Mitochondrial redox impairment and enhanced autophagy in peripheral blood mononuclear cells from type 1 diabetic patients.

Type 1 diabetes (T1D) involves critical metabolic disturbances that contribute to an increased cardiovascular risk. Leukocytes are key players in the onset of atherosclerosis due to their interaction with the endothelium. However, whether mitochondrial redox impairment, altered bioenergetics and abnormal autophagy in leukocytes contribute to T1D physiopathology is unclear. In this study we aimed to evaluate the bioenergetic and redox state of peripheral blood mononuclear cells (PBMCs) from T1D patients in comparison to those from healthy subjects, and to assess autophagy induction and leukocyte-endothelial interactions. T1D patients presented lower levels of fast-acting and total antioxidants in their blood, and their leukocytes produced higher amounts of total reactive oxygen species (ROS) and superoxide radical with respect to controls. Basal and ATP-linked respiration were similar in PBMCs from T1D and controls, but T1D PBMCs exhibited reduced spare respiratory capacity and a tendency toward decreased maximal respiration and reduced non-mitochondrial respiration, compared to controls. The autophagy markers P-AMPK, Beclin-1 and LC3-II/LC3-I were increased, while P62 and NBR1 were decreased in T1D PBMCs versus those from controls. Leukocytes from T1D patients displayed lower rolling velocity, higher rolling flux and more adhesion to the endothelium versus controls. Our findings show that T1D impairs mitochondrial function and promotes oxidative stress and autophagy in leukocytes, and suggest that these mechanisms contribute to an increased risk of atherosclerosis by augmenting leukocyte-endothelial interactions.

Effects of methadone on thyroid function in mother, fetus, and newborn.

The effects of maternal use of methadone during pregnancy on tests of thyroid function were studied in 14 women and their offspring. Twelve normal nonaddicted women and their infants served as a control group. Concentrations of thyrotropin (TSH), thyroxine (T4), and triiodothyronine (T3) were not significantly different in maternal and cord serum, and in infant serum at age 24 hours. There was no significant difference in infants' TSH concentrations at 2, 3, and 7 days of age. At 2 and 7 days, T3 levels were significantly higher in the methadone than in the control group (P = .01 and less than .01, respectively). At 3 days, differences were of borderline significance (P = .08). Increased T4 levels in the methadone group of infants were statistically significant at 2 days (P less than .01) and at 3 and 7 days (P = .05). The mechanisms responsible for the biochemical evidence of hyperthyroidism were not determined, but may have been related to altered autonomic function and/or increased metabolic activity which occurs during neonatal narcotic withdrawal.

Aortic valve replacement with cryopreserved aortic allograft: ten-year experience.

OBJECTIVE: Cryopreserved aortic allograft can be used for aortic valve replacement in congenital, rheumatic, degenerative, and infected native valve conditions, as well as failed prosthetic valves. This study was conducted to determine the long-term results of aortic valve replacement with cryopreserved aortic allografts. METHODS: Aortic valve replacement with cryopreserved aortic allografts was performed in 117 patients from July 1985 until August 1996. All patients requiring aortic valve replacement regardless of valve disease were considered for allograft replacement; the valve was preferentially used in patients under age 55 years and in the setting of bacterial endocarditis. Four operative techniques involving cryopreserved aortic allografts were used: freehand aortic valve replacement with 120-degree rotation, freehand aortic valve replacement with intact noncoronary sinus, aortic root enlargement with intact noncoronary sinus, and total aortic root replacement. Valve function was assessed by echocardiography during the operation in 78 patients (66%) and after the operation in 77 patients (65%). RESULTS: One-hundred eighteen aortic valve replacements with cryopreserved aortic allografts were performed on 117 patients; mean age was 45.6 years (range 15 to 83 years) and mean follow-up was 4.6 years (range up to 11 years). Intraoperative echocardiography disclosed no significant aortic valve incompetence. There were four operative deaths (3%) and seven late deaths; freedom from valve-related mortality at 10 years was 9:3% +/- 4.55%. New York Heart Association functional status at latest follow-up was normal in 98 (94%) patients. On postoperative echocardiography, 90% had no or trivial aortic valve incompetence. Freedom from thromboembolism at 10 years was 100% and from endocarditis, 98% +/- 2.47%. Seven (6%) patients required valve explantation, four for structural deterioration. At 10 years, freedom from reoperation for allograft-related causes was 92% +/- 3.47%. CONCLUSIONS: Aortic valve replacement with cryopreserved aortic allografts can be performed with low perioperative and long-term mortality. Most patients have excellent functional status, and reoperation for valve-related causes is unusual. Aortic valve replacement with cryopreserved aortic allografts demonstrates excellent freedom from thromboembolism, endocarditis, and progressive valve incompetence.

Early experience with minimally invasive direct coronary artery bypass grafting with the internal thoracic artery.

OBJECTIVE: Minimally invasive direct coronary artery bypass is performed under direct vision without sternotomy or cardiopulmonary bypass. The technique can be used in both primary and reoperative cases by employing the internal thoracic artery to perform arterial revascularization of the anterior surface of the heart. METHODS: Patients were selected who had significant coronary artery disease limited to 1 or 2 coronary distributions on the anterior surface of the heart. Coronary target vessels were grafted with the internal thoracic artery through a small anterior thoracotomy. After partial heparinization the anastomosis was facilitated by local coronary occlusion and handheld stabilization. RESULTS: Between August 1994 and July 1997, 162 patients underwent minimally invasive direct coronary artery bypass grafting with the internal thoracic artery. The left and right internal thoracic arteries were used for grafting of the left anterior descending artery in 142 patients (88%), the proximal right coronary artery in 7 patients (4%), existing saphenous vein grafts in 5 patients (3%), and diagonal branches in 2 patients (1%). Sequential grafting with the left internal thoracic artery was performed in 2 patients (1%) and bilateral internal thoracic artery grafting was performed in 4 patients (3%). Eight patients (4.9%) died within 30 days after the operation, 3 of cardiac causes. Seven additional patients died during the follow-up period. Nine patients (5.6%) required reintervention for graft stenosis or occlusion during follow-up. Of 141 patients seen 2 or more weeks after the operation, 135 (96%) had resolution of their anginal symptoms at a mean follow-up of 12 months (range 0-31 months). CONCLUSIONS: Anterior minimally invasive direct coronary artery bypass grafting with the internal thoracic artery avoids the risks of repeated sternotomy, aortic manipulation, and cardiopulmonary bypass. There was a low rate of reintervention, and patients had excellent resolution of anginal symptoms. Postoperative length of stay was comparatively short, and continued follow-up will be essential to evaluate long-term graft patency and patient survival.

Relationship of the long thoracic nerve to the scapular tip: an aid to prevention of proximal nerve injury.

OBJECTIVE: The objective was to determine the course of the long thoracic nerve relative to the scapula as an aid to the prevention of proximal long thoracic nerve injuries. METHODS: Eighteen fresh cadavers (7 male, 11 female) were studied. Each was sequentially placed in the transaxillary and posterolateral thoracotomy positions, and the distance of the long thoracic nerve from the scapular tip and anterior scapular border was measured. The measurements were made bilaterally; the mean, standard deviation, and 99% confidence interval were calculated for each position by gender. RESULTS: Distances from the scapular tip to the long thoracic nerve are listed as mean/outer range: transaxillary thoracotomy, male 4.9/7.0 cm left, 5.2/7.5 cm right; female 4.3/5.0 cm left, 4.7/6.0 cm right; posterolateral thoracotomy, male 3.1/6.0 cm left, 4.5/5.1 cm right; female 3.2/4.5 cm left, 3.8/5.5 cm right. In all instances, the long thoracic nerve was furthest from the scapula at its tip. CONCLUSION: For patients positioned for a transaxillary thoracotomy, incision sites should be at least 7.5 and 6.0 cm anterior to the scapular tip for male and female patients, respectively. For patients in posterolateral thoracotomy positioning, incisions should be 6.0 and 5.5 cm anterior to the scapular tip for male and female patients, respectively. By using these anatomic guidelines, we believe that the incidence of iatrogenic proximal long thoracic nerve injury can be minimized.

The changing profile of the cardiac donor.

BACKGROUND: Expansion of traditional donor criteria has become standard in most centers. To determine how this has affected donor profiles, at our institution, we reviewed all adult (age > or = 16) cardiac donors of the past 15 years. METHODS: We separated 261 cardiac donors into 2 groups based on time periods: Group I, 1983 to 1991 (n = 131), and Group II, 1991 to 1998 (n = 130). RESULTS: The groups differed significantly in mean donor age (26.2 years vs 30.9; p < 0.001), percent older than 40 years (6% vs 27%; p < 0.001), percent female (23% vs 35%; p = 0.04), percent distant procurement (54% vs 22%; p < 0.001), and percent minority donors (14% vs 29%; p < 0.001). We found an increase in non-traumatic deaths (24% vs 40%; p = 0.008). Older donors had significantly more non-traumatic deaths than younger donors (79% vs 13%; p < 0.001). Overall 5-year survival of recipients was 64% and was not significantly different between our early and late experiences (60% vs 68%; p = not significant [NS]). Recipients with hearts from older donors had a 5-year survival similar to recipients with younger donor hearts (61% vs 64%; p = NS). Traumatic and non-traumatic donors had similar 5-year survivals (64% vs 63%, p = NS). A stepwise multivariate analysis of the entire cohort identified donor age, donor weight, recipient United Network for Organ Sharing status, and cardiopulmonary bypass time as significant independent risk factors for recipient survival. Recipients of hearts from donors < 90 kg had significantly better 5-year survivals than recipients from donors > or = 90 kg (66% vs 48%; p = 0.01). CONCLUSIONS: Our evolving cardiac donor pool now has more minorities, women, and older donors whose deaths are often non-traumatic. At our institution, donor pool expansion has had no adverse effect on the long-term survival of recipients.

Initial experience with MIDCAB grafting using the gastroepiploic artery.

BACKGROUND: Minimally invasive direct coronary artery bypass grafting with the gastroepiploic artery can be used in primary operations and reoperations to revascularize the inferior or anterior surface of the heart. METHODS: Patients who had symptomatic coronary artery disease limited to a single coronary distribution were selected. Coronary targets were grafted with the pedicled gastroepiploic artery through a small midline epigastric incision. Patients were followed with scheduled outpatient clinic visits, Doppler examination, and selective recatheterization. RESULTS: Between May 1995 and November 1997, 74 patients underwent gastroepiploic artery minimally invasive direct coronary artery bypass grafting; 33 (45%) had a primary operation and 41 (55%), a reoperation. Grafting was performed to the distal right coronary artery (n = 38), the posterior descending artery (n = 28), or the distal left anterior descending coronary artery (n = 8). There were six deaths (8%) within 30 days after operation. Twenty patients (28%) underwent recatheterization; there were two graft occlusions, two graft stenoses, and five anastomotic stenoses. Of 60 patients seen 2 or more weeks after operation, 53 (88%) had resolution of anginal symptoms at a mean follow-up of 10.9 months (range, 0 to 30 months). CONCLUSIONS: Inferior minimally invasive direct coronary artery bypass grafting with the gastroepiploic artery avoids the risks of repeat sternotomy, aortic manipulation, and cardiopulmonary bypass. Patency rates, however, were lower than expected, and there is significant morbidity and mortality associated with high-risk patients undergoing the procedure. Continued follow-up is essential to evaluate long-term graft patency and patient survival.

Stroke after cardiac surgery: short- and long-term outcomes.

BACKGROUND: Stroke remains a devastating complication of cardiac surgery, but stroke prevention remains elusive. Evaluation of early and long-term clinical outcomes and brain-imaging findings may provide insight into stroke prognosis, etiology, and prevention. METHODS: Five thousand nine hundred seventy-one cardiac surgery patients were prospectively studied for clinical evidence of stroke. Stroke and nonstroke patients were compared by early outcomes. Data collected for stroke patients included brain imaging results, long-term functional status, and survival. Outcome predictors were then determined. RESULTS: Stroke was diagnosed in 214 (3.6%) patients. Brain imaging demonstrated acute infarction in 72%; embolic in 83%, and watershed in 24%. Survival for stroke patients was 67% at 1 year and 47% at 5 years. Independent predictors of survival were cerebral infarct type, creatinine elevation, cardiopulmonary bypass time, preoperative intensive care days, postoperative awakening time, and postoperative intensive care days. Long-term disability was moderate to severe in 69%. CONCLUSIONS: Stroke after cardiac surgery has profound repercussions that are independently related to infarct type and clinical factors. These data are essential for clinical decision making and prognosis determination.

The autopsy: still important in cardiac surgery.

BACKGROUND: This study examined the ability of autopsy to confirm or dispute presumptive cause of death among cardiac surgery patients. METHODS: Autopsy reports were compared with mortality conference notes that were dictated prospectively before autopsy results were available. Between January 1985 and December 1995, there were 600 hospital deaths among 13,029 adult cardiac surgery patients (4.6% mortality). Of these 600 deaths, 147 (24.5%) had postmortem examination. RESULTS: Annual autopsy rate remained constant over the course of the study. Autopsied patients were younger (60.4 +/- 15 versus 66.7 +/- 13 years [mean +/- standard error of the mean]; p < 0.0001), but their race and sex distributions were similar to deceased patients not having autopsy. Autopsy confirmed clinical presumptive cause of death in 52% (76), disputed clinical diagnosis in 9.5% (14), provided definitive diagnosis in the absence of clinical diagnosis in 13.6% (20), and failed to provide definitive diagnosis in 25% (37). One third of autopsies (39%; 57) provided information that was clinically unrecognized and might have altered therapy and outcome if known premortem. As determined by autopsy, common causes of death were cardiac (27%; 39), unknown (25%; 37), sepsis (14%; 21), stroke (8.8%; 13), cholesterol embolism (4.1%; 6), pulmonary embolism (4.1%; 6), and adult respiratory distress syndrome (4.1%; 6). CONCLUSIONS: Autopsy reveals or confirms cause of death in nearly three quarters of cardiac surgical deaths and provides information that differs significantly from premortem clinical impression more than 20% of the time. As such, the autopsy remains important to quality assurance in cardiac surgical care.

Assessing the impact of cerebral injury after cardiac surgery: will determining the mechanism reduce this injury?

BACKGROUND: Central nervous system dysfunction continues to produce significant morbidity and associated mortality in patients undergoing cardiac surgery. Using a closed-chest canine cardiopulmonary bypass model, dogs underwent 2 h of hypothermic circulatory arrest (HCA) at 18 degrees C, followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis, biochemically by analysis of microdialysis effluent, and by receptor autoradiography for N-methyl-D-aspartate (NMDA) glutamate receptor subtype expression. RESULTS: Using a selective NMDA (glutamate) receptor antagonist (MK801) and an AMPA antagonist (NBQX), glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. A microdialysis technique was employed to evaluate the role of nitric oxide (NO) in neuronal cell death. Arginine plus oxygen is converted to NO plus citrulline (CIT) by the action of NO synthase (nNOS). CIT recovery in the cerebrospinal fluid and from canine cortical homogenates increased during HCA and reperfusion. These studies demonstrated that neurotoxicity after HCA involves a significant and early induction of nNOS expression, and neuronal processes leading to widespread augmentation of NO production in the brain. To further investigate the production of excitatory amino acids in the brain, we hypothesized the following scenario: HCA--> increased glutamate, increased aspartate, increased glycine--> increased intracellular Ca2+--> increased NO + CIT. Using the same animal preparation, we demonstrated that HCA caused increased intracerebral glutamate and aspartate that persists up to 20 h post-HCA. HCA also resulted in CIT (NO) production, causing a continued and delayed neurologic injury. Confirmatory evidence of the role of NO was demonstrated by a further experiment using a specific nNOS inhibitor, 7-nitroindazole. Animals underwent 2 h of HCA, and then were evaluated both physiologically and for NO production. 7-Nitroindazole reduced CIT (NO) production by 58.4 +/- 28.3%. In addition, dogs treated with this drug had superior neurologic function compared with untreated HCA controls. CONCLUSIONS: These experiments have documented the role of glutamate excitotoxicity in neurologic injury and have implicated NO as a significant neurotoxin causing necrosis and apoptosis. Continued research into the pathophysiologic mechanisms involved in cerebral injury will eventually yield a safe and reliable neuroprotectant strategy. Specific interventional agents will include glutamate receptor antagonists and specific neuronal NO synthase inhibitors.

Reoperative MIDCAB grafting: 3-year clinical experience.

OBJECTIVE: Minimally invasive direct coronary artery bypass (MIDCAB) is performed under direct vision without sternotomy or cardiopulmonary bypass. The technique is used in reoperative patients through various incisions to revascularize one or two areas of the heart. The internal mammary artery, gastroepiploic artery, radial artery, or saphenous vein are used as graft conduits. METHODS: Anterior coronary targets are grafted with the internal mammary artery via a small anterior thoracotomy. Inferior coronary targets are grafted with the gastroepiploic artery via a small midline epigastric incision. Lateral coronary targets are grafted with radial artery or saphenous vein via a posterior thoracotomy. After partial heparinization, the anastomosis is facilitated by local coronary occlusion and stabilization. Graft follow-up consists of outpatient Doppler examination and selective recatheterization. RESULTS: Between January 1994 and August 1997, 81 patients underwent reoperative MIDCAB grafting. Twenty-one patients (25.9%) had internal mammary grafting, 39 (48.2%) had gastroepiploic grafting, and 21 (25.9%) had lateral grafting with radial artery or saphenous vein. There were nine early deaths (four cardiac, five non-cardiac), five late deaths (three cardiac, two non-cardiac), and nine myocardial infarctions in remaining patients. Sixteen patients underwent recatheterization; there were one graft occlusion, two graft stenoses, and eight anastomotic stenoses. Mean postoperative length of stay was 3.8 days. Ninety percent (55/61) of patients are free of symptoms at a mean follow-up of 7.8 months (range 0-39). CONCLUSIONS: Reoperative MIDCAB grafting avoids the risks of resternotomy, aortic manipulation, and cardiopulmonary bypass. The techniques yield an early patency rate of 94%, which includes eight patients who had postoperative catheter-based interventions. Reoperative MIDCAB grafting had lower rates of supraventricular arrhythmia and transfusion when compared with conventional coronary artery bypass grafting, but did not offer an advantage for mortality, stroke or myocardial infarction. This 3-year experience suggests that while reoperative MIDCAB grafting can effectively revascularize focal areas of the heart, patients should be carefully selected to minimize operative risk.

Freeman-Sheldon syndrome with unusual hand and foot anomalies.

A newborn with the characteristic facies of Freeman-Sheldon syndrome (whistling face syndrome) and unusual hand and foot anomalies is reported. Flexion contractures of fingers were so severe as to prevent their extension. Previously reported patients with similar hand anomalies had only mild to moderate limitation of extension. Over 75 percent of the 29 previous cases of this syndrome had equinovarus deformity. Not only was this deformity absent but the patient had polysyndactyly of the big toe, an anomaly not previously associated with this syndrome.

Modelling non-systemic pesticide residues in fruits with initial deposit variability and weather effects.

A flexible and generic model was developed to predict the decline of residues of a non-systemic pesticide for both single and multi-spray situations as well as for different tree canopy zones. The model predicts not only the average residue levels, but also the confidence interval of the residues through either a deterministic or a stochastic approach. This generic model includes several key aspects of residue fates in the environment: initial deposit, physical loss and growth dilution. The model considers a tree canopy in three distinct zones for which initial deposition of pesticides may differ. In addition to predicting the average residue within each zone, it also estimates the 95 and 99% confidence intervals of residues on individual fruit within each zone. For the purpose of evaluation, this model was parameterized specifically for captan, one of the most important non-systemic fungicides used to control disease in horticultural crops. The observed average initial deposit for each zone was used in the evaluation. The overall correlation between predicted average residues and those observed on apple fruit in two applications was 0.93. Confidence intervals were also predicted accurately.

Uncovering the design principles of circadian clocks: mathematical analysis of flexibility and evolutionary goals.

In this paper, we present the mathematical details underlying both an approach to the flexibility of regulatory networks and an analytical characterization of evolutionary goals of circadian clock networks. A fundamental problem in cellular regulation is to understand the relation between the form of regulatory networks and their function. Circadian clocks present a particularly interesting instance of this. Recent work has shown that they have complex structures involving multiple interconnected feedback loops with both positive and negative feedback. We address the question of why they have such a complex structure and argue that it is to provide the flexibility necessary to simultaneously attain multiple key properties of circadian clocks such as robust entrainment and temperature compensation. To do this we address two fundamental problems: (A) to understand the relationships between the key evolutionary aims of the clock and (B) to ascertain how flexible the clock's structure is. To address the first problem we use infinitesimal response curves (IRCs), a tool that we believe will be of general utility in the analysis of regulatory networks. To understand the second problem we introduce the flexibility dimension d, show how to calculate it and then use it to analyse a range of models. We believe our results will generalize to a broad range of regulatory networks.

Noninvasive graft flow and patency assessment following minimally invasive direct coronary artery bypass (MIDCAB) grafting.

OBJECTIVE: Assessment of graft patency following minimally invasive direct coronary artery bypass (MIDCAB) surgery is essential in order to determine the efficacy of this technique. This study was conducted to evaluate the role of intraoperative and postoperative noninvasive flow and velocity measurements to follow and predict graft performance. METHODS: Between April 1996 and July 1997, 130 patients had 133 grafts placed using MIDCAB techniques. Intraoperative transit-time ultrasound was used to assess graft patency and flow prior to wound closure. Also, serial transcutaneous doppler examinations were performed to evaluate graft patency on the first postoperative day, at two weeks, and at three months. Peak values for systolic and diastolic waveforms were measured for both flow and velocity, and the diastolic-to-systolic ratio was calculated at each time interval. Recatheterization was performed selectively for inadequate ultrasound flow or doppler velocity, or for patient symptoms. RESULTS: Seven (5.3 %) grafts developed stenosis or occlusion. When compared to normal grafts, mean intraoperative flows, flow ratios, and velocity ratios were lower. Mean postoperative diastolic peak velocity (DPV) to systolic peak velocity (SPV) ratio remained stable over time for normal grafts; however, grafts with stenosis or occlusion demonstrated a diminished DPV/SPV ratio. CONCLUSIONS: Intraoperative transit-time ultrasound and outpatient transcutaneous doppler examinations did not reach a predictive value for graft stenosis or occlusion following MIDCAB surgery in this series of patients. However, these data demonstrate trends that may help identify patients at an increased risk for unfavorable events, guiding the use of postoperative recatheterization in such patients.

Conservative management of late rejection after heart transplantation: a 10-year analysis.

OBJECTIVE: Immunosuppressive regimens for rejection after heart transplantation have been modified to reduce infectious complications without diminishing rejection treatment efficacy. A review of a single institutional series was performed to evaluate the influence of conservative management of grade 2 rejection on long-term outcomes after heart transplantation. METHODS: Before 1990, patients with late (>3 months after transplant) grade 2 rejection were treated with supplemental immunosuppressive drugs. Beginning in 1990, patients with late grade 2 rejection were treated conservatively by maintaining the current immunosuppressive regimen without additional therapy. The groups were compared for survival, incidence of subsequent rejection, and incidence of subsequent infection. RESULTS: One hundred twelve patients had one or more episodes of isolated, late grade 2 rejection; 39 (35%) were treated with supplemental immunosuppression (treated group) and 73 (65%) received no additional therapy (nontreated group). The mean time from transplantation to the first episode of isolated grade 2 rejection was 15.6 months in the treated group and 17.8 months in the nontreated group. Graft survival at 5 and 10 years was 69% and 51 %, respectively, in the treated group and 67% and 41 %, respectively, in the nontreated group (p = 0.77). The rates for overall subsequent rejection were 0.031 episodes/patient-month in the treated group and 0.029 episodes/patient-month in the nontreated group (p = 0.64). The rates for early rejection within 6 months of initial grade 2 rejection were 0.044 episodes/patient-month in the treated group and 0.035 episodes/patient-month in the nontreated group (p = 0.56). The rates for overall subsequent infection were 0.018 episodes/patient-month in the treated group and 0.012 episodes/patient-month in the nontreated group (p = 0.05). The rates for early infection within 6 months of initial grade 2 rejection were 0.070 episodes/patient-month in the treated group and 0.032 episodes/patient-month in the nontreated group (p = 0.04). Group comparisons demonstrated a significantly lower incidence of infection in the nontreated group. CONCLUSIONS: Conservative management of late grade 2 rejection neither adversely affects survival nor increases the incidence of subsequent short-term or long-term rejection. This approach lowers the early and late incidence of infection after rejection and may reduce other complications from aggressive supplemental immunosuppression.

Safety and plasma concentrations of bovine superoxide dismutase administered to human premature infants.

The safety and plasma concentrations of bovine superoxide dismutase (SOD), potentially useful in prevention of bronchopulmonary dysplasia, were evaluated in 19 prematures with severe IRDS. All were respirator dependent and required FiO2 greater than 0.7 at 24 h of age. Subcutaneous tests (0.1 mg/kg) and treatment doses (0.25 mg/kg) did not induce wheal and flare or systemic reactions. No abnormalities in serum electrolytes, calcium, glucose, creatinine concentrations, complete blood and platelet counts were noted. Following dose 1, SOD was detectable in all patients at 1 1/2 h and rose slowly to a peak at 4-8 h. Mean levels remained between 0.2 and 0.36 micrograms/ml during the 12-hour interval between doses. Similar responses resulted following doses 2-5 with mean levels between 0.36 and 0.68 micrograms/ml. SOD levels varied directly with serum creatinine levels obtained at the time of SOD administration but other factors such as skin perfusion were not controlled. The present study demonstrates that SOD at a dose of 0.25 mg/kg s.c. can be administered safely to prematures with severe IRDS and resulted in levels associated with therapeutic effects in adults.