Machine learning to predict myocardial injury and death after non-cardiac surgery.

Myocardial injury due to ischaemia within 30 days of non-cardiac surgery is prognostically relevant. We aimed to determine the discrimination, calibration, accuracy, sensitivity and specificity of single-layer and multiple-layer neural networks for myocardial injury and death within 30 postoperative days. We analysed data from 24,589 participants in the Vascular Events in Non-cardiac Surgery Patients Cohort Evaluation study. Validation was performed on a randomly selected subset of the study population. Discrimination for myocardial injury by single-layer vs. multiple-layer models generated areas (95%CI) under the receiver operating characteristic curve of: 0.70 (0.69-0.72) vs. 0.71 (0.70-0.73) with variables available before surgical referral, p < 0.001; 0.73 (0.72-0.75) vs. 0.75 (0.74-0.76) with additional variables available on admission, but before surgery, p < 0.001; and 0.76 (0.75-0.77) vs. 0.77 (0.76-0.78) with the addition of subsequent variables, p < 0.001. Discrimination for death by single-layer vs. multiple-layer models generated areas (95%CI) under the receiver operating characteristic curve of: 0.71 (0.66-0.76) vs. 0.74 (0.71-0.77) with variables available before surgical referral, p = 0.04; 0.78 (0.73-0.82) vs. 0.83 (0.79-0.86) with additional variables available on admission but before surgery, p = 0.01; and 0.87 (0.83-0.89) vs. 0.87 (0.85-0.90) with the addition of subsequent variables, p = 0.52. The accuracy of the multiple-layer model for myocardial injury and death with all variables was 70% and 89%, respectively.

A text message intervention to support women's physical and mental health after breast cancer treatments (EMPOWER-SMS): a randomised controlled trial protocol.

BACKGROUND: Breast cancer is the most common cancer diagnosed in women worldwide. In developed countries, 80-90% of women will survive five years after diagnosis but the transition from hospital-based care to health self-management and self-efficacy can be difficult. Text messaging programs offer a simple and proven way to provide support to people with chronic diseases. This study aims to test the effectiveness of a text message support program at improving women's health self-efficacy, and physical and mental health outcomes after breast cancer treatments compared to usual care at 6-months and to understand the barriers and enablers to widespread implementation. METHODS: Single-blind randomised control trial (RCT; N = 160) comparing a text message support intervention to usual care in women with breast cancer (recruited from a large tertiary referral hospital in Sydney, Australia). The intervention group will receive a six-month text message support program, which consists of semi-personalised, supportive, lifestyle-focused text messages (4 messages/week) in addition to usual care. The control group will receive usual care without the text message program. Outcomes will be assessed at 6-months. The primary outcome is change in self-efficacy for managing chronic disease. Secondary outcomes include change in clinical outcomes (body mass index), lifestyle outcomes (physical activity levels, dietary behaviours), mood (depression and anxiety scales), quality of life, satisfaction with, and usefulness of the intervention. Analyses will be performed on the principle of intention-to-treat to examine differences between intervention and control groups. DISCUSSION: This study will test if a scalable and cost-effective text-messaging intervention is effective at improving women's health self-efficacy, as well as physical and mental health outcomes. Moreover, this study will provide essential preliminary data to bolster a large multicentre RCT to helpsupport breast cancer survivors throughout recovery and beyond. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12618002020268 , 17 December 2018.

Inaccurate risk perceptions contribute to treatment gaps in secondary prevention of cardiovascular disease.

BACKGROUND: All patients with cardiovascular disease (CVD) are at high risk of recurrent events. Despite strong evidence, large treatment gaps exist in CVD secondary prevention. We hypothesise that patients' self-perception and general practitioner's (GP) assessment of future cardiovascular (CV) risk may influence secondary prevention behaviours. AIM: To examine in patients with known CVD the perceived risk of future CV events and its relationship with use of secondary prevention medications and risk factor control. METHODS: We examined patient and practitioner's perceived risk and its relationship with the uptake of secondary prevention recommendations in adults with CVD participating in the Australian Hypertension and Absolute Risk Study. RESULTS: Among the 1453 participants, only 11% reported having a high absolute risk and 29% reported high relative risk of recurrent events. The GP categorised only 30% as having a 5-year risk ≥15%. After adjusting for covariates, hospitalisation within the preceding 12 months was the only significant predictor of patients' accurate risk perception. Conventional CV risk factors were predictive of the GP's risk estimates. Patients who accurately understood their risk reported higher smoking cessation rates (7 vs 3%, P = 0.003) and greater use of antiplatelet, blood pressure lowering therapy and statins (P ≤ 0.01). However, there was no relationship between GP's risk perception and secondary prevention treatments. CONCLUSION: Both patients and GP have optimistic bias and underestimate the risk of future CV events. Patients' accurate self-perception, but not GP risk perception, was associated with improved secondary preventative behaviours. This suggests that helping patients to understand their risk may influence their motivation towards secondary prevention. Providing support to GP or programmes to help patients better understand their risks could have potential benefit on secondary prevention behaviours.

Cardiac assessment prior to non-cardiac surgery.

BACKGROUND: Increasingly, patients undergoing non-cardiac surgery are older and have more comorbidities yet preoperative cardiac assessment appears haphazard and unsystematic. We hypothesised that patients at high cardiac risk were not receiving adequate cardiac assessment, and patients with low-cardiac risk were being over-investigated. AIMS: To compare in a representative sample of patients undergoing non-cardiac surgery the use of cardiac investigations in patients at high and low preoperative cardiac risk. METHODS: We examined cardiac assessment patterns prior to elective non-cardiac surgery in a representative sample of patients. Cardiac risk was calculated using the Revised Cardiac Risk Index. RESULTS: Of 671 patients, 589 (88%) were low risk and 82 (12%) were high risk. We found that nearly 14% of low-risk and 45% of high-risk patients had investigations for coronary ischaemia prior to surgery. Vascular surgery had the highest rate of investigation (38%) and thoracic patients the lowest rate (14%). Whilst 78% of high-risk patients had coronary disease, only 46% were on beta-blockers, 49% on aspirin and 77% on statins. For current smokers (17.3% of cohort, n = 98), 60% were advised to quit pre-op. CONCLUSIONS: Practice patterns varied across surgical sub-types with low-risk patients tending to be over-investigated and high-risk patients under-investigated. A more systemised approach to this large group of patients could improve clinical outcomes, and more judicious use of investigations could lower healthcare costs and increase efficiency in managing this cohort.

Clinical guidelines on hyperlipidaemia: recent developments, future challenges and the need for an Australian review.

Large reductions in cardiovascular disease (CVD) mortality have been achieved over the last 50 years in developed countries. The health policies that have contributed so much to this success have largely been coordinated by means of expert guidelines for the management of the classic modifiable risk factors such as blood pressure, diabetes and blood lipids. National and international guidelines for lipid management have demonstrated a high degree of consistency between numerous sets of recommendations. It has been argued that some important components of the consensus that has been established over the past decade have been challenged by the latest guidelines of the American Heart Association - American College of Cardiologists (AHA-ACC). Clinicians can be reassured that continued reliance on extensive scientific evidence has reaffirmed the importance of lipid metabolism as a modifiable risk factor for atherosclerotic cardiovascular disease. On the other hand, the recent AHA-ACC guidelines suggest changes in the strategies by which metabolic risk factors may be modified. This small number of important changes should not be sensationalised because these differences usefully reflect the need for guidelines to evolve to accommodate different contexts and changing perspectives as well as emerging issues and new information for which clinical trial evidence is incomplete. This article will consider the recent policies and responses of national and supranational organisations on topics including components of CVD risk assessment, sources of CVD risk information and re-appraisal of lipid-lowering interventions. Timely review of Australian lipid management guidelines will require consideration of these issues because they are creating a new context within which new guidelines must evolve.

The influence of physical activity on vascular complications and mortality in patients with type 2 diabetes mellitus.

AIMS: There is limited evidence regarding the association between physical activity and vascular complications, particularly microvascular disease, in patients with type 2 diabetes. METHODS: From the 11 140 patients in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial, the effect of physical activity, categorized as none, mild, moderate or vigorous, and the number of sessions within a week, was examined in multivariable regression models adjusted for potential confounders. The study end-points were major cardiovascular events, microvascular complications and all-cause mortality. RESULTS: Forty-six percent of participants reported undertaking moderate to vigorous physical activity for >15 min at least once in the previous week. During a median of 5 years of follow-up, 1031 patients died, 1147 experienced a major cardiovascular event and 1136 a microvascular event. Compared to patients who undertook no or mild physical activity, those reporting moderate to vigorous activity had a decreased risk of cardiovascular events (HR: 0.78, 95% CI: 0.69-0.88, p < 0.0001), microvascular events (HR: 0.85, 95% CI: 0.76-0.96, p = 0.010) and all-cause mortality (HR: 0.83, 95% CI: 0.73-0.94, p = 0.0044). CONCLUSIONS: Moderate to vigorous, but not mild, physical activity is associated with a reduced incidence of cardiovascular events, microvascular complications and all-cause mortality in patients with type 2 diabetes.

Resting heart rate and the risk of death and cardiovascular complications in patients with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: An association between resting heart rate and mortality has been described in the general population and in patients with cardiovascular disease. There are, however, few data exploring this relationship in patients with type 2 diabetes mellitus. The current study addresses this issue. METHODS: The relationship between baseline resting heart rate and all-cause mortality, cardiovascular death and major cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) was examined in 11,140 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Study. RESULTS: A higher resting heart rate was associated with a significantly increased risk of all-cause mortality (fully adjusted HR 1.15 per 10 bpm [95% CI 1.08, 1.21], p<0.001), cardiovascular death and major cardiovascular outcomes without adjustment and after adjusting for age and sex and multiple covariates. The increased risk associated with a higher baseline resting heart rate was most obvious in patients with previous macrovascular complications (fully adjusted HR for death 1.79 for upper [mean 91 bpm] vs lowest [mean 58 bpm] fifth of resting heart rate in this subgroup [95% CI 1.28, 2.50], p = .001). CONCLUSIONS/INTERPRETATION: Among patients with type 2 diabetes, a higher resting heart rate is associated with an increased risk of death and cardiovascular complications. It remains unclear whether a higher heart rate directly mediates the increased risk or is a marker for other factors that determine a poor outcome.

What is the role of invasive versus non-invasive coronary angiography in the investigation of patients suspected to have coronary heart disease?

The improved technology of multi-slice cardiac CT angiography (CTA) has enabled production of high quality images of the coronary arteries. The sensitivity and specificity of the test in identifying patients with obstructive coronary lesions in 64-slice and later generations of scanners is high. To enable effective use of CTA in the clinical setting, a better understanding of this technology, particularly in comparison to invasive coronary angiography, is needed. In this article we discuss the characteristics of CTA in comparison to invasive coronary angiography and discuss the role of CTA in the diagnosis of coronary artery disease (CAD). Newer CTA scanners and individualized scanning protocols can minimize radiation exposure from CTA. CTA can provide more information than invasive coronary angiography on the type and burden of atherosclerotic plaque in the coronary tree. CTA is most useful in those at intermediate risk of CAD.

Effect of lifestyle focused text messaging on risk factor modification in patients with diabetes and coronary heart disease: A sub-analysis of the TEXT ME study.

AIMS: There is potential to provide public health interventions through text messaging for patients with Type 2 diabetes mellitus (T2DM). Our objective was to ascertain if lifestyle focused text messaging addressing cardiovascular risk factors in patients with coronary heart disease (CHD) and T2DM, was more effective than usual care. METHODS: This is a secondary analysis of the TEXT ME study, a randomised clinical trial of a 6-month text messaging intervention in patients with coronary heart disease. The measured outcomes include cholesterol, blood pressure (BP), body mass index (BMI), HbA1c, waist/hip circumference and smoking status. Our objective was to ascertain if lifestyle focused text messaging in patients with T2DM was more effective than usual care, and to determine if the intervention was more effective in patients with T2DM compared to those without. RESULTS: 229 participants in the TEXT ME study had T2DM (32%), 111 participants in the intervention group and 118 in the control group. At 6 months, the mean difference in systolic BP was -7.6 mmHg (95%CI -11.8, -3.37, p = 0.0003) and diastolic BP -3.7 mmHg (95%CI -6.12, -1.24, p = 0.0032). The mean difference in low density lipoprotein in the intervention arm, compared to the control arm, was -0.05 mmol/L (95%CI -0.27, 0.18, p = 0.813), and in triglycerides was -0.29 mmol/L (95%CI -0.59, 0.01, p = 0.035) respectively. The mean difference in BMI was -0.89 kg/m2 (95%CI -2.74, 0.95, p < 0.0001) in the intervention group, waist circumference -3.98 cm (95%CI -8.57, 0.61, p < 0.0001) and hip circumference -3.26 cm (95%CI -7.67, 1.16, p = 0.0006). Intervention subjects with diabetes were less likely to be smokers at 6 months. The mean difference in HbA1c between the control and intervention group was not significant (p = 0.126). The intervention was as effective in patients with diabetes, compared to those without. CONCLUSION: Among patients with coronary heart disease with T2DM, lifestyle-focused text messaging resulted in significant risk factor reduction.

The burden of fatal and non-fatal injury in rural India.

BACKGROUND: Little is known about the burden or causes of injury in rural villages in India. OBJECTIVE: To examine injury-related mortality and morbidity in villages in the state of Andhra Pradesh, India. METHODS: A verbal-autopsy-based mortality surveillance study was used to collect mortality data on all ages from residents in 45 villages in 2003-2004. In early 2005, a morbidity survey in adults was carried out using stratified random sampling in 20 villages. Participants were asked about injuries sustained in the preceding 12 months. Both fatal and non-fatal injuries were coded using classification methods derived from ICD-10. RESULTS: Response rates for the mortality surveillance and morbidity survey were 98% and 81%, respectively. Injury was the second leading cause of death for all ages, responsible for 13% (95% CI 11% to 15%) of all deaths. The leading causes of fatal injury were self-harm (36%), falls (20%), and road traffic crashes (13%). Non-fatal injury was reported by 6.7% of survey participants, with the leading causes of injury being falls (38%), road traffic crashes (25%), and mechanical forces (16.1%). Falls were more common in women, with most (72.3%) attributable to slipping and tripping. Road traffic injuries were sustained mainly by men and were primarily the result of motorcycle crashes (48.8%). DISCUSSION: Injury is an important contributor to disease burden in rural India. The leading causes of injury-falls, road traffic crashes, and suicides-are all preventable. It is important that effective interventions are developed and implemented to minimize the impact of injury in this region.

Unilateral epistaxis after swimming in a stream.

A 55-year-old Chinese woman presented with a 3-week history of unilateral left-sided epistaxis and nasal obstruction. She had swam in a freshwater stream 1 month prior to the onset of symptoms. Endoscopic examination revealed a live leech at the left middle meatus with a large part of its body inside the left maxillary antrum. Local anaesthetic was applied to anaesthetise the leech and facilitate removal. Magnetic resonance imaging performed following removal confirmed that no other leeches were present in the sinonasal area. The endoparasitism might have persisted because of the inconspicuous site of infestation and the absence of pain. This form of leech infestation has not been previously reported.

Vitamin E and oxidative stress.

Oxidative stress can result from or be enhanced by a large variety of conditions, including nutritional imbalance, exposure to chemical and physical agents in the environment, strenuous physical activities, injury, and hereditary disorders. While many enzymes and compounds are involved in protecting cells from the adverse effects of oxidative stress, vitamin E occupies an important and unique position in the overall antioxidant defense. The antioxidant function of vitamin E is closely related to the status of many dietary components. Vitamin E-depleted animals are generally more susceptible to the adverse effects of environmental agents than supplemented animals. Also, vitamin E supplementation is beneficial to certain groups of the population. However, supplementing vitamin E in experimental subjects maintained on a nutritionally adequate diet does not always provide additional protection. Differential metabolic responses in various organs and differences in experimental conditions often contribute in the discrepancies in the literature. The lack of clear evidence for the occurrence of lipid peroxidation or antioxidant function of vitamin E in vivo can be attributed partly to the presence of active pathways for metabolizing hydroperoxides, aldehydes, and other oxidation products. Specific and sensitive techniques for measuring lipid peroxidation products in biological systems are essential for understanding the role of free radical-induced lipid peroxidation in tissue damage and antioxidant function of vitamin E in vivo.

Lipid peroxidation and endothelial cell injury: implications in atherosclerosis.

Vascular endothelial cells, which play an active role in the physiological processes of vessel tone regulation and vascular permeability, form a border separating deeper layers of the blood vessel wall and cellular interstitial space from the blood and circulating cells. Damage or dysfunction of endothelial cells may reduce the effectiveness of the endothelium to act as a selectively permeable barrier to plasma components, including cholesterol-rich lipoprotein remnants. This may be involved in the etiology of atherosclerosis. Experimental evidence indicates that free radical-mediated lipid peroxidation can induce endothelial cell injury/dysfunction. Reactive oxygen species, including peroxidized lipids capable of initiating cell injury, may be generated within endothelial cells, be present in plasma components, or be derived from neutrophils or other blood-borne cells. Lipid peroxidation could initiate or promote the process of atherosclerotic lesion formation by directly damaging endothelial cells, and by enhancing the adhesion and activation of neutrophils and the susceptibility of platelets to aggregate. Endothelial cell injury by lipid hydroperoxides also could increase the uptake of LDL into the vessel wall. These events and other cellular dysfunctions may individually or collectively initiate and/or help to sustain the development of atherosclerosis.

Vitamin E regulates mitochondrial hydrogen peroxide generation.

The mitochondrial electron transport system consumes more than 85% of all oxygen used by the cells, and up to 5% of the oxygen consumed by mitochondria is converted to superoxide, hydrogen peroxide, and other reactive oxygen species (ROS) under normal physiologic conditions. Disruption of mitochondrial ultrastructure is one of the earliest pathologic events during vitamin E depletion. The present studies were undertaken to test whether a direct link exists between vitamin E and the production of hydrogen peroxide in the mitochondria. In the first experiment, mice were fed a vitamin E-deficient or-sufficient diet for 15 weeks, after which the mitochondria from liver and skeletal muscle were isolated to determine the rates of hydrogen peroxide production. Deprivation of vitamin E resulted in an approximately 5-fold increase of mitochondrial hydrogen peroxide production in skeletal muscle and a 1-fold increase in liver when compared with the vitamin E-supplemented group. To determine whether vitamin E can dose-dependently influence the production of hydrogen peroxide, four groups of male and female rats were fed diets containing 0, 20, 200, or 2000 lU/kg vitamin E for 90 d. Results showed that dietary vitamin E dose-dependently attenuated hydrogen peroxide production in mitochondria isolated from liver and skeletal muscle of male and female rats. Female rats, however, were more profoundly affected by dietary vitamin E than male rats in the suppression of mitochondrial hydrogen peroxide production in both organs studied. These results showed that vitamin E can directly regulate hydrogen peroxide production in mitochondria and suggest that the overproduction of mitochondrial ROS is the first event leading to the tissue damage observed in vitamin E-deficiency syndromes. Data further suggested that by regulating mitochondrial production of ROS, vitamin E modulates the expression and activation of signal transduction pathways and other redox-sensitive biologic modifiers, and thereby delays or prevents degenerative tissue changes.

Antioxidant and oxidative status in tissues of manganese superoxide dismutase transgenic mice.

Manganese superoxide dismutase (Mn-SOD) plays an important role in attenuating free radical-induced oxidative damage. The purpose of this research was to determine if increased expression of Mn-SOD gene alters intracellular redox status. Twelve week old male B6C3 mice, engineered to express human Mn-SOD in multiple organs, and their nontransgenic littermates were assessed for oxidative stress and antioxidant status in heart, brain, lung, skeletal muscle, liver, and kidney. Relative to their nontransgenic littermates, transgenic mice had significantly (p <.01) higher activity of Mn-SOD in heart, skeletal muscle, lung, and brain. Copper, zinc (Cu,Zn)-SOD activity was significantly higher in kidney, whereas catalase activity was lower in brain and liver. The activities of selenium (Se)-GSH peroxidase and non-Se-GSH peroxidase, and levels of vitamin E, ascorbic acid and GSH were not significantly different in any tissues measured between Mn-SOD transgenic mice and their nontransgenic controls. The levels of malondialdehyde were significantly lower in the muscle and heart of Mn-SOD mice, and conjugated dienes and protein carbonyls were not altered in any tissues measured. The results obtained showed that expression of human SOD gene did not systematical alter antioxidant systems or adversely affect the redox state of the transgenic mice. The results also suggest that expression of human SOD gene confers protection against peroxidative damage to membrane lipids.

Impaired production of nitric oxide, superoxide, and hydrogen peroxide in glucose 6-phosphate-dehydrogenase-deficient granulocytes.

Since the generation of superoxide and hydrogen peroxide by NADPH oxidase and nitric oxide (NO) by NO synthase (NOS) in granulocytes is NADPH-dependent, we investigated the production of NO, superoxide and H2O2 in glucose 6-phosphate dehydrogenase (G6PD)-deficient human granulocytes. Our results showed that upon stimulation with either 5 microg/ml of lipopolysaccharide (LPS) or 10 microM of phorbol 12-myristate 13-acetate (PMA), the production of nitrite in normal granulocytes was elevated, 252 +/- 135% and 239 +/- 72%, respectively, compared to the resting stage. In contrast, G6PD-deficient granulocytes did not produce more nitrite upon stimulation with either LPS or PMA compared to the resting stage. Western blot analysis indicated a normal expression pattern of inducible NOS in G6PD-deficient granulocytes. In addition, the production of H2O2 and superoxide was also significantly impaired in G6PD-deficient granulocytes compared to control cells. These data demonstrate that G6PD deficiency causes an impairment in the production of NO, superoxide and H2O2.

Distribution of tocopherols in human plasma and red blood cells.

The content of various tocopherols was determined in normal plasma and red blood cells. alpha-Tocopherol concentrations ranged form 6.6 to 15.0 (mean 9.6) mug/ml in plasma and from 0.9 to 1.8 (mean 1.4) mug/ml in red blood cells. gamma-Tocopherol ranged from 0.7 to 2.7 (mean 1.6) mug/ml in plasma and fron 0.1 to 0.4 (mean 0.24) mug/ml in red blood cells. Only a minute amount (smaller than 0.3 mug/ml) of each of alpha-tocotrienol, beta-tocopherol, gamma-tocotrienol and delta-tocopherol was found in plasma but none in red blood cells. No delta-tochotrienol was detected in either plasma or red blood cells. Of the total tocopherols, alpha form accounted 83 per cent in plasma and 87 per cent in red blood cells and gamma from represented 13 per cent in each system. The recovery of added 14-C-alpha-tocopherol averaged 87 per cent and 69 per cent, respectively, for plasma and red blood cells. All alpha-tocopherol in the red blood cells was found to be localized in the membrane fraction.

Effect of tamoxifen on mammographic density.

There are strong data showing that increased breast cancer risk is associated with increased mammographic density. Tamoxifen has been shown to decrease the risk of invasive breast cancer and decrease breast density. We sought to demonstrate and calculate the extent of change in mammographic density in women who have taken tamoxifen for up to 2 years. We evaluated mammograms from 28 high-risk women who were taking tamoxifen. Four different methods of evaluation were used: (a) two qualitative methods (Wolfe criteria and the American College of Radiology Breast Imaging and Reporting Data System criteria); (b) one semiquantitative method (mammograms were assigned one of five semiquantitative scores by visual inspection); and (c) one quantitative method (computer-aided calculation of fibroglandular area from digitized mammograms). The Wolfe criteria showed a 0.03 category decrease per year (P = 0.50). The American College of Radiology Breast Imaging and Reporting Data System criteria showed a 0.1 category decrease per year (P = 0.12). Semiquantitative criteria showed a 0.2 category decrease per year (P = 0.039). Digitized scores showed a 4.3% decrease per year (P = 0.0007). In conclusion, tamoxifen causes a decrease in mammographic density with use, an effect that is better quantitated with semiquantitative criteria or digitized images. Density change might become useful as a surrogate end point for the effect of tamoxifen and other chemopreventive measures, although our data do not predict an individual's degree of risk reduction.

Oxidative stress as a potential pathogenic mechanism in an animal model of Duchenne muscular dystrophy.

Dystrophin-deficiency results in degeneration of most, but not all, skeletal muscles. The mechanisms responsible for degeneration of limb muscle and sparing of extraocular muscle are not known. To address the notion that muscle pathology may be free radical-mediated, we evaluated antioxidant enzyme activities and lipid peroxidation products (TBARS) content in mdx and control mice. TBARS content and the activities of total superoxide dismutase, selenium dependent glutathione peroxidase, glucose-6-phosphate dehydrogenase and catalase were consistently higher in both affected and spared muscles of mdx mice. These data suggest that oxidative stress may be constitutively present in mdx muscle, but may not be the principal pathogenic mechanism. To further test the hypothesis of oxidative stress involvement in dystrophinopathies, control strain and mdx mice were subjected to chronic hyperoxia. The pattern of antioxidant enzyme activities and TBARS content from hyperoxic control strain mice was similar to that of normoxic mdx mice, suggesting that a similar level of oxidative stress was induced. In conclusion, this study has provided indirect evidence for oxidative stress in dystrophin-deficient muscle.

Increased 8-hydroxydeoxyguanosine in hepatic DNA of rats treated with the peroxisome proliferators ciprofibrate and perfluorodecanoic acid.

In this study we examined the ability of peroxisome proliferators to induce oxidative DNA damage in the form of 8-hydroxydeoxyguanosine (OHdG). We studied the hypolipidemic drug ciprofibrate, which is among the most potent and efficacious of the peroxisome proliferators, and perfluorodecanoic acid (PFDA), which is an inhibitor of peroxisomal beta-oxidation. Rats were fed 0.01% ciprofibrate in the diet, or were injected with PFDA at doses of 3 or 10 mg/kg every 14 days (controls and ciprofibrate-fed rats were given equivalent doses of corn oil). Rats were maintained for 10 days, 24 days, 6 weeks, 26 weeks, or 54 weeks. DNA was isolated from the liver at these times and hydrolysed to nucleosides, and the levels of OHdG as well as normal nucleosides were analysed by high-performance liquid chromatography with electrochemical detection. Ciprofibrate increased OHdG concentrations at all times except for the initial 10-day timepoint. Both doses of PFDA increased OHdG levels at all times except the last timepoint, at which only the higher dose produced a significant increase. This study shows that both ciprofibrate and PFDA induce oxidative DNA damage in the form of OHdG. Furthermore, the inhibition of peroxisomal beta-oxidation by PFDA does not affect the development of OHdG.