Relationship between oxidative stress, lipid peroxidation, and ultrastructural damage in patients with coronary artery disease undergoing cardioplegic arrest/reperfusion

OBJECTIVE: In animal models, formation of oxidants during postischemic reperfusion may exert deleterious effects ("oxidative stress"). Cardioplegic arrest/reperfusion during cardiac surgery might similarly induce oxidative stress. However, the phenomenon has not been precisely characterized in patients, and therefore the role of antioxidant therapy at cardiac surgery is a matter of debate. Thus, we wanted to ascertain whether the relationship between oxidant formation and development of myocardial injury also translates to the situation of patients subjected to cardioplegic arrest. METHODS: In 24 patients undergoing coronary artery bypass, trans-cardiac blood samples and myocardial biopsies were taken before cardioplegic arrest and again following reperfusion. RESULTS: Cardiac glutathione release (marker of oxidant production) was negligible at baseline (0.02+/-0.04 micromol/L), but it increased 15 min into reperfusion (1.10+/-0.40 micromol/L; p<0.05); concomitantly, myocardial concentration of the antioxidant ubiquinol decreased from 144.5+/-52.0 to 97.6+/-82.0 nmol/g (p<0.05). Although these changes document cardiac exposure to oxidants, they were not accompanied by evidence of injury. Neither coronary sinus blood nor cardiac biopsies showed increased lipid peroxide concentrations. Furthermore, electron microscopy showed no major ultrastructural alterations. Finally, full recovery of left ventricular systolic and diastolic function was observed. CONCLUSIONS: Careful investigation reveals that while oxidant production does occur during cardiac surgery in patients with chronic ischemic heart disease, cardiac oxidative stress may not progress through membrane damage and irreversible injury.     

Electroanatomic analysis of sinus impulse propagation in normal human atria

INTRODUCTION: Better understanding of atrial propagation during sinus rhythm (SR) in normal hearts under the most normal physiologic conditions may be propaedeutic to pathophysiologic studies of complex atrial arrhythmias. In this study, qualitative and quantitative analyses of sinus impulse propagation in both atria were performed by electroanatomic mapping in patients with no organic heart disease who were undergoing an electrophysiologic procedure. METHODS AND RESULTS: Seven patients (5 men and 2 women; age 37 +/- 11 years) undergoing ablation of a left-sided accessory pathway were considered. Associated heart disease and coexisting atrial arrhythmias were excluded. After obtaining informed consent, electroanatomic mapping of both atria was performed during SR using a nonfluoroscopic system in the postablation phase. Mapping was accomplished in all patients with no complications. Qualitative analysis showed that sinus impulse propagation gives a reproducible activation pattern with minor individual variations. During interatrial propagation, two breakthroughs (anterior and posterior) in the left atrium are observed in the majority of cases. The anterior breakthrough, which reflects conduction over Bachmann's bundle, is predominant and shows a peculiar "preexcitation-like" endocardial activation pattern. Quantitative analysis showed minimal individual variations of propagation time intervals. Atria are activated simultaneously for 65% +/- 9% of the duration of the atrial systolic time interval. CONCLUSION: In normal humans, electroanatomic mapping of SR identifies a typical and reproducible propagation pattern during SR. Bachmann's bundle plays the most important role in interatrial propagation. Atria are activated simultaneously by sinus impulse for a relevant portion of the systolic time interval.     

An economic analysis of developmental detection methods

OBJECTIVE: To assess the costs and benefits of various approaches to early detection of developmental disabilities. DESIGN: Cost-benefit analyses based on data from previously published studies of developmental screening tests. SETTING: General pediatric practices and day care centers. PATIENTS AND OTHER PARTICIPANTS: A total of 247 parents and their 0- to 6-year-old children-103 from day care centers and 144 from pediatric practices. MAIN OUTCOME MEASURES: Licensed psychological examiners administered a screening test of parents' concerns about children's development and one or two direct screening tests: the Denver-II and/or the Battelle Developmental Inventory Screening Test. For the day care sample, examiners also administered to each child measures of intelligence, adaptive behavior, and language. In the pediatric sample, children were administered additional assessments. At the same time, diagnostic measures were administered to a randomly selected subsample to make determinations about developmental status. Each screening method was evaluated for its short-term costs (administration, interpretation, diagnosis, and treatment) and long-term benefits (impact of early intervention on adult functioning as inferred from longitudinal studies by other researchers). RESULTS: When the long-term costs and benefits were considered, none of the approaches emerged as markedly superior to another. When viewing the short-term costs, the various screening approaches differed markedly. The use of parents' concerns was by far the least costly for physicians to administer and interpret. CONCLUSION: Physicians can incur tremendous expenses when attempting to detect children with developmental problems. Although the benefits of early detection and intervention are substantial, physicians are not well-compensated for providing a critical service to society. Health policymakers and third-party payers must reconsider their minimal investment in early detection by health care providers. Nevertheless, our findings have encouraging implications for practice, because the use of parents' concerns as a screening technique offers substantial savings over and above other methods.     

Contribution of genetic and nutritional factors to DNA damage in heavy smokers

Prior epidemiological evidence suggests that genes controlling the metabolism of carcinogens and antioxidant/nutritional status are associated with lung cancer risk, possibly through their ability to modulate DNA damage by carcinogens. We performed a cross-sectional analysis of 159 heavy smokers from a cohort of subjects enrolled in a smoking cessation program. A total of 159 blood samples were analyzed to determine the relative contributions of genetic polymorphisms [CYP1A1 MspI and exon 7 and glutathione S-transferase M1 (GSTM1)] and plasma micronutrients to polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adduct levels. DNA damage in smokers was affected by genetic polymorphisms and nutritional status. Smokers with the CYP1A1 exon 7 valine polymorphism had significantly higher (2-fold, P < or = 0.03) levels of DNA damage than those without. In parallel models, PAH-DNA adducts were inversely associated with plasma levels of retinol (beta = -0.93, P = 0.01), beta-carotene (beta = -0.18, P = 0.09), and alpha- tocopherol (beta = -0.28, P = 0.21) in 159 subjects. The association between smoking-adjusted plasma beta-carotene levels and DNA damage was only significant in those subjects lacking the GSTM1 detoxification gene (beta = -0.30, P = 0.05, n = 75). There was a statistical interaction between beta-carotene and alpha-tocopherol; when beta- carotene was low, alpha-tocopherol had a significant protective effect (beta = -0.78, P = 0.04) on adducts, but not when beta-carotene was high (beta = -0.16, P = 0.57). Plasma alpha-tocopherol was significantly correlated with beta-carotene (r = 0.36, P = 0.0005) and less strongly with retinol (r = 0.20, P = 0.0005). These results suggest that several micronutrients may act in concert to protect against DNA damage and highlight the importance of assessing overall antioxidant status. In conclusion, a subset of smokers may be at increased risk of DNA damage and possibly lung cancer due to the combined effect of low plasma micronutrients and genetic susceptibility factors. The use of biological markers to assess efficacy of interventions and to study mechanisms of micronutrients is timely given the current debate regarding the use of chemopreventive agents in high risk populations.      

Unexpected Formation of Atactic Blocks in Propylene/1‐Pentene Copolymers from rac‐Me2Si(2‐MeBenz[e]Ind)2ZrCl2

Summary: Supplementary experimental findings are reported in addition to those presented in a previous paper dealing with the microstructure of propylene/1‐pentene copolymers prepared with rac‐Me₂Si(2‐MeBenz[e]Ind)₂ZrCl₂. The fractionation results which demonstrate that the atactic part of the copolymer can not be separated from the isotactic one confute the hypothesis suggested by other authors according to which the catalyst used could contain a percent of impurities of the meso (aspecific) form. This evidence is in agreement with the observed narrow polydispersities and the almost random distribution of the comonomers (r_P · r_Cm ≈ 1) which are typical of single site catalysts.

¹³C NMR methyl region of pentane‐soluble (a) and pentane‐insoluble (b) fractions of copolymer prepared with MBI .     

Mice Lacking PKCγ Exhibit Decreased Anxiety

To investigate the contribution of the PKC isoform of protein kinase C (PKC) in neurochemical pathways regulating anxiety, mice lacking the gene encoding PKC were tested with heterozygote and wild-type littermates in three approach-avoidance tests of anxiety. Null mutant mice consistently displayed a decrease in baseline anxiety-related behaviors in the elevated plus-maze, the black/white box, and the mirrored chamber. In the elevated plus-maze, mutant mice entered the open arms significantly more often and spent more time in the open arms of the maze. In the black/white box, transitions between the compartments were greatest in the null mutant mice, and in the mirrored chamber, mutant mice were markedly less anxious with significantly decreased latencies to enter and more time spent in the chamber. Indices of locomotor activity in the mazes and tests of activity in home cages indicated that the reduced anxiety observed in the mutant mice was not due to baseline locomotor activity differences among the genotypes. These results suggest that PKC be considered as one factor in the etiology of anxiety, perhaps via its post-synaptic regulation of GABA_A and 5-HT₂ receptors, two receptors implicated in the neurobiology of anxiety.