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Eur J Cardiothorac Surg 2001;19:756-764
© 2001 Elsevier Science NL
a Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, New York University, One Gustave L. Levy Place, New York, NY 10029, USA
b Department of Neurology, Mount Sinai School of Medicine, New York University, New York, NY, USA
c Department of Neurosurgery, Mount Sinai School of Medicine, New York University, New York, NY, USA
d Department of Biomathematics, Mount Sinai School of Medicine, New York University, New York, NY, USA
Received 18 October 2000; received in revised form 26 March 2001; accepted 26 March 2001.
Corresponding author. Tel.:+1-212-241-8181; fax: +1-212-534-3357
e-mail: chagl{at}hotmail.com
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Key Words: Cyclosporine A • Cycloheximide • Hypothermic circulatory arrest • Intracranial pressure • Apoptosis • Pigs
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Experiments in small animal models provide evidence that a number of very specific and less specific substances seem able to inhibit apoptosis induced by ischemia. The general protein synthesis inhibitor cycloheximide (CHX) has been reported to reduce ischemia-induced apoptosis by inhibiting production of pro-apoptotic substances. Cyclosporine A (CsA), an immunosuppressive agent widely used to reduce rejection after transplantation and to treat autoimmune disorders, also has been shown to have a favorable impact on ischemia-induced reperfusion injury in the brain. Although the mechanism of its action is not fully understood, there are indications that CsA acts both by influencing the inflammatory response of the body to ischemia and reperfusion, and by blocking apoptotic pathways.
The present study was undertaken to assess whether either CsA or cycloheximide can reduce ischemia-induced neurological damage in a chronic porcine model of HCA. Hemodynamic, neurophysiological and behavioral assessments of recovery after HCA were carried out on drug-treated animals and on controls. After 7 days, the brains were harvested for detailed evaluation of the possible effect of CsA or CHX on apoptosis, and the results of this evaluation are presented in the accompanying manuscript.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Each animal underwent preoperative behavioral assessment, intraoperative hemodynamic and metabolic monitoring, and recording of quantitative EEG and cervical as well as cortical somatosensory evoked potentials (SSEP). Postoperative awakening time and scores for early recovery were recorded, and detailed daily gross behavioral/neurological assessment was performed until elective sacrifice on postoperative day (POD) 7. For histopathological assessment all brains were selectively perfused and analyzed by two different methods for a quantitative evaluation of the amount of apoptosis, as described in the accompanying report by Tatton et al. [8].
2.2. Perioperative management and anesthesia
All animals received humane care in compliance with the guidelines ‘Principles of Laboratory Animal Care’ formulated by the National Society for Medical Research and the ‘Guide for the Care and Use of Laboratory Animals’ published by the National Institute of Health (NIH Publication No. 88–23, revised 1985). The protocols for all experiments were approved by the Mount Sinai Institutional Animal Care and Use Committee.
After pretreatment with intramuscular ketamine (15 mg/kg), and atropine (0.03 mg/kg), animals were anesthetized with intravenous pentobarbital (20 mg/kg). After endotracheal intubation, the pigs were ventilated mechanically with a FiO2 of 0.5 and isoflurane 1–2% to maintain deep anesthesia. Paralysis was achieved with intravenous pancuronium (0.1 mg/kg). The ventilator rate and the tidal volume were adjusted to maintain the arterial carbon dioxide tension at about 40 mmHg. End-expiratory carbon dioxide, and inspiratory and expiratory isoflurane were monitored continuously (PPG Biomedical Systems, Model 2010-200 R, Lenexa, KS, USA). Before intervention and after surgery, all animals received cephazoline (15 mg/kg) intravenously.
A bladder catheter (Foley 8-10F) was inserted for online measurement of urine output and temperature probes were placed in the esophagus, rectum and the brain via a small burr hole in the skull. An arterial line was placed in the left femoral artery for pressure monitoring and blood sampling (pH, oxygen tension, carbon dioxide tension, oxygen saturation, base excess, hematocrit, hemoglobin and glucose, lactate, Blood Gas Analyzer, Ciba Corning 865, Chiron Diagnostics, Norwood, MA, USA). A thermodilution catheter (Baxter Healthcare Corp., Irvine, CA, USA) for assessment of cardiac output was inserted in the femoral vein and advanced into the pulmonary artery.
2.3. Electrophysiological evaluation
Electroencephalograpy (EEG): As described previously [2], the periosteum was removed to expose the sagittal and coronal sutures of the calvarium via a midline incision. Five stainless steel screw electrodes were drilled in the skull 2.5 cm to the left and right of the sagittal suture, directly behind the coronal suture and 2.5 cm anterior to the posterior electrodes. The reference and ground electrode was placed over the frontal sinus. Electrodes were connected to a Spectrum 32 EEG machine (Spectrum 32, Cadwell Laboratories Inc., Kennewick, WA, USA), where the signal was amplified, filtered, digitized, and stored on a optical disk for subsequent analysis. At each measurement timepoint, 5 min of continuous EEG was recorded. Because the prognostic value of the EEG is hampered by the use of anesthetic drugs, isoflurane was adjusted to 1% in all animals, and pancuronium was given for muscle paralysis.
Somatosensory evoked potential recording (SSEP): Somatosensory evoked potentials (SSEPs) were recorded from the cervical spine and contralateral parietal cortex in response to stimulation of the left and right median nerves. Amplifiers were set at a 5000 gain with bandpass filters settings of 30–1000 Hz for cervical responses and 10–300 Hz for cortical responses. Electrical stimulation (25 mA, 0.1 ms duration) of the median nerve was delivered through a pair of stainless steel needle electrodes that were inserted at the most distal joint on the posterior surface of each forelimb.
The cervical recording electrode was a long stainless steel needle that was insulated except at the tip (impedance <3000 ohms). The electrode was inserted at approximately the second cervical vertebra and lowered until the spine was contacted. The electrode and its wire lead were held in place by a suture. The most repeatable potential from the cervical site was a negative–positive wave. The latency of the negative wave was 6–8 ms, and the latency of the positive peak was 8–10 ms.
Using a nose reference, a large negative–positive complex could be recorded from electrodes placed at skull sites overlying the parietal cortex. The peak latency of the negative potential was 17–19 ms. Two sets of SSEPs were recorded for each median nerve at each of the measurement timepoints. Each waveform was obtained by averaging the responses to 500 stimuli. The latencies and amplitudes were measured for the positive cervical potential at 7–9 ms and the negative cortical potential at 19–21 ms for all animals. The amplitudes of the responses at the first recording session were used as a baseline. All subsequent amplitude measurements were converted to a percent of the baseline amplitude.
2.4. Intracranial pressure (ICP)
For continuous intracranial pressure monitoring, a parenchymal pressure probe was inserted via a small burr hole in the skull and connected to a transducer (Codman ICP ExpressTM, Johnson and Johnson Prof. Inc., Raynham, MA, USA).
2.5. Operative technique
The chest was opened via a right thoracotomy in the fourth intercostal space. After heparinization (300 IU/kg) the ascending aorta was cannulated with a 16 F arterial cannula, and the right atrium with a single 26 F cannula. Non-pulsatile CPB, using alpha-stat pH management, was initiated at a flow rate of 100 ml/kg per min and then adjusted to maintain a minimum mean arterial pressure of 50 mmHg. To avoid distension of the left ventricle during CPB, a 10 F vent catheter was inserted via the superior pulmonary vein. After initiation of CPB the lungs were allowed to collapse. A heat exchanger was utilized for core cooling, and surface cooling was achieved with the use of a cooling blanket.
The cardiopulmonary bypass circuit included roller pumps, cardiotomy reservoir, and a membrane oxygenator (VPCML Plus, Cobe Cardiovascular Inc., Arvada, CO, USA) which was primed with a bloodless solution consisting of 1000 cc 0.9% NaCl, furosemide (1 mg/kg), heparin (5000 IU) and KCl (1.5 meq/kg). After initiation, CPB was continued for 45 min to reach a deep brain temperature of 20°C and to insure thorough cooling and to avoid an upward drift of the temperature during the period of circulatory arrest. The operating room temperature during HCA was maintained at 18–20°C for the same reason.
In all animals, myocardial protection was afforded by applying iced saline (~4°C) topically during the 90 min interval of HCA. Thereafter, CPB was reinstituted, and core and surface rewarming were begun and continued to an esophageal temperature of approximately 35–36°C. Care was taken to avoid a temperature difference between the perfusate and core temperature of more than 10°C. During weaning from CPB, 3–5 mg/kg per min dobutamine was frequently utilized. In cases with low vascular resistance, norepinephrine was occasionally necessary.
All pigs received intramuscular cephalosporine (15 mg/kg) as well as pain killers (buterophenol 0.1 mg/kg) for the first 3 postoperative days, and were kept in separated pens for the entire observation period, with a 12 h light–dark cycle, and a room temperature of 22–24°C. Animals that refused liquids orally during the first 24 h were treated intravenously with 500 ml of Ringer's solution over 8 h. If solids were refused from the bowl, hand-feeding was performed.
2.6. Study protocol
Measurements of hemodynamics (heart rate, central venous pressure, mean arterial pressure, pulmonary arterial pressure and cardiac output), arterial blood gases, hematocrit, glucose and lactate, as well as temperatures, EEG and SSEP were recorded at six timepoints during the experiments.
Prior to CPB, pigs received in a blinded fashion either CsA, 2.5 mg/kg (n=8), or placebo (50% castor oil, 50% olive oil) (n=6), both diluted in 100 ml 0.9% NaCl over a 10 min interval. Hemodynamic measurements were performed at 5 min intervals for 15 min to study possible drug side-effects. Another 2.5 mg/kg dose of CsA or placebo was given 1 h after CPB in the same fashion. Postoperatively, all animals received daily doses of 5 mg/kg CsA or placebo subcutaneously until elective sacrifice.
Animals in the CHX group (n=8) received a single dose of 1 mg/kg cycloheximide after hypothermic circulatory arrest and weaning from CPB. The CHX-treated and the six control animals in this group had no further injections thereafter until sacrifice on POD7.
2.7. Neurological assessments
After the last hemodynamic and metabolic measurements and closure of the chest, isoflurane was stopped to allow spontaneous breathing via the endotracheal tube. Awakening time was recorded, as was the time at which adequacy of breathing, movement, and recovery of consciousness allowed extubation. For the first 3 h after extubation, animals underwent examination and evaluation and were scored for what we have termed ‘early recovery.’
Early activity
We also tried to assess mental/emotional status and orientation during the same early recovery interval.
Lack of confusion
The maximum score in each early recovery category is 3, indicating optimal progress in awakening.
2.8. Behavioral score
From POD 1 to POD 7, all animals were scored on a gross behavioral grading scale that evaluated mental status, appetite, and gait, by a physician blinded to the experimental protocol, as described in earlier reports [1]. Daily scores were determined after several time-standardized inspections in the morning, at noon and in the evening. A score of 9 is normal, and 0 indicates coma or death.
2.9. Perfusion-fixation and tissue preparation
Brains were perfusion-fixed in situ using buffered formaldehyde, with the head packed in ice. Details of the technique and of subsequent tissue preparation can be found in the accompanying article.
2.10. Histological assessment
Histological evaluation was carried out by a neurobiologist with extensive experience evaluating apoptosis who was blinded to the experimental intervention. Details of the technique, as well as the results, are to be found in the accompanying article in this journal [8].
2.11. Statistical methods
Animals were randomized to control and treatment groups by an independent party, who also coded and labeled all doses of CsA, CHX and placebo. Although the necessity of subcutaneous injection of cyclosporine differentiated those animals given either cyclosporine and its control from those given either cycloheximide or its control, this should not have introduced any bias since cyclosporine and cycloheximide groups were not directly compared with one another, but each only with control animals. The control groups were combined to conserve the number of animals required for the experiment: as anticipated, they did not differ from one another. Thus, even the surgical team, in addition to the individuals analyzing the behavior, the results of EEG recovery, and the results of histopathologic analysis were fully blinded with regard to the treatment groups.
Groups were compared separately at baseline, during CPB, and after CPB. The t-test or the Mann–Whitney test, as appropriate, was used for comparisons at baseline. When the data were consistent with normality and equal variance assumptions, the measurements during CPB as well as those after CPB were compared using repeated measures ANOVA, with tests for average differences between groups and for group-time interactions (change in the difference between groups over time). Otherwise the groups were compared separately at each time point using the Mann–Whitney or Fisher exact tests. We report P values unadjusted for multiple testing: their purpose is not for an exact global assessment but rather as a guide to help interpret the pattern of differences between groups at different times. The Bonferroni correction was not utilized because we expect these tests at successive time points to be highly correlated. Analyses were implemented with SAS software on a VAX computer and StatXact 4 for Windows.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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3.2. Comparability of experimental groups
A comparison of preoperative animal weights (CsA: 29.6±1.9 kg vs. placebo: 29.7±1.8 kg vs. CHX: 30.1±1.7 kg) and age (in weeks, CsA: 14.3±1.0 vs. placebo: 14.0±0.9 vs. CHX: 14.6±0.9) showed no differences between the groups. There were no intra- or inter-group differences concerning the weights on POD 7 before sacrifice (CsA: +0.7±2.5 kg vs. placebo: +0.9±1.2 kg vs. CHX: +0.4±1.0 kg).
Basic hemodynamic data showed some minor variations, but no clinically relevant differences between groups in heart rate, mean arterial pressure, central venous pressure, pulmonary artery pressure, or cardiac output. There were also no significant differences in rectal, esophageal or brain temperatures between the groups; the mean brain temperature of 20°C corresponded to a mean esophageal temperature ranging from 20.2 to 21.3°C in the different groups, and a mean rectal temperatures from 22.3 to 22.9°C. Slight but not significant differences were observed in the upward drift of the intracranial temperature during HCA, but all brain temperatures remained between 19.5 and 20.5°C. Acid-base, blood gas and metabolic parameters are shown in Table 1, and also revealed no differences among the groups.
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3.4. Electrophysiological recovery
EEG recovery, ranging from 8 to 55% of baseline values 3 h after HCA, was observed in 4 of 8 CsA treated animals, but in only 1 of 12 controls (P=0.11), Fig. 2, and in one of eight CHX-treated animals.
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The Early Activity Score was higher in the CsA-treated animals 1 h after extubation, (P=0.03), but that difference diminished considerably by 2 h. The amount of confusion was greater in the control group than in animals treated with CsA, but particularly at 3 h after extubation (P=0.04), Fig. 4. The CHX-treated animals were similar to controls in both scales of early recovery.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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The rationale for using cycloheximide was the idea that this general inhibitor of protein synthesis could interfere with the proteolytic cascade leading to apoptosis by preventing the synthesis of the specific proteases involved [9]. In the current study, however, we were unable to show any beneficial effects of cycloheximide on neurological recovery after HCA. In pilot studies, healthy pigs showed a reduction in total proteins following CHX treatment without other detrimental effects. But protein synthesis may be required for systemic recovery after cardiopulmonary bypass and hypothermic circulatory arrest, and the failure to synthesize these recovery proteins may offset any potential benefits of inhibiting synthesis of the specific proteins involved in neuronal apoptosis. That inhibition of all new protein synthesis may hamper general recovery after HCA is suggested by the high mortality rate in our study, and by the disappointing outcome in another pilot study, in which animals received CHX before CPB and developed marked tissue edema, low systemic vascular resistance and major hemodynamic instability. It is also possible that the dose of CHX used, which was based on small animal studies [9], may have been too high. The failure of cycloheximide to improve outcome or reduce apoptosis following HCA in this study does not preclude the possibility that a more specific protein synthesis inhibitor or some other drug which interferes with apoptosis might be effective in enhancing cerebral recovery following HCA in our model.
And, in fact, our results using cyclosporine A do show promise. Cyclosporine A is an 11-amino acid cyclic peptide of fungal origin which is of great value in reducing rejection after organ transplantation, and which has also been shown to have some neuroprotective benefit in experimental animal models of stroke [10]. The mechanisms responsible for the effect of CsA in reducing ischemia-induced injury are not fully understood, and may be multiple. It has recently been demonstrated [10] that immunological reactions play an important role in ischemia-reperfusion injury in the brain, and CsA is an effective immunosuppressive agent.
CsA is known to inhibit a phosphatase called calcineurin, which is activated by high intracellular calcium concentrations, which are known to occur after ischemia and during reperfusion [11]. Via this mechanism, CsA can inhibit the production of interleukin-2 [12], gamma interferon and other lymphokines [13]. Furthermore, CsA can reduce the expression of an intercellular adhesion molecule which is a target for the leukocyte-endothelial interaction and promotes neutrophil infiltration and subsequent inflammation. It is well-known that cardiopulmonary bypass even without hypothermic circulatory arrest leads to a significant increase of acute phase reactants [14] and induces an inflammatory reaction throughout the body. Some cytokines (e.g. interleukin-2) are responsible or at least involved in the pathogenesis of the immunologically-induced capillary leak syndrome, resulting in tissue edema.
Cerebral edema is a little-discussed consequence of cardiopulmonary bypass even without HCA. In a radiology study of patients undergoing coronary bypass surgery, significant cerebral edema was present in all patients immediately after surgery [15], and in a pathological study of 40 patients who died after open-heart surgery, cerebral edema was present in all cases [16]. Lundar et al. [17] showed that epidural pressures in patients after open-heart surgery were significantly elevated, and considered ICP monitoring a valuable guide in postoperative management.
Recent interest in the mechanism by which retrograde cerebral perfusion (RCP) during HCA may affect cerebral outcome has led to the recognition that cerebral edema often occurs following RCP, but also after HCA. From animal studies, there is some evidence that modified ultrafiltration [18] as well as a higher hematocrit [19] improve cerebral recovery after circulatory arrest: we speculate that the benefits noted may have been related to small reductions in cerebral edema even though no decreases in total body edema were demonstrated [20]. Further observations have augmented the evidence suggesting that measures which reduce intracranial pressure often improve cerebral recovery, whereas high ICP correlates with worse outcome [21]. In the present study, we were able to show significantly lower ICP in the CsA-treated animals throughout reperfusion and early recovery following HCA. The lower ICP in CSA-treated animals correlated with evidence of more rapid EEG, cortical SSEP and early behavioral recovery, and with consistently higher behavioral scores for the first 4 days after HCA in CsA-treated animals.
In addition to reducing postoperative cerebral edema, CsA may improve postoperative neuronal function via two other routes. CsA has been shown to exert neurotrophic effects by binding to immunophilins that are independent of calcineurin inhibition [22]. In addition, CsA may enhance neuronal survival by interfering with apoptosis. CsA can bind to mitochondrial cyclophilin D and inhibit opening of the mitochondrial permeability transition pore (PTP), an early event in some apoptotic signaling pathways. Loss of mitochondrial membrane potential via opening of the PTP due to withdrawal of trophic support leads to the release of apoptosis-initiating factors from the mitochondria which can stimulate the activation of specific caspases
On the basis of the present study, it is unclear whether the more pronounced cerebral edema in the control animals is responsible for their slower recovery after HCA, or whether higher ICP is simply a sign rather than a cause of more severe, albeit subtle neurological injury. It is possible that the blood supply in the cerebral capillary vascular bed may be compromised by high ICP, and lead to the clinical features of disorientation, confusion and agitation often observed in patients following aortic surgery utilizing HCA There is clear evidence that this clinical syndrome, which we have termed transient neurological dysfunction, reflects inadequate cerebral protection, and results in long-term cognitive deficits [23]. Our early recovery scores, an attempt to find an experimental equivalent for TND, revealed some evidence that CsA-treated animals had better neurological recovery than control pigs. The idea that improved early recovery in the CsA-treated group may be related to lower ICP seems plausible, especially since the relationship between lower ICP and improved cerebral recovery after hypothermia has also been observed in studies involving retrograde cerebral perfusion, both by us [2] and by others [24]. The question of whether high ICP can trigger apoptosis has, to our knowledge, not been explored.
Whereas better early recovery following HCA seems likely to be related to lower ICP in the CsA-treated animals, higher neurobehavioral scores in the successive postoperative days seem more likely to be a consequence of a favorable impact of CsA on something more fundamental, perhaps the incidence of apoptosis. Pilot studies ascertained that apoptosis is an ongoing process which lasts for at least 7 days after HCA, although its peak seems to occur between 48 and 72 h. In the current study, which was designed to allow full behavioral recovery in this chronic model, we may have missed the optimal time for detection of apoptosis and therefore obscured a beneficial effect of CsA via this mechanism, as discussed in detail in the accompanying report. On the other hand, the failure to find a significant reduction in apoptosis in treated animals may mean that inhibition of apoptosis is not an important mechanism by which CsA exerts its neuroprotective influence.
We elected not to do any postoperative CsA blood levels because of concern about a higher risk of infection with indwelling lines and/or difficulty in evaluating behavioral recovery with intermittent sedation in the absence of such catheters. Mijares and coworkers [25] have recently shown that subcutaneous administration of CsA in pigs is effective and reliable, and pilot studies showed that a subcutaneous daily injection of 5 mg/kg CsA was sufficient to maintain a blood level of 200–300 µg/ml in our pigs. We were reluctant to use the higher doses of CsA (15 mg/kg) reported in smaller animals, which showed clear neuroprotective effects after experimental strokes, with blood levels as high as 1000 µg/ml: the well-known dose-dependent side effects of CsA (e.g. nephrotoxicity) suggest that such high doses of CsA would prove toxic. Further study will be needed to determine the minimal dose of CsA which is neuroprotective but does not result in immunosuppression or other problems.
4.1. Conclusions
Our results indicate that pre-and post-ischemic treatment with CsA improves neurological recovery after deep hypothermic circulatory arrest in a porcine model. It is not clear whether faster EEG recovery and improved neurological/behavioral scores are related to a lower ICP during reperfusion in CsA-treated animals (indicating less cerebral edema), are a consequence of blocking apoptotic pathways, arise from inhibition of post-bypass inflammatory reactions, or result from a combination of several mechanisms.
The neuroprotective impact of CsA, if confirmed in further studies, would make its clinical application in this context conceivable. But even if the nephrotoxicity of CsA and the enhanced risk of infection associated with CsA-induced immunosuppression eventually contraindicate its clinical use as a neuroprotective agent, our results demonstrate the possibility of devising promising pharmacological strategies for mitigating neurological injury after HCA, and improving cerebral outcome.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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N. A. Tatton, C. Hagl, S. Nandor, S. Insolia, D. Spielvogel, and R. B. Griepp Apoptotic cell death in the hippocampus due to prolonged hypothermic circulatory arrest: comparison of cyclosporine A and cycloheximide on neuron survival Eur. J. Cardiothorac. Surg., June 1, 2001; 19(6): 746 - 755. [Abstract] [Full Text] [PDF]
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