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Circulating neopterin is derived from monocytes and/or macrophages that produce it upon stimulation by interferon-gamma released from activated T cells. Neopterin production has been proposed as a marker of biological response in the clinical administration of a number of cytokines. Changes in neopterin production as indicated by urinary neopterin excretion were studied in four patients with ovarian carcinoma receiving intraperitoneal interleukin-2 and lymphokine-activated killer cells. Neopterin production increased approximately threefold during treatment with interleukin-2 at doses which represent or exceed the maximum tolerated dose by this route of administration. Increased neopterin apparently was derived from systemic, not regional, tissues. The physiologic role(s) of pterins in immune responses is uncertain. In an in vitro system, the presence of neopterin or tetrahydrobiopterin or the pterin synthesis inhibitor, N-acetyl serotonin, did not modulate cytotoxic effects of lymphokine-activated killer cells.

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Echocardiography was used in the serial evaluation of 50 patients at 1, 3, and 7 years after aortic valve replacement with a new bovine pericardial aortic bioprosthesis. For valve sizes of 19-27 mm, at 7 years of follow-up mean transvalvular gradients (xGrad) ranged from 15.2 to 8.0 mm Hg, and calculated mean valve areas (AVA) ranged from 1.06 to 1.79 cm2. Acceptable xGrad and AVA were directly related to valve size and did not change in 48 asymptomatic patients. One patient at 7 years had marked calcific stenosis and degeneration requiring explanation. Echocardiography is useful in the long-term evaluation of bioprosthetic function, yielding information equivalent to cardiac catheterization data. This bovine pericardial valve offers good clinical and hemodynamic results at 7 years and is a suitable alternative when a bioprosthesis is indicated.

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Mitral valve repair for mitral regurgitation has been reported to have more favorable early and late results than mitral valve replacement. From July 1985 through July 1990, 63 patients have undergone valve repair at Good Samaritan Hospital. Twenty-two men and 41 women whose ages ranged from 34 to 81 years (mean 67.9 years) were treated. Twenty-eight patients were in New York Heart Association functional class III or IV. Twelve (19%) had undergone prior cardiac surgery. Isolated valve repair was performed in 18 patients. Valve repair was combined with coronary artery bypass grafting, other valve procedures, or aneurysm resection in the remainder (71%). Two patients (3%) died while in the hospital, and four deaths (one valve-related) occurred after discharge. Leaflet resection for ruptured chordae was done in 24 patients (38%), chordal shortening in 5 patients (8%), and leaflet transposition in 2 patients. Rigid ring annuloplasty (Carpentier) was performed in 62 patients. Eight patients required mitral valve replacement at the same operation because of unsatisfactory valve repair. Results of valve repair evaluated by echocardiography at discharge show that 48 patients (88%) are free of significant regurgitation. Follow-up to date reveals that all surviving patients who underwent valve repair have clinically improved and are stable. Four of five patients with moderate mitral regurgitation are currently asymptomatic. There have been two valve-related late failures requiring reoperation. Based on this early experience, we conclude that valve repair compared with mitral valve replacement has a low operative mortality with good early results. Continued efforts to preserve native mitral valve function in the presence of mitral regurgitation appear justified.

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A consecutive series of 7104 patients undergoing isolated coronary artery bypass grafting during an 18-year period (1971 to 1988) included 469 patients older than 75 years. Results were analyzed to determine comparative risk factors for morbidity, early and late survival, and functional outcome. Patients younger than 75 years (group I) and patients older than 75 years (group II) were identical for ejection fraction and standard hemodynamic indices. Mean number of grafts and crossclamp time were greater for group II patients (p less than 0.01). Mean age of group I was 58.6 years and group II, 77.6 years (p less than 0.01). Women composed 19.7% (1308/6635) of group I and 36.2% (170/469) of group II patients (p less than 0.05). Mammary grafts were placed in 57.7% (3830/6635) of group I and 41.6% (195/469) of group II patients (p less than 0.05). Overall perioperative mortality rate was 2.1% for group I and 6.8% for group II (p less than 0.05). Perioperative myocardial infarction rate was similar for the two groups. Ventricular and supraventricular arrhythmias, renal insufficiency, neurologic complications, prolonged ventilatory support, increased hospital cost, and prolonged hospitalization were significantly more prevalent (all p less than 0.05) in patients older than 75 years. Five and 10 years postoperatively, there were no significant differences between groups I and II with regard to event-free status including angina, myocardial infarction, and reoperation. The 5-year survival rate was 92% for group I and 80% for group II (p less than 0.05), similar to that of age-matched control subjects. The significantly increased potential for complications and expense of coronary bypass in patients over 75 years of age mandates judicious patient selection and preoperative counseling. Despite a significantly increased early mortality and an anticipated decreased long-term survival paralleling normal life table survival curves, good intermediate functional improvement can be realized in patients older than 75 years, comparable with that expected in a much younger age group.

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Phosphorothioate oligodeoxynucleotides (S-ODNs) have potential as anti-viral agents and are being investigated for the chemotherapy of AIDS. A high-performance liquid chromatographic method is described for the analysis, in urine and plasma, of a 28-unit deoxycytidine homopolymer (S-dC28) and a 28-unit S-ODN "antisense" to the rev gene of the human immunodeficiency virus. This method employs ion-pairing HPLC with a polymeric column. Tetrabutylammonium is used as the ion-pairing agent in a mobile phase of acetonitrile in pH 7.0 phosphate buffer. Analysis of the S-ODNs is relatively rapid (20 min) and sensitive (20 nm) and is accomplished by a gradient elution (22.5-30.0% acetonitrile) followed by ultraviolet (266 or 272 nm) absorption detection. This method is likely applicable, with appropriate modifications, to all S-ODNs of similar molecular weight regardless of sequence. The S-ODNs bind very strongly to plasma proteins but are readily prepared for analysis by a phenol extraction procedure. In a preliminary pharmacokinetic study in mice with S-dC28, very rapid elimination of the oligomer from plasma was observed (half-time, 11.6 min). Estimates for the apparent volume of distribution and total body clearance were 3 ml and 0.2 ml/min, respectively. It appears that the majority of the oligomer is eliminated by renal clearance (glomerular filtration), a property likely shared by all S-ODNs of similar molecular mass.

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During an 18-year period a consecutive series of 6591 patients underwent primary coronary bypass grafting and 508 patients underwent reoperative bypass. The mean patient age for the reoperative group was identical to that of the primary group, 59.8 years, but the mean age at initial operation for the reoperative group was 55.2 years. Mammary grafts were done at initial operation in 59% of patients who have had one operation versus only 46% of patients who subsequently required reoperation (p less than 0.001). The overall operative mortality rate was 2.0% (134/6591) for primary coronary bypass versus 6.9% (35/508) for reoperations (p less than 0.001). Patients with a reoperative interval of 1 to 10 years had a 6.0% (18/312) mortality rate, compared with 17.6% (13/74) for those in whom the interval between operations was greater than 10 years (p less than 0.01). Ventricular arrhythmias, excessive bleeding, prolonged ventilatory support, intraaortic balloon pump insertion (all p less than 0.05), and perioperative myocardial infarction (p less than 0.001) were all more prevalent after reoperations. Including perioperative mortality, the actuarial survival rate at 5 years was 80% for reoperations versus 90% for primary operations. The corresponding figures at 10 years were 65% and 75%. The probability of undergoing reoperation within 5 and 10 years was 0.034 +/- 0.003 and 0.055 +/- 0.005, respectively. Ten years postoperatively, 36% of patients having the initial operation had recurrent angina whereas 58% of the reoperative group had significant recurrent angina. Ten years after reoperation, 30% of operative survivors were free of heart-related morbidity and mortality compared with 50% of patients having a primary operation. Univariate analysis of factors increasing the probability of reoperation include the absence of a mammary graft and younger age at operation. Patients undergoing a second bypass operation represent a substantially higher risk subgroup than patients undergoing initial operation in terms of perioperative morbidity, mortality, decreased long-term survival, and decreased relief of recurrent cardiac morbidity.

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A hybrid of the techniques of cellular adhesion chromatography and field-flow fractionation has been used for the effective separation of rat mesenteric B and T lymphocytes with nearly complete recovery of both cell species. Use of this hybrid technique also allows the relative binding strengths of cells to biomaterials and other surfaces to be rapidly and simply estimated. For the copolymer surface used here, B cells appear to bind with a force five times greater than T cells.

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Overflow of dopamine has been measured with a rapid superfusion apparatus in an attempt to obtain a system in which overflow is a measure of the primary release process. The tissue samples employed, chopped tissue and synaptosomes, were prepared from rat striatum. The superfusion system employed an on-line amperometric detector to provide temporal information. In addition, liquid chromatography with electrochemical detection was used for identification and quantification of dopamine. Dopamine release could be induced from both samples by exposure to K+ in the presence of Ca2+. The presence of pargyline (0.1 mM) did not significantly affect overflow from either sample. In addition, dopamine stores could be replenished in both samples by exposure to 0.5 microM DA, an effect blocked by amphetamine, nomifensine, and amfonelic acid. However, overflow from synaptosomes showed considerably less distortion from interactions of released substances with the tissue than from chopped tissue. The temporal profile of overflow was more rapid and uptake inhibitors did not affect overflow during depolarization. Since overflow from synaptosomes appears to be more closely related to release, the temporal response of this preparation to K+ stimulations was examined in more detail. A linear relation between dopamine overflow and log (K+) was obtained with 3-s exposures to K+. In contrast, a sigmoidal relationship was obtained with 30-s exposures. Thus, the data support the concept that depolarization of nerve terminals by K+ is a biphasic process that can be temporally resolved.

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Uptake of dopamine (DA) by chopped tissue prepared from rat corpus striatum has been examined to determine whether one or two kinetically distinct uptake sites exist. Two methods were used: direct measurement of accumulated [3H]DA and determination of the rate of formation of 3,4-dihydroxyphenylacetic acid (DOPAC) after exposure to DA. The rate of formation of DOPAC in the latter experiments is a direct function of the rate of DA uptake. The rates of [3H]DA uptake and DOPAC formation are both linear with time in the presence of 10 microM substrate. Studies of [3H]DA accumulation into chopped tissue reveal two apparent components with Km values of 160 nM and 3.8 microM, whereas similar experiments with striatal homogenate or synaptosomes yield a single uptake component with a Km equivalent to the lower value found in chopped tissue. Evaluation of DA uptake via the rate of DOPAC formation gave a Km value of 2.3 microM. (High substrate values were used, so a lower value for Km is not apparent in the data.) The high Km-value component was absent in animals with a lesioned striatum induced by prior nigral injections of 6-hydroxydopamine. Several pharmacologic agents (benztropine, amfonelic acid, bupropion, nomifensine and ouabain) were evaluated. All reduced the uptake of DA in chopped tissue, but with reduced potencies compared with the effect of these agents in synaptosomes. The high Km activity in chopped tissue, as well as the apparent reduced potency of uptake inhibitor, appears to arise from the diffusional barrier present inside more intact tissue. This barrier is not present in homogenates or synaptosomes, and, thus, a single uptake process is seen.

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The incidence of prior percutaneous transluminal coronary angioplasty in surgical cases is nearly doubling yearly. In 1985, 11.4% of our bypass patients had one or more prior angioplasties. One hundred thirty-five patients with prior angioplasty are compared to 2,205 patients without angioplasty undergoing surgical revascularization. The mortality is 3.2 times higher in the angioplasty patients than in the control patients and the perioperative infarction rate is 2.5 times higher. Forty-four patients were taken directly to the operating room from the catheterization laboratory, 50 were operated on within 10 days, and 41 underwent operation more than 10 days after angioplasty. All of these late failures were of the lesion previously dilated. The infarction rate was less in patients taken immediately to the operating room on an emergency basis than in those whose operation was delayed up to 10 days (30% versus 70%). All patients who died had angioplasty of the anterior descending coronary artery. Angioplasty of this artery increases operative mortality should surgical treatment become necessary acutely. Patients should be informed before angioplasty of the increased surgical risks after a failed angioplasty procedure.

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In vivo voltammetry has been used to measure the release of dopamine evoked by electrical stimulation of the medial forebrain bundle (MFB). Simultaneous measurements have been made with voltammetric-sensing electrodes ipsilateral to the stimulating electrode in the nucleus accumbens and the caudate nucleus of the anesthetized rat. During the stimulation, the species observed in both regions is voltammetrically identical to dopamine. Further evidence for the identity of dopamine is provided by anatomical, physiological, pharmacological, and postmortem data. Postmortem analysis of these brain regions after a single stimulation demonstrates that dopamine levels are unchanged, while dihydroxyphenylacetic acid (DOPAC) levels are increased in both regions. Systemic application of synthesis inhibitors results in a decrease in evoked release for each brain region. Amfonelic acid results in a restoration of stimulated release after synthesis inhibition. Evoked release is affected differently by pargyline in the two brain regions. The evoked release of dopamine is significantly elevated in the nucleus accumbens as a result of pargyline administration, but similar effects are not seen in the caudate nucleus. Tissue levels of dopamine are increased in both brain regions by pargyline, but the increase is significantly greater in the accumbens. Electrolytic lesions of the striatonigral pathway or systemic administration of picrotoxin eliminates the pargyline-induced difference in evoked release of dopamine. Amphetamine causes a reduction in stimulated release in the caudate nucleus with little effect on that observed in the nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)

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An increase in the concentration of ascorbate in the extracellular fluid of the rat striatum following systemic amphetamine administration previously has been demonstrated with the use of in vivo electrochemistry, push-pull cannula and in vivo dialysis. In this report, the effect of infusions of amphetamine into the substantia nigra on extracellular ascorbate levels in the striatum is further investigated by in vivo electrochemistry. Electrolytic lesions in the crus cerebri of the striatonigral pathway abolish this effect. Furthermore, these lesions abolish the effect of systemic amphetamine in the striatum ipsilateral to the lesion but not on the contralateral side. This phenomenon is independent of neostriatal dopamine or gamma-aminobutyric acid since levels were shown to be unchanged relative to the intact side. These results lend further support to the hypothesis that ascorbate secretion in the striatum after amphetamine is mediated in the central nervous system, and indicate that a pathway that courses through the crus cerebri is necessary for this release.

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Currently it is possible to account for an incidence of perfusion-related perioperative stroke of about 1%. The sources of stroke over which cardiac surgeons have some control relate to the perfusion circuit, the conducting of coronary pulmonary bypass, the operative approach to the patient with intracardiac clot, maneuvers that eliminate air during left heart procedures, control of biochemical factors such as hyperglycemia, and to the choice of anesthetic agents and drugs given during the procedure. The availability of equipment that allows in-line continuous monitoring of arterial and venous O2 saturations, control of physiologic parameters within certain limits, selective use of encephalographic monitoring for high-risk patients, along with careful attention to the details of the procedure, may allow the surgeon to alter favorably the numbers of patients suffering neurologic complications as a consequence of cardiac surgery. We have limited our investigation in this study to those neurologic events occurring from the onset of anesthesia through the recovery from anesthesia when the patient can be neurologically examined.

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Release of endogenous dopamine (DA) and gamma-aminobutyric acid (GABA) from superfused rat caudate synaptosomes was monitored with liquid chromatography with electrochemical detection. Dopamine was analyzed by oxidative detection following alumina extraction while GABA was analyzed with reductive detection following pre-column derivatization with trinitrobenzenesulfonic acid and extraction. Both spontaneous and K+-stimulated (40 mM) release were examined as well as the effect of several possible neuromodulatory agents (DA, GABA, muscimol, ascorbic acid, acetylcholine). The content of GABA in the sample and the amount released by K+ were approximately fifty times those of DA although the relative amounts released by repetitive K+ stimulations were similar. Muscimol and DA significantly attenuated both the spontaneous and stimulated release of GABA while ascorbate and acetylcholine had no effect. Acetylcholine significantly increased both the stimulated and spontaneous release of DA while the other agents had no effect. Dopamine showed an absolute dependence on calcium for stimulated release while GABA exhibited a significant calcium-independent release. These results indicate that profound differences exist in the factors which modulate the release of endogenous DA and GABA.

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Gamma-aminobutyric acid (GABA) was found to induce the release of ascorbic acid from rat striatal homogenates and minces. This release was studied with the use of a rapid superfusion system with an on-line amperometric detector that monitors for the presence of easily oxidized substances (i.e., ascorbate, 3,4-dihydroxyphenylethylamine). The release was found to be calcium-independent and depolarization-dependent. This releasable pool of ascorbate could be replenished through nonstereospecific uptake. The releasing action of GABA was mimicked by the GABA agonist, muscimol, and was completely inhibited by the GABA antagonist, picrotoxin. The structural analogues of GABA, beta-alanine and gamma-hydroxybutyric acid, had no effect. These data indicate that ascorbate release is GABA-receptor mediated and synaptically localized.

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Microvoltammetric electrodes were used to monitor dopamine released in the caudate nucleus of the rat after electrical stimulation of the medial forebrain bundle. The time resolution of the technique is sufficient to determine in vivo concentration changes on a time scale of seconds. Direct evidence identifying the substance released as dopamine was obtained both voltammetrically and pharmacologically. Administration of alpha-methyl-p-tyrosine terminates the release of dopamine, although tissue stores of dopamine are still present. Thus there appears to be a compartment for dopamine storage that is not available for immediate release. This compartment appears to be mobilized by amfonelic acid, since administration of this agent after alpha-methyl-p-tyrosine returns the concentration of dopamine released by electrical stimulation to 75 percent of the original amount.

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Surgical therapy for dissection of the thoracic aorta has been associated with a high mortality rate due in part to intraoperative bleeding at the suture lines and through the prosthesis. A technique has been devised to obviate some of these problems which utilizes a sutureless prosthesis that can be placed within the aorta. This device is now commercially available. Because of the infrequent use and the need to maintain a wide variety of lengths and diameters of these grafts, several Portland area hospitals jointly purchased grafts to reduce inventory and cost. From November 1981 through September 1982, four patients in two Portland area hospitals were treated with intraluminal grafts for descending thoracic dissections. All patients survived the surgical treatment and were discharged without complications. Based on a review of the literature and our initial experience, the intraluminal prosthesis appears to represent a significant improvement over conventional graft placement for treatment of both acute and chronic aortic dissection.

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A consecutive series of 3,707 patients over a 12 year period undergoing isolated coronary artery bypass grafting (CABG) included 250 diet/oral medication-controlled and 162 insulin-dependent patients with diabetes mellitus. Analysis of 20 pre- and 18 intra-operative variables revealed a higher incidence of hypertension, left ventricular hypertrophy, and tobacco consumption for both diabetic groups. The extent of diffuse coronary disease as judged angiographically and at operation was significantly greater in both diabetic groups than in nondiabetic CABG patients. No difference was noted in the incidence of localized coronary disease between the groups. Average number of grafts was greater in both diabetic groups. The perioperative mortality was greater for both diabetic groups (5.1% for non-insulin-dependent diabetes, 4.5% for insulin-dependent diabetes) than for nondiabetic CABG patients (2.5%). The incidences of sternotomy complications and renal insufficiency were equal in the diabetic groups and both were significantly greater than in the nondiabetic group. The number of total hospital days was also greater in both diabetic groups. Actuarially determined survival and cardiac event-free curves revealed no difference between the diabetic groups but a significant difference between both diabetic groups as compared to the nondiabetic patient population, with follow-up extending to 10 years after CABG. Results indicate that diabetic patients have quantitatively and qualitatively more coronary artery disease than nondiabetic patients and have higher perioperative morbidity and mortality and a lower long-term survival rate than nondiabetic patients. However, results continue to justify selection of patients for CABG based on clinical and anatomic criteria regardless of diabetic status. Diabetes mellitus should be considered a patient-related risk factor, both short- and long-term, following CABG.

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