optimal time for operative intervention, to identify factors responsible for failure of operative treatment, and to determine long-term survival rates. Patients were referred for operation after expectant medical management had failed or after 6 weeks electively. The operative mortality rate was 42% and ranged from 90% for those who required operation within 1 day of 11% for those underwent surgery after 1 month. In a multivariate discriminant analysis of preoperative variables, we found that inferior infarction with perforation (P less than 0.02) and preoperative multisystem failure (evidenced by abnormal mental status, P less than 0.02) were the major factors correlating with high operative risk. Early operation per se did not affect operative mortality rates. Technical problems with early operation were not a source of major morbidity and mortality. Actuarial long-term survival was good, and 88.5% of survivors were alive 5 years after surgery. Because preoperative multisystem failure is often progressive, we recommend immediate operation for all patients with postinfarction ventricular septal defect unless no deterioration is present. Moreover, because of the high risk of those patients with inferior infarction and perforation, we recommended immediate surgery for this group regardless of symptomatic status.

Aged↗

PubMed1980

Changes in sterol biosynthesis accompanying cessation of glial cell growth in serum-free medium.

C-6 glioma cells, grown in medium supplemented with 5% delipidated foetal calf serum, were induced to enter a quiescent state by removing serum from the medium. Within 24h there was a 75-80% decline in the rate of incorporation of [(14)C]acetate or (3)H(2)O into digitonin-precipitable sterols. Experiments with [(3)H]mevalonolactone as a labelled sterol precursor suggested that the decline in sterol synthesis was regulated primarily at a point in the pathway before the formation of mevalonate. The specific activities of 3-hydroxy-3-methylglutaryl-CoA synthase and 3-hydroxy-3-methylglutaryl-CoA reductase decreased sharply in conjunction with the decline in sterol synthesis in the serum-free cultures; however, the activity of acetoacetyl-CoA thiolase was altered only slightly. The magnitude of the initial decline in reductase activity was not affected when 50-mm-NaF was included in the preincubation and assay buffers to prevent activation of physiologically inactive enzyme. However, after 6h of serum deprivation the decline in 3-hydroxy-3-methylglutaryl-CoA reductase activity was due to a decrease in the amount of latent activity. The sterol concentration in C-6 cells was unchanged after 24h in serum-free medium, although a 20% decrease in the sterol/fatty acid molar ratio occurred as a result of a small increase in the fatty-acid concentration. Incorporation of (3)H(2)O into fatty acids was inhibited in the serum-deprived glial cells; however, this inhibition developed more slowly and was not as pronounced as the diminution in sterol synthesis. The results suggest that in C-6 glia, which resemble the glial stem cells of the developing brain, the decreased demand for membrane sterols in the quiescent state results in a decline in sterol synthesis, mediated primarily through co-ordinate changes in the activities of 3-hydroxy-3-methylglutaryl-CoA synthase and 3-hydroxy-3-methylglutaryl-CoA reductase.

Acetates↗

PubMed1980

Malignant lymphoma in cyclosporin A treated allograft recipients.

Explore the source record for details and available documents.

Animals↗

PubMed1980

Long-term low-dose prostaglandin E1 administration.

Explore the source record for details and available documents.

Ductus Arteriosus, Patent↗

PubMed1980

Sequential orthotopic heart transplantation in man.

Between January 1968 and March 1980, 202 hearts had been transplanted into 185 patients at Stanford University Medical Center. Occasionally, patients after transplantation develop myocardial failure which is amenable only to retransplantation. Sixteen patients underwent initial orthotopic allograft using standard techniques. Eight patients developed accelerated arteriosclerotic coronary disease, six had unrelenting rejection, and two had donor heart dysrrhythmia or right ventricular failure requiring retransplantation. One patient required a third transplant because of donor left ventricular ischemia. All sequential transplants were managed similarly to the primary transplant. Of the initial transplant hearts at risk, 60% survived for more than 1 year, and 57% survived for more than 2 years. These results are similar to those of patients not requiring retransplantation. Of the secondary transplant hearts at risk, 31% survived for more than 1 year and 29% survived for more than 2 years. The severity of infection and/or rejection contributed most significantly to secondary heart transplant mortality. Sequential orthotopic cardiac transplantation offers an acceptable alternative to patients with allograft failure. Survival is not as favorable as with initial transplantation because of the prolonged immunosuppression during sequential transplantation.

Graft Rejection↗

PubMed1980

The effect of stenosis of bypass grafts on coronary blood flow. A mechanical model study.

A mechanical model of a branched coronary artery with a graft bypassing an 80% stenosis of one branch was used to study the reduction in coronary flow due to stenosis of the bypass graft. Flow Reynolds number and ratio of aortic pressure to dynamic pressure were matched to the living system. Changes in coronary flow were measured for a range of stenoses (0-100%) of bypass grafts with graft-to-coronary-diameter ratios of 4:1, 3:1, 2:1 and 1:1 for conditions that simulated rest and exercise. The results of these studies indicate that: 1) marked stenosis of bypass grafts is needed to decrease coronary flow in the resting state, and even moderate stenosis will decrease flow during exercise when the diameter of the bypass is large relative to the coronary artery; 2) coronary flow is decreased with mild stenosis for bypass grafts of the same diameter as the coronary artery; and 3) a marked decrease in flow due to stenosis of a bypass graft occurs only when the diameter of a stenosis in a graft is less than the diameter of the coronary artery.

Arterial Occlusive Diseases↗

PubMed1980

Heart and lung transplantation: autotransplantation and allotransplantation in primates with extended survival.

Combined heart and lung transplantation was performed in rhesus or cynomolgus monkeys in order to confirm the ability of primates to withstand complete cardiopulmonary denervation, to develop a satisfactory operative method, and to obtain survival of allotransplant recipients using Cyclosporin-A immune suppression. Twenty-seven monkeys weighing 2.6 to 10.1 kg received either autotransplants or allotransplants by two different operative techniques. Seventeen animals were operated upon with hypothermia and circulatory arrest. One autotransplant recipient is alive at 368 days, but all allotransplant recipients (untreated) died within 5 days despite normal breathing patterns. Ten animals operated upon with the aid of cardiopulmonary bypass fared better. Three autotransplant recipients are alive 60, 199, and 312 days postoperatively. Three of seven allotransplant recipients treated with Cyclosporin-A (25 mg/kg, then tapered) and azathioprine (2 mg/kg for 14 days) were long-term survivors. One died at 144 days of lymphoma and two are currently living 156 and 191 days postoperatively. The results suggest that heart and lung transplantation is possible in primates and that allografted recipients can survive for extended periods with Cyclosporin-A used for immune suppression.

Animals↗

PubMed1980

Concomitant resection of ascending aortic aneurysm and replacement of the aortic valve: operative and long-term results with "conventional" techniques in ninety patients.

We reviewed a consecutive series of 90 patients undergoing concomitant resection of ascending aortic anerysm and aortic valve replacement (AVR) utilizing noncomposite "conventional" techniques in order to assess the early and late results, to define limitations of this operative approach, and thereby to clarify the indications for composite reconstruction of the aortic root. Mean age was 55 years. Twenty percent had Marfan's syndrome, and 13% had aortic dissections. The cause of the aneurysm was dissection in 13% of cases, syphilis in 11%, atherosclerosis in 9%, and degeneration (with or without cystic medionecrosis) in 67%. Follow-up averaged 3.8 years and extended to 11.5 years maximum. AVR and complete excision of the aneurysm (preserving small tongues of aortic wall circumscribing the coronary artery ostia) coupled with tubular graft replacement of the ascending aorta were performed. Nineteen percent of patients required individual technical modifications relating to the coronary arteries. Operative mortality rate was 13%, with the majority of deaths being due to cardiac causes. Contemporary (1975 to 1978) operative mortality rate was 4.3%. Seven percent required re-exploration for hemorrhage and 2.4% had perioperative myocardial infarctions. Late functional results were generally good (average N.Y.H.A. Class 1.4). Late thromboembolism, angina, myocardial infarction, and congestive heart failure occurred at linearized rates of 3.4% per patient-year, 4.9% per patient-year, 1.1% per patient-year, and 5.2% per patient-year, respectively. No prosthetic valve endocarditis, graft infection, or recurrent aneurysms of the aortic root were observed. Late reoperation was necessary in eight patients (3% per patient-year), but reoperation for disease confined to the ascending aorta accounted for only three of these cases (1.1% per patient-year). Overall actuarial survival rates were 67% +/- 5% at 5 years and 50% +/- 9% at 10 years; survival rates for the 78 operative survivors were 77% +/- 5% and 57% +/- 10% at the same time intervals, respectively. Only one late death could be attributed to complications arising in the reconstructed aortic root. These results confirm that such simple, noncomposite techniques are safe, portend minimal risk of late complications and the attendant necessity for reoperation, and provide satisfactory long-term survival. We believe that composite techniques should be primarily reserved for selected cases of advanced necrotizing prosthetic or natural endocarditis.

Adult↗

PubMed1980

Distant heart procurement for human transplantation. Ultrastructural studies.

The paucity of donor hearts for human transplantation can be remedied by distant heart procurement. In the present study, 12 donor hearts obtained at distant locatins were preserved by infusion with 500 ml of cardioplegic solution at 4 degrees C at 150 mm Hg and immersion in 4 degrees C saline for rapid transmural cooling. They were transported in ice-cold saline. Maximal ischemic times were 110-182 minutes. Septal biopsies before coronary reperfusion showed normal mitochondria (11 and 12), normal nuclei (seven of 12), myofibrillar I-bands (six of 12), and capillary endothelial swelling (12 of 12). Septal biopsies 30 minutes after reperfusion showed mitochondrial swelling (six of 10), nuclear damage (10 of 10), myofibrillar contraction (10 of 10), and endothelial swelling (eight of 10). All grafts functioned satisfactorily. Eight of the 12 patients were alive 6-15 months later; four patients died (one of pulmonary hypertension and three of infection). We concluded that (1) human hearts show significant ultrastructural changes after 3 hours of ischemia, but (2) these worsen after reperfusion, and (3) distant heart procurement is feasible for human transplantation.

Cell Nucleus↗