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The quality of healthcare is an emerging concern worldwide. In any health care process, adverse events resulting from errors are inevitable. The role of the medical autopsy is evolving yet it remains a cornerstone in the progress of healthcare quality and diagnostic medicine. Although the autopsy has been instrumental in understanding disease processes for the past 3000 years, there has been a concerning decrease in autopsy rates. This trend is influenced by barriers pertaining to resources, consent, and medicolegal hesitations. Reversing the trend in falling autopsy rates will require recognition of the role of the medical autopsy as an essential feedback mechanism in healthcare quality improvement. The autopsy has shaped the current state of medicine and with appropriate implementation, support, and collaboration will continue to guide the path forward.

In any health care process, adverse events resulting from errors are inevitable. Failure to inform the patient of adverse events caused by a medical error compromises the autonomy of the patient. Disclosure of an adverse event is an important element in managing the consequences of a medical error. Physicians should seek to disclose medical errors to patients and their families on both ethical and pragmatic grounds. Effective communication between health care providers, patients and their families throughout the disclosure process is integral in sustaining and developing the physician patient relationship.

Oxygen-free radicals have been implicated in hypercholesteolemic atherosclerosis. It is possible that hypercholesterolemia produces oxidative stress in myocardium. We therefore investigated the effects of a high cholesterol diet in the absence or presence of vitamin E on serum cholesterol and lipid peroxidation product malondialdehyde (MDA), chemiluminescence (M-CL), a measure of antioxidant reserve, and activity of antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)] in cardiac muscles of rabbits. Rabbits were divided into four groups: Group I, regular rabbit chow diet; Group II, same as Group I + vitamin E; Group III, high cholesterol diet; Group IV, high cholesterol + vitamin E. The heart was removed under anesthesia at the end of 4 months on their respective diets for various biochemical measurements. Serum cholesterol in Groups III and IV increased to a similar extent. There was an increase in the levels of MDA, M-CL, GSH-Px activity and a decrease in SOD activity in hypercholesterolemic rabbits in the absence of vitamin E. Vitamin E prevented the hypercholesterolemia-induced changes in cardiac MDA, M-CL, and GSH-Px. These results suggest that hypercholesterolemia produces oxidative stress in the myocardium which may be due to a decrease in the antioxidant reserve, and that vitamin E is effective in preventing hypercholesterolemia-induced oxidative stress on the myocardium.

Effects of purpurogallin (PPG), an antioxidant on high cholesterol diet-induced atherosclerosis, and changes in blood lipid profile and lipid peroxidation product malondialdehyde (MDA), aortic tissue MDA, chemiluminescence (M-CL), a marker for antioxidant reserve and antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)] were investigated in rabbits. The rabbits were divided into three groups: Group I, regular rabbit chow; Group II, same as Group I+cholesterol (1%); and Group III, same as Group II+PPG (14 mg/kg, orally, daily). Serum concentrations of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and blood MDA were measured before and after 4 and 10 weeks on the respective diets. The aorta was removed at the end of 10 weeks for assessment of atherosclerotic changes, MDA concentration, M-CL, and antioxidant enzymes. Coronary arteries were also examined for atherosclerotic changes. Serum TC, LDL-C, and LDL-C/HDL-C ratio increased whereas HDL-C decreased in Group II and their values were similar in Groups II and III. Aortic tissue MDA, M-CL, CAT, and GSH-Px activity increased in Group II but these values in Group III were lower than in Group II except for MDA which was greater in Group III than in Group II. Atherosclerotic changes were greater in Group II than in Group III. Histological changes were similar in Groups II and III. Atherosclerotic changes were also observed in the coronary arteries of Groups II and III, however, they were less in Group III than in Group II. Increased levels of aortic MDA and decreased levels of antioxidant reserve, which were associated with the development of atherosclerosis, suggest a role for oxygen radicals in the pathogenesis of hypercholesterolemic atherosclerosis. The protection afforded by PPG, which was associated with reversal of the antioxidant reserve to control level, in spite of hypercholesterolemia, supports the hypothesis that oxygen radicals are involved in the development of hypercholesterolemic atherosclerosis. These results suggest that PPG retard the development of hypercholesterolemic atherosclerosis because of its antioxidant activity without lowering blood cholesterol level.

Oxygen free radicals (OFRs) derived from activated polymorphonuclear (PMN) leukocytes have been implicated in the ischemia-reperfusion cardiac injury. Hypochlorous acid (HOCl) is produced by activated PMN leukocytes and can damage tissue directly or through formation of hydroxyl radicals. We therefore investigated the effects of methionine (a quencher of HOCl) on cardiac function and cardiac contractility; oxygen-free, radical-producing activity of PMN leukocytes (PMN-CL); serum malondialdehyde (MDA); activity of creatine kinase (CK) and MB fraction of CK (CK-MB); blood lactate, and pH and infarct size after 3 hours of reperfusion following 1.5 hours of occlusion of the left circumflex coronary artery (LCX) in anesthetized dogs. The dogs were divided into three groups: Group I, complete ligation of LCX for 4.5 hours; Group II, ligation of LCX for 1.5 hours followed by 3 hours of reperfusion; Group III, similar to Group II but received methionine 60 mg/kg, i.v. 10 minutes before ligation, 10 minutes before reperfusion, and 60 minutes after reperfusion. Measurements of hemodynamic parameters and collection of blood samples for biochemical parameters were made at various intervals. In general, myocardial contractility was unaltered whereas cardiac function decreased to a similar extent in the three groups. The area at risk was similar and infarct size was greater in Groups II and III, but both were greater than in Group I. The size in Group III was smaller than in Group II. CK and CK-MB activity increased in all groups but more in Groups II and III than in Group I. The increases were smaller in Group III than in Group II. PMN-CL activity increased significantly in Group II but remained unchanged in Groups I and III. Serum MDA remained unchanged. Changes in blood lactate and pH were similar in the three groups. These results suggest that (1) the area at risk in unperfused ischemic myocardium is smaller than in perfused ischemic myocardium; (2) reperfusion produced greater myocardial necrosis as compared with unperfused ischemic myocardium; (3) methionine is very effective in preventing ischemia-reperfusion-induced myocardial necrosis.

The prevalence of medical errors in health care systems has generated immense interest in recent years. The research on adverse events in hospitalized populations has consistently revealed high rates of adverse events. Some of these adverse events result from medical errors and a majority of these errors may be preventable. These errors can occur anywhere and at anytime in health care processes. The consequences of these errors may vary from little or no harm to being ultimately fatal to the patients. It is important to recognize that a degree of error is inevitable in any human task and human fallibility in health care should be accepted. The underlying precursors for many of these human errors may primarily be attributed to latent systemic factors inherent in today's increasingly complex health care system. The focus of adverse event analyses on individual shortcomings without appropriate attention to system issues leads to ineffective solutions. The cognitive influence on medical decision-making and error generation is also significant and should not be discounted.

The Institute of Medicine (IOM) report (1999) stated that the prevalence of medical errors is high in today's health care system. Some specialties in health care are more risky than others. A varying blunder/error rate of 0.1-9.3% in clinical diagnostic laboratories has been reported in the literature. Many of these errors occur in the preanalytical and postanalytical phases of testing. It has been suggested that the errors occurring in clinical diagnostic laboratories are smaller in number than those occurring elsewhere in a hospital setting. However, given the quantum of laboratory tests used in health care, even this small rate may reflect a large number of errors. The surgical specialties, emergency rooms, and intensive care units have been previously identified as areas of risk for patient safety. Though the nature of work in these specialties and their interdependence on clinical diagnostic laboratories presents abundant opportunities for error-generating behavior, many of these errors may be preventable. Appropriate attention to system factors involved in these errors and designing intelligent system approaches may help control and eliminate many of these errors in health care.

1. Oxygen free radicals have been suggested to be a contributory factor in complications of diabetes mellitus. There are many reports indicating the changes in parameters of oxidative stress in diabetes mellitus. In this study we aimed to identify whether oxidative stress occurs in the liver and pancreas in the initial stages of development of diabetes. 2. We therefore investigated the lipid peroxide level (thiobarbituric acid-reactive substances, TBARS) and activities of antioxidant enzymes [superoxide dismutase (SOD), catalase and glutathione peroxidase] in liver and pancreas of control and streptozotocin-induced diabetic rats at various stages of development of diabetes. 3. Male Sprague—Dawley rats were divided into two groups: group I, control (n = 42) and group II, diabetic (n = 42). Each group was further subdivided into seven groups consisting of six rats each. Rats in these subgroups were studied at weekly intervals (0 to 6 weeks). Plasma glucose levels, TBARS levels and activities of antioxidant enzymes were measured in liver and pancreas at various time intervals. 4. There was a significant (P < 0.05) and progressive increase in TBARS levels of liver and pancreas in the diabetic group. Total SOD and Cu—Zn-SOD activity increased (P < 0.05) with progression of diabetes while Mn-SOD activity showed no significant change in either tissue. Catalase and glutathione peroxidase activities increased significantly (P < 0.05) in liver and pancreas. 5. Immunohistochemical study of pancreatic islet revealed a decrease in the expression of insulin with progression of diabetes. However, glucagon and somatostatin showed an increase in immunoreactivity and a difference in their distribution pattern. 6. The findings of the present study suggest that oxidative stress starts at early onset of diabetes mellitus and increases progressively. In conclusion, the structural damage to these tissues or complications of diabetes mellitus may be due to oxidative stress.

Oxygen free radicals (OFRs) have been suggested to be a contributory factor in complications of diabetes mellitus. In the present study, we investigated the lipid peroxide level measured as thiobarbituric acid reactive substances (TBARS) and activities of antioxidant enzymes viz., [superoxide dismutase (SOD), catalase (CAT) and glutathione-peroxidase (GSH-Px)]in the kidney of streptozotocin induced diabetic rats at various stages of development of diabetes. Sprague Dawley rats were divided into two groups: group I, control (n = 42) and group II, diabetic (n = 42). Each group was further subdivided into seven groups each consisting of six rats. Rats in subgroups were studied at weekly intervals (0 to 6 weeks). Blood glucose levels were estimated at the time of sacrifice. TBARS levels and activity of antioxidant enzymes were measured in kidney. The levels of TBARS in the diabetic group increased initially, dropped to baseline level after 2 weeks and then progressively increased at 5th and 6th week (p < 0.05). There was an increase in catalase activity at first week after that it decreased as compared to control group. However, GSH-Px activity in the diabetic group increased after 1 week and then remained at the same level except a small drop in the 2nd week. Total SOD and CuZn-SOD activity increased significantly in diabetic kidney as compared to controls at all time intervals, while Mn-SOD activity showed no change. The present findings suggest that oxidative stress accompanies at early onset of diabetes mellitus and the susceptibility of the kidney to oxidative stress during the early stages may be an important factor in the development of diabetic nephropathy.

We investigated the effects of chronic volume overload in the absence or presence of vitamin E supplements on the cardiac function and contractility, cardiac malondialdehyde (MDA) —a lipid peroxidation product —cardiac antioxidant enzyme activity and antioxidant reserve in canine model. The dogs were divided into three groups of seven dogs each: group I, control; group II, mitral regurgitation (MR) of 4 months duration; and group III, MR of 4 months duration receiving vitamin E (40 U /kg /daily) orally. MR was created by detaching two or more chordae tendinae to raise left atrial pressure to 2.5 to three times normal. MR produced a decrease in the index of myocardial contractility with little change in myocardial function. Decrease in myocardial (left and right ventricles) contractility was associated with an increase in cardiac MDA, and a decrease in cardiac antioxidant reserve and antioxidant enzyme activity. Prevention of volume overload-induced decrease in myocardial contractility by vitamin E was associated with a decrease in cardiac MDA and an increase in cardiac antioxidant reserve and glutathione peroxidase activity towards control levels. Superoxide dismutase and catalase activity remained depressed in vitamin E-treated group. The results indicate that chronic volume overload decreases the contractility of both right and left ventricles and is associated with oxidative stress in both ventricles. These results support the hypothesis that oxygen free radicals are involved in the chronic volume overload-induced cardiac depression.

Medical errors are a prominent issue in health care. Numerous studies point at the high prevalence of adverse events, many of which are preventable. Although there is a range of severity in errors, they all cause harm, to the patient, to the system, or both. While errors have many causes, including human interactions and system inadequacies, the focus on individuals rather than the system has led to an unsuitable culture for improving patient safety. Important areas of focus are diagnostic procedures and clinical laboratories because their results play a major role in guiding clinical decisions in patient management. Proper disclosure of medical errors and adverse events is also a key area for improvement. Globally, system improvements are beginning to take place, however, in Canada, policies on disclosure, error reporting and protection for physicians remain non-uniform. Achieving a national standard with mandatory reporting, in addition to a non-punitive system is recommended to move forward.

Lipid peroxidation of membranes by oxygen free radicals has been implicated in various disease states. Different antioxidants and iron chelators have been used to reduce lipid peroxidation. Lazaroids have been used for the acute treatment of central nervous system disorders such as trauma and ischemia wherein lipid peroxidative processes take place. In this study we evaluated the effect of lazaroids (U-785 18F and U-74389F) on the release of acid phosphatase activity and formation of malondialdehyde (MDA) in rat liver lyosomes subjected to exogenously generated oxygen free radicals. There was a significant increase in the acid phosphatase release and MDA formation in the presence of oxygen free radicals. This was prevented by both the lazaroids. In a separate study the effect of lazaroid U-74389F was seen on the zymosan-stimulated polymorphonuclear (PMN) leukocyte-derived chemiluminescence. The PMN leukocyte chemiluminescent activity was attenuated by the lazaroid in a dose-dependent manner. These studies suggest that lazaroids may inhibit lipid peroxidation and stabilize the membrane.

The dramatic decline in the risk of stroke is most likely secondary to a better control of risk factors, especially hypertension. An increase in low-density lipoprotein (LDL) cholesterol or a decrease in high-density lipoprotein (HDL) cholesterol may be additional risk factors for cerebrovascular diseases. In this study, we prospectively evaluated patients with ischemic stroke (except for cardioembolic) and age-matched controls for serum cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, very low-density lipoprotein cholesterol, and apoprotein A and B. Blood levels were determined at least 8 weeks after the acute stroke or transient ischemic attack. Between September 1989 and September 1990,59 patients and 60 controls were investigated. There were no differences among total cholesterol, triglycerides, LDL cholesterol, and apoproteins in the two groups. HDL cholesterol, however, was significantly higher in patients with stroke. In stroke patients, total cholesterol (p < 0.05), LDL cholesterol (p < 0.05), and apolipoprotein B (p < 0.05) were significantly higher in female patients compared to male patients. This study confirms that low HDL cholesterol may be a risk factor for stroke. Additionally, ally, we show that lipid abnormalities may appear to be more significant in women.

Oxygen free radicals (OFRs) are known to produce a decrease in cardiac function and contractility. The decrease in cardiac contractility and function in chronic volume overload heart failure might be due to an increased level of OFRs and/or decrease in the antioxidant status. We, therefore, studied the effects of chronic volume overload in the absence and presence of vitamin E (antioxidant) on cardiac function and contractility, cardiac malondialdehyde (MDA), a lipid peroxidation product and a fingerprint for levels of OFRs, cardiac antioxidant enzyme activity and antioxidant reserve in canine model. Volume overload heart failure was produced by creating mitral regurgitation (MR). Volume overload produced a decrease in the index of myocardial contractility manifested by an increase in left ventricular end diastolic pressure LVEDP without a significant change in cardiac index (CI). There was an increase in pulmonary vascular resistance (PVR) and total systemic vascular resistance (TSVR).The decrease in cardiac contractility was associated with an increase in cardiac MDA and a decrease in cardiac antioxidant reserve and antioxidant enzyme activity. Prevention of volume overload induced decrease in cardiac contractility by vitamin E was associated with a decrease in cardiac MDA and an increase in cardiac antioxidant reserve and glutathione peroxidase activity towards control levels. Superoxide dismutase and catalase activity remained depressed in vitamin E-treated animals. These results suggest that the oxygen free radicals are involved in the chronic volume overload heart failure.

1. Oxygen free radicals have been suggested to be a contributory factor in complications of diabetes mellitus. In the present study, we investigated the lipid peroxide level [thiobarbituric acid-reactive substances (TBARS)] and activities of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) in aorta, heart and blood of control and streptozotocin-induced diabetic rats at various stages of development of diabetes (0 to 6 weeks). 2. There was no change in the TBARS levels of aorta, heart and blood in the control group. A significant (P < 0.05) increase in TBARS levels of aorta, heart and blood was observed in the diabetic group. 3. There were no significant changes in the activities of superoxide dismutase, catalase and glutathione peroxidase in the aorta, heart and blood of control rats at all time intervals. In the diabetic group, there was a significant (P < 0.05) increase in the activity of superoxide dismutase and glutathione peroxidase in aorta from the fourth week onwards while the activity of catalase increased at all time intervals. In the heart of diabetic rats, the activity of total superoxide dismutase and Cu—Zn-superoxide dismutase increased significantly (P < 0.05) from the second week onwards while activity of Mn-superoxide dismutase decreased at the fourth week and increased at the sixth week. The activity of catalase and glutathione peroxidase increased significantly (P < 0.05) at all time intervals. In the blood, the activity of superoxide dismutase and glutathione peroxidase increased from the third week while catalase activity increased from the fourth week. 4. The present findings suggest that oxidative stress starts at early onset of diabetes mellitus and increases progressively.

Glutamate is one of the principal neurotoxins in the pathogenesis of ischemic neuronal injury. Elevated glutamate levels in ischemia have been well documented in many animal stroke models. Recent work in humans also shows a similar trend. We have used our acute focal ischemic model of the human brain to study the response of glutamate levels by in vivo microdialysis during ischemia using two different perfusates. The addition of 30 mM of glucose to the perfusate attenuated the percentages of dialysate glutamate levels from 4.27 +/- 1.7 to 1.34 +/- 0.47 (P0.001) during partial ischemia and from 21.42 +/- 6.05 to 7.25 +/- 1.43 (P0.05) with total ischemia. The pre-ischemic values of glutamate were similar with the two perfusates. These results indicate that the ischemia-induced rise in glutamate is attenuated by exogenous glucose delivery in the human stroke model.

The release of neurotransmitters principally glutamate during cerebral ischemia has been extensively studied. It is well recognized that ischemia induced release of glutamate plays a key role in “excitotoxic” neuronal death. The role of monoaminergic neurotransmitters is however unclear. The purpose of this study was to evaluate the extracellular norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA) and serotonin (5-HT) under varied degrees of ischemia in the acute focal ischemic model of the human brain by in-vivo microdialysis. The ischemic response of these amines was correlated with the glutamate levels. Our study concludes that these amines and metabolites can be detected in the human “stroke” model. No marked fluctuations were noted in the levels of norepinephrine and DOPAC. However, significant changes to partial and total ischemia were noted in the extracellular levels of 5-HIAA and 5-HT. These compounds showed a dramatic increase with the onset of ischemia with higher detectable levels in the partial ischemic state in comparison to the total ischemic dialysate levels. The exact role played by the differential increase in the levels of 5-HT to the other catecholamines in the pathogenesis of ischemic neuronal damage remains unclear and warrants further study.

We hypothesized that oxygen free radicals (OFRs) may be involved in pathogenesis of diabetic complications. We therefore investigated the levels of lipid peroxidation by measuring thiobarbituric acid reactive substances (TBARS) and activity of antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)] in tissues and blood of streptozotocin (STZ)-induced diabetic rats. The animals were divided into two groups: control and diabetic. After 10 weeks (wks) of diabetes the animals were sacrificed and liver, heart, pancreas, kidney and blood were collected for measurement of various biochemical parameters. Diabetes was associated with a significant increase in TBARS in pancreas, heart and blood. The activity of CAT increased in liver, heart and blood but decreased in kidney. GSH-Px activity increased in pancreas and kidney while SOD activity increased in liver, heart and pancreas. Our findings suggest that oxidative stress occurs in diabetic state and that oxidative damage to tissues may be a contributory factor in complications associated with diabetes.

GABAergic neurons in the striatum are very sensitive to the effects of ischemia. The progressive decline in striatal GABA following transient forebrain ischemia in gerbils may be secondary to either a decreased production or an increase in reuptake mechanisms or both. The current experiment was designed to evaluate release of GABA by stimulation with K+ or inhibition of its uptake with nipecotic acid or their combination (K+ nipecotic) after repetitive forebrain ischemia in gerbils by in-vivo microdialysis on Days 1, 3, 5, and 14 following the insult. Infusion of nipecotic acid or potassium chloride, resulted in a significant increase in extracellular GABA. This response was significantly decreased in the post-ischemic animals. The synergistic effect of increased GABA concentrations by the infusion of nipecotic acid + potassium chloride seem in the controls was not evident in the post-ischemic animals. In conclusion, though there is a reduction in the extracellular GABA concentrations in the first week following an ischemic insult, restorative mechanisms are operative in the second week as seen by the increasing GABA concentrations.

Exogenous oxygen free radicals (OFRs) have been reported to depress cardiac function and contractility. The decrease in cardiac function and contractility in chronic volume overload could be due to increased levels of OFRs. We therefore investigated the effects of volume overload of 9 months duration in the absence and presence of catalase treatment on cardiac function and contractility; left ventricular malondialdehyde (MDA), a lipid peroxidation product; and left ventricular antioxidant reserve, measured as left ventricular chemiluminescence (LV-CL) in dogs. Dogs were divided into three groups: group I, control; group II, mitral regurgitation (MR) of 9 months duration; and group III, same as group II but supplemented with polyethylene glycol (PEG)-catalase (5000IU/kg/week, intravenously).

The purpose of this study was to better establish the morphologic basis of the early mucosal lesions of experimental inflammatory bowel disease because understanding the development of these lesions has important pathogenetic implications. Sprague-Dawley rats were given 1.5% hydrolyzed lambda-carrageenan orally for 30 days. This produced small intestinal lesions which were then evaluated. Light microscopy showed an increased amount of inflammatory cells in the gut wall with prominent Peyer's patches, microgranulomas, crypt abscesses, pin-point ulcerations, and a repair reaction. Scanning electron microscopy revealed pin-point ulcerations in relation to Peyer's patches. Transmission electron microscopy, in addition to the above findings, showed disruptions of enterocyte microvilli and terminal webs. Follicle-associated epithelium appeared to be a predictive site for the development of crypt abscesses and pin-point ulcerations. Enzyme-linked immunoadsorbent assays indicated that orally administered carrageenan elicited a systemic antibody response. Our results suggest that damage to enterocyte microvilli and terminal webs may be important early events in the morphogenesis of the lesions.

We investigated the effects of a high-cholesterol diet in the presence and absence of vitamin E on the lipid peroxidation product malondialdehyde of blood and aortic tissue, the oxygen-free-radical-producing activity of polymorphonuclear leukocytes (PMNs) (PMN chemiluminescence), and the blood lipid profile in rabbits. The animals were divided into four groups each of which comprised 10 rabbits. Rabbits in group I received a regular rabbit chow diet; those in group II received vitamin E; those in group III received high cholesterol + vitamin E; and those in group IV received a high-cholesterol diet. Blood concentrations of triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol (VLDL-C), malondialdehyde, and PMN chemiluminescence were measured. The aorta of each rabbit was removed at the end of the protocol for assessment of atherosclerotic changes (gross and microscopic) and malondialdehyde. Serum triglycerides, total cholesterol, HDL-C, LDL-C, and VLDL-C increased while HDL/LDL ratio decreased in groups III and IV but remained unchanged in group I. There was an increase in the HDL-C component and HDL/LDL ratio and a decrease in the LDL-C component and triglycerides in group II. Blood and aortic tissue malondialdehyde increased in group IV but decreased in groups II and III. PMN chemiluminescence increased in groups III and IV. Atherosclerotic changes were marked in group IV as compared with those in group III. However, histologic changes in the aortas were similar in groups III and IV. The increased levels of blood and aortic tissue malondialdehyde and PMN chemiluminescence, which were associated with development of atherosclerosis, suggest a role of oxygen free radicals in the pathogenesis of hypercholesterolemia-induced atherosclerosis. The protection afforded by vitamin E, which was associated with a decrease in blood and aortic tissue malondialdehyde concentration in spite of hypercholesterolemia, supports the hypothesis that oxygen free radicals are involved in the development of hypercholesterolemic atherosclerosis.

Various methods have been used in the past to assess the implication of oxygen free radicals (OFR) in ischemia-reperfusion-induced cardiac injury. Luminol-enhanced tert-butyl-initiated chemiluminescence in cardiac tissue reflects oxidative stress and is a very sensitive method. It was used to elucidate the role of OFR in cardiac injury due to ischemia and reperfusion. Studies were conducted on perfused isolated rabbit hearts in three groups (n = 8 in each): I, control; II, submitted to global ischemia for 30 min; III, submitted to ischemia for 30 min followed by reperfusion for 60 min. The heart tissue was then assayed for chemiluminescence (CL); content of malondialdehyde (MDA), an indicator of OFR-induced cardiac injury; and activity of tissue levels of antioxidants [superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px)]. The control values for left and right ventricular CL and malondialdehyde were 81.1 +/- 15.4 (S.E.) and 182.4 +/- 50.3 (S.E.), mv.min.mg protein-1; and 0.024 +/- 0.006 (S.E.) and 0.324 +/- 0.005 (S.E.) nmoles.mg protein-1 respectively. Ischemia produced an increase in the cardiac CL (3.3 to 4.4 fold) and MDA content (2 to 2.6 fold). Reperfusion following ischemia also produced similar changes in CL and MDA content. The control values for activity of left ventricular SOD, catalase, and GSH-Px were 45.77 +/- 1.73 (S.E.) U.mg protein-1, 5.35 +/- 0.51 (S.E.) K.10(-3).sec-1.mg protein-1, and 77.50 +/- 7.70 (S.E.) nmoles NADPH.min-1.mg protein-1 respectively. Activities of SOD and catalase decreased during ischemia but were similar to control values in ischemic-reperfused hearts. The GSH-Px activity of left ventricle was unaffected by ischemia, and ischemia-reperfusion. GSH-Px activity of the right ventricle increased with ischemia, and ischemic-reperfusion. These results indicate that cardiac tissue chemiluminescence would be a useful and sensitive tool for the detection of oxygen free radical-induced cardiac injury.

Oxygen free radicals (OFRs) have been suggested in the pathogenesis of Parkinson's disease (PD). These free radicals exert their cytotoxic effect by peroxidation of lipid membrane resulting in the formation of malondialdehyde (MDA). Polymorphonuclear (PMN) leukocyte is one of the major sources of OFR. However, the oxygen free radical producing activity of PMN leukocytes in patients with PD is not known. We therefore studied the oxygen free radical producing activity of polymorphonuclear leukocytes and MDA levels in the serum of healthy subjects and in patients with Parkinson's disease. The oxygen free radical producing activity of PMN leukocytes in blood and the MDA content in serum were significantly higher in patients with Parkinson's disease than in healthy subjects. These results indicate a possible role of oxygen free radicals in the pathogenesis of Parkinson's disease.

It has been suggested that oxygen free radicals (OFR) depress the excitation-contraction coupling in cardiac muscle. It is possible that a decrease in the cardiac contractility in the failing heart may be due to an increased OFR producing activity of polymorphonuclear (PMN) leukocytes. We studied the OFR producing activity (chemiluminescence) of PMN leukocytes from blood in dogs with heart failure due to chronic volume overload. The animals were divided into two groups: I) normal, (n = 10): II) dogs with mitral insufficiency (MI) of 6 to 9 months duration, (n = 10). Hemodynamic studies were done to establish the presence of heart failure. Blood samples were collected to measure PMN leukocyte chemiluminescence. There was a decrease in the cardiac index and index of myocardial contractility (dp/dt/IIP) and an increase in the left ventricular end-diastolic pressure in dogs with MI indicating left ventricular failure. The peak chemiluminescent activity of the PMN leukocytes in blood of dogs with failure was about four folds greater than that in the blood from normal dogs. These results suggest that there may be an increased OFR generation in dogs with volume overload heart failure. The decrease in the myocardial contractility in the failing heart might be due to an increase in the OFR produced by the PMN leukocytes.

Endothelin, a peptide that is derived from vascular endothelial cells, is a potent constrictor of mammalian blood vessels in in vitro studies. Various clinical conditions have been reported to be associated with an increase in the blood and tissue levels of endothelin. In the present study, the effects of two doses (2.059 and 4.118 micrograms/kg, intravenously) of endothelin on cardiac function and contractility; blood lactate, gases, and pH levels; blood and cardiac tissue MDA levels; PMN leukocyte chemiluminescence activity; and total WBC and PMN leukocyte counts were investigated in anesthetized dogs. Hemodynamic measurements and collection of blood samples for various biochemical measurements were made before and at various intervals up to 2 hours after endothelin administration. Endothelin in the large dose (4.118 micrograms/kg) produced a prolonged decrease in the indices of cardiac contractility and cardiac function and increases in TSVR, PVR, and mean right atrial pressure. The changes in the hemodynamic parameters with the smaller dose (2.059 micrograms/kg) were similar but of smaller magnitude. Significant decreases in dp/dt at CPIP:PAW and CI and increases in TSVR and PVR were observed with the smaller dose of endothelin. There were decreases in the blood HCO3- and pH levels and an increase in H+ and blood lactate concentration and CK activity with the high dose of endothelin. No changes were observed in blood PO2 and PCO2 with either dose of endothelin. Circulating WBCs and PMN leukocytes decreased significantly with both doses of endothelin. There were no changes in the oxygen free radical-producing activity of PMN leukocytes and in the blood and cardiac tissue MDA levels. These results suggest that endothelin decreased cardiac function and cardiac contractility and increased SVR and PVR. The decrease in cardiac function and contractility may be due to ischemia from constriction of coronary arteries. The hemodynamic changes are unlikely be due to oxygen free radicals since there was no increase in the blood and cardiac tissue MDA levels and no change in the PMN chemiluminescence. These studies suggest that increases in endothelin levels in certain clinical conditions might cause added deleterious effects on cardiovascular function.

Oxygen free radicals (OFR) have been implicated as a causative factor of cell damage in several pathologic conditions. It is possible that OFR could have effects on cardiac function and contractility. The present investigation deals with the effects of OFR in the absence and in the presence of scavangers of OFR (superoxide dismutase and catalase) on cardiac function, index of cardiac contractility, serum creatine kinase (CK), and blood lactate, PO2 and pH in the anesthetized dogs. The hemodynamic measurements and collection of blood samples for measurement of CK, lactate, PO2 and pH were made before and at various intervals after administration of OFR for 1 hour. Xanthine and xanthine oxidase were used to generate OFR. OFR produced a decrease in cardiac function and indices of myocardial contractility and an increase in the serum CK. OFR produced an increase in the systemic and pulmonary vascular resistance. Although there was a tendency for an increase in the blood lactate, the increase was not significant. The blood PO2 and pH were not affected. Superoxide dismutase (SOD), alone or in combination with catalase, tended to protect cardiac function against the deleterious effects of OFR. Scavangers of OFR prevented the OFR-induced rise in serum CK. Although the protective effect of SOD plus catalase was slightly better than SOD alone, the results were not significantly different from each other. These results suggest that OFR are cardiac depressant and increase the peripheral vascular resistance besides causing cellular damage. Scavangers of OFR may be beneficial in counteracting the deleterious effects of OFR on hemodynamic parameters and cellular integrity.

We hypothesize that oxygen free radicals are involved in the genesis and maintenance of volume and pressure overload heart failure. Pressure and vol ume overload would produce myocardial ischemia. During ischemia there will be an increase in xanthine and xanthine oxidase; and a decrease in the superox ide dismutase and glutathione peroxidase activity leading to an increase in the oxygen free radicals. A decrease in the cellular pH during ischemia would re lease phospholipase which would, in turn, release arachidonic acid from phos pholipids. Leukotrienes and prostaglandins will be synthesized through arachidonic acid metabolism. During this synthesis not only oxygen free radi cals will be produced but also there will be formation of leukotriene, LTB4, which is known to activate neutrophil and hence increased secretion of oxygen free radicals. Increased circulatory catecholamines due to compensatory mech anism would also lead to an increase in the oxygen free radicals. Oxygen free radicals are known to depress Ca++ binding and uptake of sarcoplasmic retic ulum which would lead to a decrease in the myocardial contractility. We have shown that oxygen free radicals depress cardiac function and cardiac contractil ity. It is, therefore, suggested that oxygen free radicals might be involved in the development of heart failure. The use of agents that reduce the amount of oxy gen free radicals would be of value in the prevention and treatment of heart failure.

Oxygen free radicals have been linked to a wide variety of cellular damage in biological systems. Poly morphonuclear (PMN) leukocytes stimulation is one of the known sources for oxygen free radicals. It has been suggested that oxygen free radicals depress the excitation-con traction coupling in cardiac muscle. It is possible that a decrease in the myocardial contractility in heart fail ure might be due to an increased oxy gen-free-radical-producing activity of PMN leukocytes. The authors studied, therefore, the release of oxy gen free radicals, as measured by luminol-dependent chemilumines cence activity, from the PMN leuko cytes in dogs with heart failure due to aortic stenosis. Hemodynamics and phagocytic activity of PMN leuko cytes were studied in 6 control dogs and 6 dogs with aortic stenosis of six to nine months' duration. There was a significant decrease in the index of myocardial contractility and an in crease in the left ventricular end- diastolic pressure in dogs with aortic stenosis, suggesting left ventricular failure in these dogs. Although there was a tendency for a decrease in the cardiac index in dogs with aortic stenosis, the decrease was not signifi cant. Phagocytic activity of PMN leu kocytes in blood was studied in con trol dogs and dogs with aortic steno sis. Phagocytosis was initiated by ad dition of opsonized zymosan and chemiluminescence was monitored by use of a luminometer. The peak chemiluminescence activity of the PMN leukocytes in blood of dogs with heart failure was about threefold greater than that in the blood from control dogs. The presence of super oxide dismutase, a scavenger of oxy gen free radicals, reduced the chemi luminescence from PMN leukocytes in both the control dogs and dogs with aortic stenosis. These results suggest that the increased production of oxygen free radicals by PMN leu kocytes might contribute to a de crease in the myocardial contractility and, hence, to heart failure in dogs with aortic stenosis.