Comparison of computer-assisted instruction (CAI) versus traditional textbook methods for training in abdominal examination (Japanese experience).

PURPOSE: This study aimed to compare the effects of computer-assisted, text-based and computer-and-text learning conditions on the performances of 3 groups of medical students in the pre-clinical years of their programme, taking into account their academic achievement to date. A fourth group of students served as a control (no-study) group. METHOD: Participants were recruited from the pre-clinical years of the training programmes in 2 medical schools in Japan, Jichi Medical School near Tokyo and Kochi Medical School near Osaka. Participants were randomly assigned to 4 learning conditions and tested before and after the study on their knowledge of and skill in performing an abdominal examination, in a multiple-choice test and an objective structured clinical examination (OSCE), respectively. Information about performance in the programme was collected from school records and students were classified as average, good or excellent. Student and faculty evaluations of their experience in the study were explored by means of a short evaluation survey. RESULTS: Compared to the control group, all 3 study groups exhibited significant gains in performance on knowledge and performance measures. For the knowledge measure, the gains of the computer-assisted and computer-assisted plus text-based learning groups were significantly greater than the gains of the text-based learning group. The performances of the 3 groups did not differ on the OSCE measure. Analyses of gains by performance level revealed that high achieving students' learning was independent of study method. Lower achieving students performed better after using computer-based learning methods. CONCLUSION: The results suggest that computer-assisted learning methods will be of greater help to students who do not find the traditional methods effective. Explorations of the factors behind this are a matter for future research.

Therapeutic potential of platelet-activating factor antagonism in the management of myocardial infarction.

BACKGROUND: Antagonists of platelet-activating factor (PAF) reduce myocardial postischemia reperfusion injury when given before the onset of ischemia. However, the effects of PAF antagonists when administered at a clinically modelled time (during ischemia but before reperfusion) are controversial. Moreover, the extended survival (eight day) and the characteristics of scar formation after treatment with PAF antagonists have not been investigated. OBJECTIVES: To determine the therapeutic potential of PAF antagonist TCV-309 for the treatment of regional myocardial ischemia-reperfusion injury; and to determine the effects of TCV-309 on cardiovascular recovery, evolution of scar formation and survival eight days after a myocardial infarction treated with reperfusion. ANIMALS AND METHODS: Swine underwent regional myocardial ischemia for 60 mins by ligation of the left anterior descending coronary artery, followed by reperfusion for eight days. The treated group (n=7) received PAF antagonist TCV-309 (0.1 mg/kg) 45 mins after ligation; the untreated group (n=7) received vehicle only. RESULTS: Untreated animals experienced significantly (P<0.001) lower systemic arterial blood pressure during the reperfusion period than animals treated with TCV-309. Furthermore, untreated animals required significantly more (P<0.01) antiarrhythmic and inotropic support. Only two of seven animals in the untreated group survived, which was significantly different (P<0.05) from the six of seven treated animals that survived for eight days. Morphometric analyses did not show differences between groups in the characteristics of scar formation following reperfusion for eight days. CONCLUSIONS: PAF antagonist TCV-309 improves survival and reduces cardiovascular dysfunctions associated with regional myocardial ischemia reperfusion injury when administered at a clinically modelled time.

The role of inflammatory mediators in the mechanism of the host immune response induced by ischemia-reperfusion injury.

Our previous study suggested that inflammatory mediators released due to IRI lead to host's immune response by upregulating MHC II in the host's peripheral T lymphocytes. This study hypothesized the role of platelet-activating factor (PAF) in the mechanism of induced MHC II upregulation due to IRI on peripheral T lymphocytes. The objectives of this study were to investigate the role of PAF in the induction of host immune reactivity and the protective effect of PAF-antagonist TCV-309 in combination with prostaglandin E1 (PGE1) against the host's immune response caused by IRI. Thirty female domestic swine were divided into three groups. Group A (6 donors, 6 recipients) had no pharmacological intervention. Group B (6 donors, 6 recipients) was the experimental group treated with TCV-309 + PGE1. Group C underwent sham operation. The ex vivo preservation time for groups A and B was 4 hr at 4 degrees C. To detect the changes in MHC II expression on T cells due to IRI, blood samples were collected before reperfusion (baseline level), 1, 2, and 3 days post-reperfusion. Two-colour flow cytometry analysis (FACS) was used to study MHC II-DR-beta expression in peripheral T lymphocytes. Swine anti-MHC II and anti-CD3 antibodies were used for this purpose. The FACS analyses demonstrated that in group A, there was a significant increase (p < 0.05) in MHC II intensity on peripheral T lymphocytes on day 2 post-reperfusion. By the third day post-reperfusion, MHC intensity had a tendency to decrease but did not reached the baseline level. In group B and C, however, there was no significant change in the level of MHC II in T lymphocytes at any of the post-reperfusion times. In group A, the number of CD3+MHC+ T lymphocytes significantly decreased (p < 0.05) by one day post-reperfusion and remained at this level until the third day post-reperfusion. In groups B and C, no significant change in the number of CD3+MHC+ T cells was observed. The results of this study suggested that the release of inflammatory mediators (e.g. PAF) due to IRI played a role in the mechanism of IRI-induced host's immune response. The results also suggested that the combination of TCV-309 + PGE1 could reduce this immune response.

Liver bridging techniques in the treatment of acute liver failure.

The introduction of orthotopic liver transplantation in the management of acute liver failure has dramatically increased the survival rates of patients at the cost of removing the patient's native liver and life-long dependence on immunosuppression. However, it is well known that in many patients with acute liver failure the diseased liver has the potential to recover. Death in these patients is often due to increased intra-cranial pressure or infection. Liver bridging techniques are assigned to temporarily provide liver function and enable the native liver to recover in patients with acute liver failure. They represent an attractive alternative to conventional liver transplantation in the management of acute liver failure, since after recovery of the native liver the patient is freed from immuno-suppression with all associated side-effects and risks. Auxiliary liver transplantation, artificial liver support devices and hepatocyte transplantation represent different ways of bridging liver function in acute liver failure. The aim of this review is to present the ideas and principles of these three different liver bridging techniques. We will discuss the relative importance and the future potential of theses bridging techniques in the treatment of acute liver failure by comparing the experimental and clinical results.

The increase in the steady-state level of major histocompatibility complex mRNA in the host peripheral T lymphocytes due to ischaemia-reperfusion injury.

In our previous study, using a swine model of single lung transplantation, a relationship between the level of major histocompatibility complex (MHC II) expression on host T lymphocytes and the extent of the ex vivo preservation time was observed. Furthermore, a model of ischaemia by simple cross-clamping proved MHC II up-regulation to be independent of tissue incompatibility. The mechanism through which ischaemia-reperfusion injury (IRI) induces MHC up-regulation in host peripheral T cells has not been reported. The objective of this study was to determine whether IRI induces MHC II up-regulation in T cells by altering the intracellular steady-state level of MHC II mRNA. Group A (seven donors, seven recipients) was an allotransplantation model of 15 h of cold storage (4 degrees C) while in group B (n = 6) animals underwent 2 h of warm ischaemia. Group C (n = 6) underwent sham operation. For quantification of mRNA extracted from peripheral T lymphocytes isolated before and after surgery, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to determine the time at which mRNA levels reached its peak. The mRNA at pre-reperfusion and the time, at which mRNA peaked, was used for competitive RT-PCR. The results of RT-PCR analyses demonstrated that IRI induced an increase in the steady-state level of MHC II mRNA (p < 0.02) within 2 h post-reperfusion, irrespective of type of ischaemia and tissue incompatibility. In conclusion, this study suggested that IRI up-regulates the MHC II expression in peripheral T cells by altering the intracellular steady-state level of MHC II-DR-beta.

Platelet-activating factor plays a role in the mechanism of major histocompatibility complex in T lymphocytes.

In recent studies, using a swine model of single lung transplantation, we demonstrated that IRI alone increased MHC II expression in the host's peripheral T lymphocytes. The inhibition of increased MHC II expression with TCV-309, a specific platelet-activating factor (PAF) antagonist suggested that PAF might play a role in the mechanism of increased MHC II expression. The purpose of the current study was two fold: 1) to investigate the mechanism of PAF-induced increased expression of MHC II in T lymphocytes, 2) to determine whether a specific PAF-antagonist, TCV-309, is capable of inhibiting the increased expression in an in vitro system. This study was subdivided, using four in vitro conditions: 1) purified resting T cells, 2) purified proliferating T cells, 3) PBL treated with PAF, and 4) PBL preincubated with TCV-309 and treated with PAF. The level of MHC II on T cells were measured by two color flow cytometry analysis (swine anti-CD3, MHC II-DR-(beta)antibodies). Both MHC II intensity and the number of CD3+MHC+ T cells did not change in resting purified T cells once treated with PAF, Furthermore, MHC II intensity did not change in purified proliferating T cells treated with PAF. The number of CD3+MHC+ T cells, however, increased significantly (p<0.05) from day 1 to day 4 as compared with pre-treatment value (day 0) for purified proliferating T cells. Treatment of PBL with PAF (10(-7)M) resulted in a significant (p<0.05) increase in MHC II expression from day 2 to day 4 post-treatment. The number of CD3+MHC+ T cells in PBL, however, did not change significantly upon treatment with PAF. The results of this study indicated that PAF did not have a direct effect on increased MHC II expression in resting or proliferating purified T lymphocytes. However, the mechanism of PAF-induced increased expression of MHC II in T cells may be via an indirect pathway involving accessory cells. TCV-309, a specific PAF receptor antagonist, is capable of inhibiting this PAF-induced increased expression of MHC II in T cells.

High dose propofol enhances red cell antioxidant capacity during CPB in humans.

PURPOSE: To compare low vs. high dose propofol and isoflurane on red cell RBC antioxidant capacity in patients during aortocoronary bypass surgery (ACBP). METHODS: Twenty-one patients, for ACBP, were anesthetized with sufentanil 0.5-10 microg x kg(-1) and isoflurane 0-2%; ISO = control; n = 7), or sufentanil 0.3 microg x kg(-1), propofol 1-2.5 mg x kg(-1) bolus then 100 microg x kg(-1) min(-1) before, and 50 microg x kg(-1) x min(-1) during CPB (LO; n = 7), or sufentanil 0.3 microg x kg(-1), propofol 2-2.5 mg x kg(-1) bolus then 200 microg x kg(-1) x min(-1) (HI; n = 7). Venous blood was drawn pre- and post-induction, after 30 min CPB, 5, 10, and 30 min of reperfusion, and 120 min post-CPB to measure red cell antioxidant capacity (malondialdehyde (MDA) production in response to oxidative challenge with t-butyl hydrogen peroxide) and plasma propofol concentration. Pre- induction blood samples were analyzed for antioxidant effects of nitrates on red cells. The tBHP concentration response curves for RBC MDA in ISO, LO and HI were determined. RESULTS: Preoperative nitrate therapy did not effect RBC MDA production. Perioperative RBC MDA production was similar in ISO and LO groups. Sustained intraoperative decrease in RBC MDA was seen with propofol 8.0+/-2.4 - 11.8+/-4.5 microg x ml(-1) in HI (P<0.05-0.0001). MDA production vs. log plasma propofol concentration was linear in HI dose. CONCLUSIONS: During CPB, RBC antioxidant capacity is enhanced and maintained with HI dose propofol. Propofol, at this dose, may prove useful in protecting against cardiopulmonary ischemia-reperfusion injury associated with ACBP.

Teaching and evaluation of basic surgical techniques: the University of British Columbia experience.

Surgical technical education has traditionally followed an apprenticeship format. The need for innovative undergraduate programs using dry and wet labs prior to clinical exposure continues to be an area of debate. Specific programs have been described to improve surgical skills; however, an accepted platform for training and evaluation of surgical skills programs has not been recognized. Therefore, introduction of specific programs to teach undergraduate medical students surgical skills is essential. This article describes the Basic Surgical Technique (BST) program taught at the University of British Columbia and reports the effectiveness of this program in improving the practical skills of undergraduate medical students. The program includes BST I for third-year students performed in a dry lab setting, and BST II for medical student interns (MSI) performed at the animal laboratories using female domestic swine as subjects. A total of 87 students participated in the study. The program is designed using Piaget's and Vygotsky's pedagogical philosophy of "learning by doing." A semiquantitative method is used to measure and analyze the outcome of this project. Data were validated using student self-evaluation tests and by quantitative evaluation by surgical staff from the surgical wards. Results of this prospective project indicated that the BST program significantly (p < .05) improved the surgical performance of undergraduate students, and that the time lapse between BST I and II has had a negative impact in retention of acquired surgical skills. This study concludes that the BST program taught at the University of British Columbia significantly improves the surgical skills of medical students and improves their self-confidence during their internship.

The role of platelet-activating factor in regional myocardial ischemia-reperfusion injury.

BACKGROUND: This swine model was designed to elucidate the role of platelet-activating factor in regional myocardial ischemia-reperfusion injury. METHODS: In groups 1 and 2 (n = 12 each), the left anterior descending coronary artery was ligated for 60 minutes to induce regional myocardial ischemia followed by 6 hours of reperfusion. Group 1 received the platelet-activating factor antagonist TCV-309 before ischemia, whereas group 2 did not. Group 3 (n = 3) had a sham operation. RESULTS: Animals in group 2 exhibited significant (p < 0.05) hemodynamic instability and myocardial depression during the reperfusion period. Despite preventive measures, 7 of the 12 animals experienced severe dysrhythmias in the form of atrial and ventricular fibrillation leading to cardiac arrest. In contrast, animals in group 1 in whom the effects of platelet-activating factor were blocked by the specific platelet-activating factor receptor antagonist TCV-309 were hemodynamically stable and had significantly (p < 0.05) better myocardial function. This significant difference in global myocardial function between the groups was observed in the presence of similar morphologic findings and regional myocardial function. CONCLUSIONS: These results suggest that platelet-activating factor has a definite influence on global myocardial dysfunction associated with regional myocardial ischemia-reperfusion injury.

The relationship of ischemia-reperfusion injury of transplanted lung and the up-regulation of major histocompatibility complex II on host peripheral lymphocytes.

OBJECTIVES: This study was designed to examine the relationship between ex vivo preservation time of the transplanted lung and the extent of injury and to relate this to the severity of rejection with and without allogenicity. METHODS: Single lung transplantation was performed on two groups of domestic swine. Group A (n = 7) and group B (n = 6) had ex vivo preservation times of 4 and 15 hours, respectively, at 4 degrees C hypothermia. Group C (n = 6) underwent 2 hours of warm ischemia via dissection and isolation of the left lung with ligation of its bronchial artery and crossclamping of the left pulmonary artery, vein, and bronchus without explantation. Assessment measures included lung function, antioxidant enzyme activities in the plasma and lung tissue, levels of inflammatory mediators in the recipient plasma, and quantification of major histocompatibility complex II HLA-DR-beta on host peripheral lymphocytes. RESULTS: All groups demonstrated increases in interleukin-10, lung weight, and HLA-DR-1beta expression and decreases in lung-tissue antioxidant enzyme activities, gas exchange, and lung compliance. There was a strong positive correlation between ex vivo preservation time and the expression of HLA-DR-beta and a negative correlation between ischemic time and lung-tissue superoxide dismutase. CONCLUSIONS: These results suggest that the intensity of the host immunogenic response is related to the severity of ischemia-reperfusion injury and is independent of tissue incompatibility and/or the type of ischemic insult. We conclude that the extension of ex vivo preservation time may predispose the transplanted lung to more severe rejection.

Propofol enhances red cell antioxidant capacity in swine and humans.

PURPOSE: To determine the effect of an anaesthetic with antioxidant potential, propofol, on red blood cell (RBC) antioxidant enzyme activities and RBC susceptibility to peroxidative challenge. METHODS: Propofol was administered by intravenous bolus (2.5 mg.kg-1) and continuous infusion (36 and 72 ml.hr-1 in nine swine; 216 ml.hr-1 in two swine), to achieve serum concentrations between 5 and 30 micrograms.ml-1 for two hours at each rate. Arterial blood sampling was at 0, 10, 30, 60, and 120 min for each rate of infusion, for measurement of plasma propofol concentration, activities of plasma and RBC superoxide dismutase, glutathione peroxidase, glutathione reductase, RBC catalase, and RBC malondialdehyde (MDA) formation in response to ex vivo oxidative challenge with t-butyl hydrogen peroxide (tBHP; 1.5 mM). Antioxidant mechanisms were determined by in vitro study of MDA formation, GSH depletion, and oxidation of haemoglobin to methaemoglobin in human erythrocytes exposed to propofol 0-75 microM. The antioxidant potential of propofol was compared with that of alpha-tocopherol utilising the reaction with 2,4,6-tripyridyl-s-triazine (TPTZ). RESULTS: Propofol had no effect on plasma or RBC antioxidant enzyme activities. It inhibited RBC MDA production over the range of 0-20 micrograms.ml-1 (y = -18.683x + 85.431; R2 = 0.8174). Effective propofol concentrations for 25% and 50% reductions in MDA levels were 7-12 and 12-20 micrograms.ml-1, respectively. Propofol has a similar effect on human erythrocytes in vitro (R2 = 0.98). CONCLUSION: Propofol antagonises the effects of forced peroxidation of red cells at anaesthetic and sub-anaesthetic concentrations in swine. Its actions include scavenging of oxygen derived free radicals in a tocopherol-like manner.

Extended lung preservation with platelet-activating factor-antagonist TCV-309 in combination with prostaglandin E1.

BACKGROUND: Ischemia-reperfusion injury is one of the major problems in organ transplantation. The role of platelet-activating factor (PAF) in the pathophysiology of ischemia-reperfusion injury and the protective effect of a novel phospholipid PAF analog (TCV-309) alone and combined with prostaglandin E1 (PGE1) is investigated in an extended (20 hours) ex vivo lung preservation. METHODS: Forty-two swine were divided into three groups. Group A was the control. In groups B and C, the effect of PAF was blocked with TCV-309 administered 1 hour before cross-clamping for donor and recipient. Group C received PGE1 50 micrograms bolus in the donor pulmonary plegia, and the recipients received a 50 micrograms bolus plus 0.003 microgram/kg/min infusion at the time of implantation. Donor lungs were perfused with cold modified Collins solution and maintained in hypothermic storage (4 degrees C) for 20 hours. Hemodynamics, lung mechanics, gas exchange, and biochemistry were assessed before transplantation (donor) and at 30 minutes and 24 hours after reperfusion (recipient). At 24 hours after reperfusion, the histopathologic condition of transplanted lungs was evaluated. RESULTS: Radioimmunoassay demonstrated a significant (p < 0.001) increase in the production of PAF and TXB2 in transplanted lungs at 24 hours after transplantation for group A only. Hemodynamics, gas-exchange parameters, and lung compliance were significantly (p < 0.05) better after transplantation for groups B and C. Wet lung weight was significantly less (p < 0.05) for group C. Semiquantitative morphometric analysis demonstrated the highest degree of damage for group A compared with groups B and C. A strong correlation (r2 = 70) between lung weight and histologic injury scores was observed among groups. CONCLUSIONS: This study suggests that PAF is responsible in part for the deleterious effects of ischemia and reperfusion, that PAF-antagonist TCV-309 protects lungs from extended (20 hours) ischemic injury, and that PGE1 seems to have an additional beneficial effect.

Experimental use of somatosensory evoked potential for intraoperative identification of spinal cord blood supply.

The role of sensory evoked potentials (SEPs) to be used intraoperatively to reliably predict spinal cord ischemia, caused by interruption of intercostal and of lumbar and sacral arteries, was evaluated in a canine model. Two groups were assessed: (A) interruption of intercostal arteries (n = 6) and (B) interruption of all posterior branches (n = 6). SEPs were evaluated intraoperatively as control and interruption of posterior vessel groups, and at 18-22 h after surgery. Neurologic assessment was performed preoperatively and 18-22 h postoperatively by modified Tarlov criteria. Morphological assessments were also performed. The assessment of the groups demonstrated prolongation of latency and loss of amplitude of SEP, but individual changes of SEPs were poor predictors of paraplegia. Ultrastructural changes correlated with neurologic findings. SEPs were unreliable for intraoperative identification of vessels critical to spinal cord blood supply, possibly related to anatomically different blood supply of sensory and motor tracts.

Platelet activating factor and thromboxane B2 production after cardiopulmonary bypass.

Platelet-activating factor (PAF) is believed to have a central role in the pathogenesis of ischemia-reperfusion injury. The purpose of this study was to investigate the relationships among production of PAF, thromboxane B2 (T alpha B2), and cardiopulmonary sequelae in patients undergoing coronary artery bypass graft surgery (CABGS). Venous blood from nine patients (eight men, one woman) undergoing scheduled CABGS, was sampled from central venous catheters before anesthetic induction, pre-cardiopulmonary bypass (CPB), 10 and 30 minutes post-CPB, 10 and 30 minutes post-aortic declamping, and 120 minutes and 24 hours after the conclusion of CPB. Plasma levels of PAF and T alpha B2 were determined by radioimmunoassay kits (Amersham Canada Ltd.). PAF and T alpha B2 were significantly different between high-risk patients (group I; Canadian Cardiovascular Society class 3-4; n = 4) and low-risk patients (group II; Canadian Cardiovascular Society class 2; n = 5): group I PAF = 960 pg/mL, group II PAF = 159 pg/mL (P = 0.0029); group I T alpha B2 = 320 pg/mL, group II T alpha B2 = 229 pg/mL (P = 0.0262). Group I PAF was significantly greater than group II PAF: before CPB = 825 pg/mL (group I), 138 pg/mL (group II); during initiation of CPB = 1600-2015 pg/mL (group I), 158-200 pg/mL (group II) (P = 0.0143). Correlations between duration of CPB and peak PAF (r = 0.7049, P = 0.0339), peak PAF level, and time to extubation (r = 0.8863, P = 0.0079) were significant. PAF levels were different in patients requiring postoperative epinephrine (2124 +/- 700 pg/mL) or dopamine (667 +/- 266 pg/mL) (P = 0.0042). The production of PAF is determined by preoperative patient characteristics and duration of CPB. Increased levels of PAF in patients with unstable angina, left main coronary artery disease, or recent myocardial infarction are associated with the need for increased inotropy and prolonged ventilatory support following CABGS. The degree of PAF production during CPB may be a factor in postoperative instability in high-risk patients.

Animal model for investigation of spinal cord injury caused by aortic cross-clamping.

The objective of this experimental protocol was to design a large animal model that could simulate the ischemic condition caused by aortic cross-clamping during the operation for intrathoracic and thoraco-abdominal aneurysm. Domestic swine weighing 25 to 30 kg were used for this model. The thoracic cavity was opened through the fourth intercostal space. Cross-clamp was applied below the left subclavian artery. Duration of cross-clamp was 30 min and the reperfusion period was 24 h. Methods of assessment included Tarlov's criteria, histology transmission electron microscopy, and spinal cord perfusion with microspheres. This model is reproducible. The results of experimental protocols completed using this model are referenced. This article discusses the details of the experimental protocol with steps toward reproduction of the model and rationalization. This animal model can be used for the evaluation of the pathophysiology of spinal cord injury and sensory- and motor-evoked potentials, and most importantly it can also be used for the examination of pharmacological interventions for prevention and treatment of ischemia reperfusion injury caused by aortic cross-clamping.

Control of oxygen cytotoxicity with allopurinol and superoxide dismutase: a canine model of global myocardial ischemia-reperfusion injury.

The purpose of this study was to assess the effects of acute pharmacological interventions on the ischemia-reperfusion damage in a canine model of hypothermic global myocardial ischemia. Three experimental groups each consisting of seven animals were subjected to 2 h of global ischemia followed by 1 h of reperfusion. Group A (control) used Tyers' iso-osmolar potassium cardioplegia solution; group B received allopurinol (40 mg/kg), 95% intravenously (IV) systemically with 5% added to the final infusion of Tyers' solution. In group C, superoxide dismutase (6.5 mg/kg) was used, one third of the total dose in the final delivery of the Tyers' cardioplegia solution and two thirds IV during the initial 5 min of reperfusion. In all three groups, myocardial temperature was maintained between 15 and 19 degrees C. Methods of evaluation included hemodynamic and echocardiographic parameters of ventricular function. Assessment was performed at three time periods: pre-cardiopulmonary bypass (control), 60 min postreperfusion and immediately post-volume loading (at 2 h after cardiopulmonary bypass). No significant deterioration of myocardial function was observed in either of the experimental groups after the use of these preservation techniques. Comparison of regression slopes based on analysis of covariance for myocardial performance, systolic function, and diastolic compliance did not demonstrate any significant differences between the groups. Two hours of global ischemia was not sufficient to cause measurable damage to the myocardium on the basis of which the pharmacological intervention with allopurinol and superoxide dismutase could be evaluated. The controversy surrounding the use of allopurinol and superoxide dismutase is discussed with the findings of this experimental protocol and is brought up for scientific dialogue.

Platelet-activating factor antagonism: a new concept in the management of regional myocardial ischemia-reperfusion injury.

Reperfusion therapies for treatment of myocardial infarction successfully reduce patient mortality; however, regional myocardial ischemia-reperfusion (RMIR) causes its own expression of cardiovascular dysfunction, including myocardial depression, hemodynamic instability, and dysrhythmias, which have increased patient mortality within the first 24 h after starting reperfusion therapy. Current evidence suggests that the release of oxygen-derived reactive substances and subsequent inflammatory mediators during ischemia-reperfusion contribute toward this injury. Platelet-activating factor (PAF), a mediator released during RMIR, has been emphasized by many investigators as playing a central role in causing RMIR injury. Similar cardiovascular dysfunctions that occur during RMIR, including myocardial depression, hemodynamic instability, and dysrhythmias, occur after administration of PAF and are ameliorated with PAF antagonists. Further, PAF antagonists have been shown to be cardioprotective and improve survival when administered before onset of reperfusion. A variety of phospholipid analogues, naturally derived compounds, and synthetic compounds have been developed that form the different classes of PAF antagonists, each with unique antagonizing properties. Several of these compounds have successfully passed safety and efficacy testing in humans; however, to date, no clinical trials have investigated the protective effects of PAF antagonists against RMIR injury. A current theory in the pathogenesis of RMIR injury considers the ischemic and necrotic portion of the myocardium and regional dysfunction due to tissue necrosis to be solely responsible for global cardiac dysfunction leading to hemodynamic instability and death. Evidence now suggests, however, that the global dysfunction is also due to the effect of inflammatory mediators such as PAF, thromboxanes, leukotrienes, and endothelins that are released during RMIR and are distributed throughout the heart on reperfusion. Antagonizing a central inflammatory mediator such as PAF, as adjunct treatment with currently used reperfusion therapies, improves cardiovascular function and survival in animals and should be introduced into clinical trials to investigate if similar protective effects can be provided in humans.

Additive effect of allopurinol and deferoxamine in the prevention of spinal cord injury caused by aortic crossclamping.

Fourteen domestic swine were divided into two groups. Group A (n = 7) was the control group, in which no pharmacologic intervention was applied. In group B (n = 7), the ischemic-reperfused spinal cord was treated with the combination of allopurinol (50 mg/kg/day for 3 days before the day of operation) and deferoxamine (Desferal, 50 mg/kg administered intravenously over 3 to 4 hours). The administration of deferoxamine was completed 1 hour before crossclamping. The crossclamp was placed on the descending aorta just distal to the left subclavian artery for 30 minutes. Proximal hypertension was controlled with sodium nitroprusside and volume depletion. Methods of assessment included an evaluation of the neurologic status of the animals by quantitative Tarlov criteria, blood flow by radiolabeled microspheres, and histologic examination of the spinal cord. All animals in the control group, group A, were completely paraplegic with 0% recovery by Tarlov criteria at 24 hours after the removal of the crossclamp. In contrast, all animals in group B, in which the combination of allopurinol and deferoxamine was used, completely recovered (100% recovery by Tarlov criteria), and at 24 hours after the ischemic episode they were able to walk with no difficulty and had intact sensation. Functional parameters of these animals fully correlated with the morphologic findings. Widespread acute neuronal injury and vacuolation of neuropil were observed in the control group of animals. In contrast, animals in group B showed much less pronounced morphologic changes after the same period of ischemia. In summary, the combined use of these agents significantly (p < 0.001) reduced the incidence of paraplegia induced by aortic crossclamping with 82% additivity.