Electrophysiological basis of arrhythmogenicity of QT/T alternans in the long-QT syndrome: tridimensional analysis of the kinetics of cardiac repolarization

Tachycardia-dependent QT/T alternans occurs in patients with the congenital or idiopathic form of long-QT syndrome (LQTS) and may presage the onset of polymorphic ventricular tachyarrhythmias. To examine the electrophysiological basis of arrhythmogenicity of QT/T alternans in LQTS, the tridimensional repolarization pattern of QT/T alternans was studied in the anthopleurin-A model of LQTS, a surrogate for LQT3. In 11 anesthetized mongrel puppies, tridimensional repolarization and activation patterns were analyzed from 256 to 384 unipolar electrograms. Cardiac repolarization was evaluated as the activation-recovery interval (ARI) of local electrograms. To induce QT/T alternans, the pacing cycle length (CL) was abruptly shortened in steps of 50 ms from a basic drive of 1000 ms. ARIs were calculated at epicardial (Epi), midmyocardial (Mid), and endocardial (End) sites. ARI restitution at each site was assessed by using a single premature stimulation delivered after the basic drive. ARI alternans occurred at longer CLs at Mid sites compared with End and Epi sites, and the magnitude of alternans at Mid sites was greater. Two factors contributed to the modulation of ARI during QT/T alternans: (1) differences in restitution kinetics at Mid sites, characterized by larger DeltaARI and a slower time constant (tau), and (2) differences in diastolic intervals resulting in different input to restitution at the same constant CL. These 2 factors could explain not only the onset of alternans at Mid sites at longer CLs but also the critical observation that ARI dispersion between Epi and Mid sites during alternans was greater than during the slower basic CL. Marked ARI alternans could be present in local electrograms without manifest alternation of the QT/T segment in the surface ECG. The latter was seen at critically short CLs associated with reversal of the gradient of ARI between Epi and Mid sites, with a consequent reversal of polarity of the intramyocardial QT wave in alternate cycles. The arrhythmogenicity of QT/T alternans was primarily due to the greater degree of spatial dispersion of repolarization during alternans than during slower rates not associated with alternans. This could result in functional conduction block and reentrant ventricular tachyarrhythmias during the fixed drive associated with alternans.     

Continuous measurements of cardiac output in the perioperative period

Management of critically ill patients is based on knowledge of fundamental physiological variables. Automatized and continuous measurement of these variables is preferable. A new system based upon the thermodilution method has been developed to measure cardiac output automatically and continuously. We evaluated the system in the potentially unstable perioperative period with possible great and rapid changes in cardiac output. Twenty patients, scheduled for open heart or abdominal aortic aneurysm surgery, were included into the study, which was approved by the local ethical committee. The patients were monitored for up to 30 hours. At random intervals five iced bolus thermodilution cardiac output (BCO) determinations were made and compared to the continuous measurements (CCO). Two hundred and thirty-one pairs of data were obtained. The cardiac outputs ranged from 2.5-14.9 l/min. The absolute bias was 0.31 l/min (95% limits of agreement -1.4 l/min to 2.0 l/min). The mean relative error was 4.7% with a standard deviation of the relative error of 15.4%. The linear regression was represented by: CCO = 11.352 x BCO - 0.36. The correlation coefficient R was 0.90 (p < 0.001). In conclusion, the CCO measurement technique is a promising clinical method. The method is straightforward, requires no calibration, is independent of vascular geometry and measures with its limitations volumetric flow. Finally automatic and continuous patient monitoring provides more information and has potential to reveal previously undetected haemodynamic events.     

The effect of interruptions on postcompletion and other procedural errors: An account based on the activation-based goal memory model.

A postcompletion error (PCE) is a specific kind of cognitive slip that involves omitting a final task step after the main goal of the task is accomplished. It is notoriously difficult to provoke (and hence study) slips under experimental conditions. In this paper, the authors present an experimental task paradigm that has been shown to be effective for studying PCEs in routine procedural tasks. Two studies were carried out to examine the effect of interruption position and task structure on the prevalence of PCEs. It was found that significantly more PCEs were obtained when an interruption occurred just before the PC step than when an interruption occurred at any other position in the task. The authors account for this effect in terms of Altmann and Trafton's activation-based goal memory model. The same interruption effect was obtained for some, but not all, other procedural errors; the authors discuss the nature of these errors and likely explanations for the differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The folding of centromeric DNA strands into intercalated structures: a physicochemical and computational study

We have carried out a physicochemical and computational analysis on the stability of the intercalated structures formed by cytosine-rich DNA strands. In the computational study, the electrostatic energy components have been calculated using a Poisson-Boltzmann model, and the non-polar energy components have been computed with a van der Waals function and/or a term dependent on the solvent-accessible surface area of the molecules. The results have been compared with those obtained for Watson-Crick duplexes and with thermodynamic data derived from UV experiments. We have found that intercalated DNA is mainly stabilized by very favorable electrostatic interactions between hydrogen-bonded protonated and neutral cytosines, and by non-polar forces including the hydrophobic effect and enhanced van der Waals contacts. Cytosine protonation electrostatically promotes the association of DNA strands into a tetrameric structure. The electrostatic interactions between stacked C.C+ pairs are strongly attenuated by the reaction field of the solvent, and are modulated by a complex interplay of geometric and protonation factors. The forces stabilizing intercalated DNA must offset an entropic penalty due to the uptake of protons for cytosine protonation, at neutral pH, and also the electrostatic contribution to the solvation free energy. The latter energy component is less favorable for protonated DNA due to the partial neutralization of the negative charge of the molecule, and probably affects other protonated DNA and RNA structures such as C+-containing triplexes.     

Determining the cost of a clinical intervention through the use of shadow pricing

This article reviews the scientific literature in several areas important to the delivery of palliative care: multicultural issues, education, comprehensive outcome measures and ethics. Most of the research can be classified as fundamental rather than intervention research according to the Cancer Control Framework of the National Cancer Institute of Canada. Desired outcomes of interventions are most often defined from the health care professional's perspective but need to be defined from the patient's perspective. In areas such as multicultural issues and the effect of the volunteer on the patient, there is almost no research. The complexity of studying the best way to deliver palliative care would benefit from the input of colleagues who have experience addressing these issues in other patient populations.     

An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer's disease

Oxidative stress may contribute to neuronal loss in Alzheimer's disease (AD). The present study compares the levels of oxidative damage to proteins, lipids, and DNA bases from seven different brain areas of AD and matched control tissues by using a range of techniques. No differences in levels of lipid peroxidation were found in any of the brain regions by using two different assay systems. Overall, there was a trend for protein carbonyl levels to be increased in AD in frontal, occipital, parietal, and temporal lobe, middle temporal gyrus, and hippocampus, but a significant difference was found only in the parietal lobe. Gas chromatography-mass spectrometry was used to measure products of damage to all four DNA bases. Increased levels of some (8-hydroxyadenine, 8-hydroxyguanine, thymine glycol, Fapy-guanine, 5-hydroxyuracil, and Fapy-adenine), but not all, oxidized DNA bases were observed in parietal, temporal, occipital, and frontal lobe, superior temporal gyrus, and hippocampus. The baseline level of oxidative DNA damage in the temporal lobe was higher than in other brain regions in both control and AD brain. The finding of increased oxidative damage to protein and DNA strengthens the possibility that oxidative damage may play a role in the pathogenesis of AD in at least some key brain regions.     

Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication

Cilostazol is an antiplatelet agent and vasodilator marketed in Japan for treatment of ischemic symptoms of peripheral vascular disease. It is currently being evaluated in the United States for treatment of symptomatic intermittent claudication (IC). Cilostazol has been shown to improve walking distance in patients with IC. In addition to its reported vasodilator and antiplatelet effects, cilostazol has been proposed to have beneficial effects on plasma lipoproteins. We examined the effect of cilostazol versus placebo on plasma lipoproteins in 189 patients with IC. After 12 weeks of therapy with 100 mg cilostazol BID, plasma triglycerides decreased 15% (P<0.001). Cilostazol also increased plasma high density lipoprotein cholesterol (HDL-C) (10%) and apolipoprotein (apo) A1 (5.7%) significantly (P<0.001 and P<0.01, respectively). Both HDL3 and HDL2 subfractions were increased by cilostazol; however, the greatest percentage increase was observed in HDL2. Individuals with baseline hypertriglyceridemia (>140 mg/dL) experienced the greatest changes in both HDL-C and triglycerides with cilostazol treatment. In that subset of patients, HDL-C was increased 12.2% and triglycerides were decreased 23%. With cilostazol, there was a trend (3%) toward decreased apoB as well as increased apoA1, resulting in a significant (9.8%, P<0.002) increase in the apoA1 to apoB ratio. Low density lipoprotein cholesterol and lipoprotein(a) concentrations were unaffected. Cilostazol treatment resulted in a 35% increase in treadmill walking time (P=0.0015) and a 9.03% increase in ankle-brachial index (P<0.001). These results indicate that in addition to improving the symptoms of IC, cilostazol also favorably modifies plasma lipoproteins in patients with peripheral arterial disease. The mechanism of this effect is currently unknown.     

Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer

BACKGROUND: In a recent randomized intervention trial, the risk of prostate cancer for men receiving a daily supplement of 200 microg selenium was one third of that for men receiving placebo. By use of a nested case-control design within a prospective study, i.e., the Health Professionals Follow-Up Study, we investigated the association between risk of prostate cancer and prediagnostic level of selenium in toenails, a measure of long-term selenium intake. METHODS: In 1986, 51,529 male health professionals aged 40-75 years responded to a mailed questionnaire to form the prospective study. In 1987, 33,737 cohort members provided toenail clippings. In 1988, 1990, 1992, and 1994, follow-up questionnaires were mailed. From 1989 through 1994, 181 new cases of advanced prostate cancer were reported. Case and control subjects were matched by age, smoking status, and month of toenail return. Selenium levels were determined by neutron activation. All P values are two-sided. RESULTS: The selenium level in toenails varied substantially among men, with quintile medians ranging from 0.66 to 1.14 microg/g for control subjects. When matched case-control data were analyzed, higher selenium levels were associated with a reduced risk of advanced prostate cancer (odds ratio [OR] for comparison of highest to lowest quintile = 0.49; 95% confidence interval [CI] = 0.25-0.96; P for trend = .11). After additionally controlling for family history of prostate cancer, body mass index, calcium intake, lycopene intake, saturated fat intake, vasectomy, and geographical region, the OR was 0.35 (95% CI = 0.16-0.78; P for trend = .03). CONCLUSIONS: Our results support earlier findings that higher selenium intakes may reduce the risk of prostate cancer. Further prospective studies and randomized trials of this relationship should be conducted.