Adriamycin depresses in vivo and in vitro phosphatidylethanolamine N-methylation in rat heart sarcolemma

Adriamycin, an effective anticancer chemotherapeutic agent, causes an insidious and delayed cardiotoxicity. Different subcellular abnormalities including calcium transport changes in the sarcolemma (SL) as well as downregulation of the adrenergic system have been shown to be associated with the development of this cardiomyopathy. Since both of these activities are influenced by phospholipid methylation, effects of adriamycin on the three catalytic sites of SL phosphatidylethanolamine N-methyltransferase were examined. Rats were administered with a cumulative dose of adriamycin (15 mg/kg) over 2 weeks and examined after 3 weeks. Vehicle injected animals served as controls. Dyspnea, high mortality rate, ascites and decrease in aortic and left ventricular systolic pressure, as well as increase in left ventricular end diastolic pressure were seen in the adriamycin group. Myocardial cell damage typical of adriamycin cardiomyopathy, i.e. sarcotubular swelling, vacuolization and myofibrillar drop-out, was also apparent. Total methyl group incorporation into SL phosphatidylethanolamine using radiolabeled S-adenosyl-L-methionine as the donor was significantly depressed in the 3 week group at catalytic sites II and III. Decreased production of methylated intermediates, phosphatidyl-N-monomethylethanolamine and phosphatidyl-N,N-dimethylethanolamine as well as phosphatidylcholine (PC) was seen. Depression of phosphatidylethanolamine N-methylation was also noticed when SL, isolated from untreated hearts, was exposed in vitro to different concentrations (10, 100 and 1000 microM) of adriamycin. Inhibition of phosphatidylethanolamine N-methylation appears to be mediated by adriamycin-induced increase in the oxidative stress and may contribute in the pathogenesis of subcellular changes associated with this cardiomyopathy.     

Development of a numerical simulation model of the cardiovascular system

A numerical simulation model of the cardiovascular system has been developed. It consists of a model of the left atrium, the left ventricle, the coronary vascular system, the aorta, the arterial system, and the venous system. The input of the complete model is the elastance (pressure/volume ratio) developed by the left ventricle. The shape of this elastance is constant in different circumstances. Left ventricular (LV) myocardial oxygen consumption and the amount of oxygen offered to the left ventricle can be calculated with the model. The model has been validated using data from a patient suffering from coronary artery disease. The measured clinical hemodynamical waveforms could be fitted to those generated by the model. With the numerical simulation model, it is possible to predict the functioning of the left ventricle under different circumstances. This makes it possible to study in vitro various pathological clinical situations.     

Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery

This study assesses the reliability of a self-reported health questionnaire completed by 413 subjects aged 25-74 yr in the Erie County Periodontal Disease (ECPD) Study. Specific questions on general and oral health conditions were completed by each subject during a first visit and at a follow-up examination 2 yr later, and the two compared. Results showed that the overall measure of agreement between the two visits is substantial (average kappa, kappa = 0.80). Variation by gender and age were minimal. Questions regarding allergy to medications, oral treatment, reason for tooth extraction, health symptoms and history of systemic diseases exhibited high levels of agreement (kappa ranged from 0.71-0.90). Information on vitamin and mineral intake yielded kappa = 0.63. Oral conditions scored the lowest but were still acceptable (kappa = 0.57). These findings indicate that there were no significant discrepancies in self-reported responses to the health questionnaire used in the ECPD Study. Although the information provided by the subject may not be as accurate as compared to laboratory testing, it is nevertheless a reliable source of information which can be utilized cost-effectively in research studies.     

Cortical and hippocampal volume deficits in temporal lobe epilepsy

PURPOSE: To use quantitative magnetic resonance imaging (MRI) methods to examine the extent of volume abnormalities in the hippocampus and in extrahippocampal brain regions in localization-related epilepsy of temporal lobe origin (TLE). METHODS: Hippocampal, temporal lobe, and extratemporal lobe volumes were examined with 3-mm spin-echo coronal MRI scans in patients with unilateral TLE who were candidates for temporal lobe resection. Measures were adjusted for normal variation due to intracranial volume and age based on 72 healthy male controls. Group differences between 14 male TLE [7 left TLE (LTLE), 7 right TLE (RTLE)] patients and a subset of 49 age range-matched controls were examined with analysis of variance (ANOVA). RESULTS: As compared with controls, patients with TLE had smaller temporal lobe and frontoparietal region gray matter volumes, bilaterally, smaller temporal lobe white matter volumes bilaterally, and larger ventricular volumes. In contrast to these bilateral tissue volume deficits, hippocampal volume deficits in TLE were ipsilateral to the epileptogenic temporal lobe. CONCLUSIONS: Extrahippocampal volume abnormalities were bilateral and occurred in both temporal and extra-temporal cortical regions in TLE, whereas hippocampal deficits were related to the side of the epileptogenic focus. These data suggest that brain abnormalities in TLE are not limited to the epileptogenic region.     

Reversal of multidrug resistance phenotype by surfactants: relationship to membrane lipid fluidity

Previous studies have suggested that multidrug resistance (MDR) reversal by polyoxyethylene surfactants involves alterations in plasma membrane lipid physical state of resistant cells as one of the possible mechanism(s). To date, however, a detailed and critical examination of the relationship between membrane lipid fluidity and MDR reversal by these surfactants has not been performed. In the present studies, therefore, a series of experiments were conducted to critically examine the role of membrane lipid physical state in MDR reversal by employing a unique class of clinically important nontoxic lipophilic surfactants and the KB-8-5-11 drug-resistant cell line. MDR reversal was assessed by rhodamine-123 uptake. The effect of surfactants on plasma membrane lipid fluidity of these cells was assessed utilizing a fluorescence polarization technique with fluorophores DPH, TMA. DPH, 2-AS, and 12-AS. Our studies demonstrated that: (i) in vitro addition of active MDR-reversing surfactants (Solutol HS-15, Tween 40, and Cremophor EL, 10 micrograms/ml each) decreased lipid fluidity of isolated crude plasma membranes of resistant cells; (ii) the inactive surfactants (octylglucoside, hecameg) failed to influence membrane lipid fluidity; (iii) cells grown in the presence of active surfactants also exhibited a decreased plasma membrane lipid fluidity as measured with intact cells utilizing the probe TMA.DPH; and (iv) active surfactants did not influence lifetimes of the excited state of the fluorophores. These findings demonstrate that decrease of the plasma membrane lipid fluidity of KB 8-5-11 resistant cells may be one of the important mechanism(s) of MDR reversal by polyoxyethylene surfactants.     

HIV disease progression in Australia in the time of combination antiretroviral therapies

OBJECTIVE: To examine the effect of recent developments in antiretroviral therapy on HIV disease progression and survival. DESIGN: Retrospective cohort study. PARTICIPANTS AND SETTING: Two cohorts of people with HIV were defined retrospectively from the records of a large immunology laboratory. The first cohort were subjects whose CD4+ T cell counts had dropped to 200 x 10(6)/L during 1990, and the second were subjects whose CD4+ T cell counts had dropped to 200 x 10(6)/L in 1994. MAIN OUTCOME MEASURES: HIV disease progression and survival was determined over a minimum three years of follow-up for each cohort (i.e., 1990-1993; 1994-1997). RESULTS: 346 subjects were included in the analysis (193 subjects from 1990 and 153 from 1994). The relative risk of progression to AIDS in the 1994 cohort compared with the 1990 cohort was 0.57 (95% confidence interval, 0.35-0.91; P = 0.018) and the relative risk of death was 0.20 (95% confidence interval, 0.08-0.49; P < 0.001). CONCLUSIONS: There were 43% fewer AIDS cases and 80% fewer deaths in the time following the increased availability of combination antiretroviral therapy in Australia.     

Cyclic HIV protease inhibitors: design and synthesis of orally bioavailable, pyrazole P2/P2' cyclic ureas with improved potency

Highly potent HIV-1 protease (HIVPR) inhibitors have been designed and synthesized by introducing bidentate hydrogen-bonding oxime and pyrazole groups at the meta-position of the phenyl ring on the P2/P2' substituents of cyclic ureas. Nonsymmetrical cyclic ureas incorporating 3(1H)-pyrazolylbenzyl as P2 and hydrophilic functionalities as P2' show potent protease inhibition and antiviral activities against HIV and have good oral bioavailabilities. The X-ray structure of HIVPR.10A complex confirms that the two pyrazole rings of 10A form bidentate hydrogen bonds with the side-chain oxygen (C=O) and backbone nitrogen (N-H) of Asp30/30' of HIVPR.     

Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction

Adherence with inhaled beta-agonists and corticosteroids in 24 asthmatic children was tracked over 3 months utilizing the metered-dose inhaler chronolog (MDIC). Patients seldom took all of their medications as prescribed, and failed to take any inhaled corticosteroid doses on a median of 41.8% of days or inhaled beta-agonists on 28.1% of days despite prescribed daily use. Medication nonadherence was correlated with lower levels of asthma knowledge (Asthma Knowledge Questionnaire) and family dysfunction (Family Assessment Device), but not child behavior disorder (Child Behavior Checklist). Patients tended to dramatically over-report medication use. Improved identification of the markers of nonadherence can directly facilitate more efficient targeting of behavioral interventions, resulting in improved adherence, better illness control, and less requirement of urgent medication intervention.     

Effect of cytokines on anticryptococcal activity of human microglial cells

Since blood is a biologic product, it is unlikely that the risk for transfusion-transmitted infection will ever be reduced to zero. The approach to emerging infections associated with transfusion of blood and blood products includes assessing the transmissibility of the agent by this route; developing effective prevention strategies, including screening tests and donor deferral policies; improving viral and bacterial inactivation procedures; and surveillance for known, as well as emerging and poorly characterized, transfusion-transmitted agents. Vigilance is needed to help ensure proper balance between safety and the availability of blood. Finally, vigilance needs to extend to the developing world, where the basic elements to reduce transfusion-transmitted infections and systems of disease surveillance are often not available.