We monitored, by the Holter method, 23 clinically stable maintenance hemodialysis patients for 5 +/- (SEM) 2 hours before hemodialysis, 5.0 +/- 0.5 hours during hemodialysis, and 13 +/- 3 hours after hemodialysis. Of 23 patients, 9 (39%) had unexpected frequent or complex ventricular arrhythmias recorded and after hemodialysis with a potassium dialysate bath concentration of 2.0 mEq/liter. Patients with ventricular arrhythmias were more likely to be using digoxin (8/9 vs. 1/4) and to have evidence of left ventricular hypertrophy (9/9 vs. 7/4 than were those patients without arrhythmias. Of these 9 patients with arrhythmias, 6 underwent repeat Holter monitoring during multiple dialysate protocols. Of the 6 patients, 4 had a significant reduction in the frequency of ventricular ectopy when a dialysate of 3.5 mEq/liter potassium was used (P < 0.05), but of these 6, 3 still had complex arrhythmias. The use, however, of a 3.5 mEq/liter potassium dialysate plus the administration of a 400-mg dose of quinidine sulfate orally 45 min prior to hemodialysis was successful in reducing ventricular ectopic frequency and complexity in all the patients studied. Conclusion. Maintenance hemodialysis patient using digoxin and with left ventricular hypertrophy have an unexpectdly high indicence of occult, potentoial serious, ventricular arrhythmias during and after hemodialysis, revealed by Holter monitoring. There is preliminary evidence that a low-potassium bath concentration may play a role in predisoposing patients to these arrhythmias. Further prospective studies with largaer number of patients will be needed, however, to evaluate the significance of these findings.
Recent technological innovations have facilitated widespread illegal downloading of recorded music. While this points towards a decreased willingness to pay for music, the increase in the popularity of live music suggests otherwise. This is especially so when taking into account the rising cost of concert tickets, likely the result of reduced recorded music revenues. In the present study, a consideration of the unique motivations of why music fans decide on whether or not to attend live concerts is of interest. Drawing from a sample of 249 participants (55.02% female) with a mean age of 26.49, an open-ended questionnaire was analysed thematically with four key themes defined: Experience, Engagement, Novelty and Practical. The results highlight that participants want to "be there", to be a part of something unique and special, sharing the experience with likeminded others. Other social dimensions such as the use of live music events as a means to demonstrate fan worship were also found. The unknown, novel aspects of live music were key motivators, such as hearing new material and watching support bands. Notably, price was not a contributing factor when choosing to attend a concert, suggesting that live music offers fans something special that they are more than willing to pay for.
Cyclosporin A is a cyclic peptide believed to exist as multiple conformers in aqueous solution. Two major conformations, distinguished by a single cis-trans isomerization and the presence of four either intramolecular or intermolecular hydrogen bonds, have been confirmed depending on whether CsA is characterized in organic solvents or bound in aqueous complex with cyclophilin. The relationship between CsA conformation and its ability to penetrate biological membranes is currently unknown. Using Caco-2 cell monolayers, we documented a remarkable increase (more than 2 orders of magnitude) in the membrane permeation of the peptide as temperature was increased from 5 to 37 degrees C. The solubility of CsA was 72 microM at 5 degrees C, but decreased by more than an order of magnitude at 37 degrees C. Moreover, CsA partitioned into non-hydrogen bond donating solvents linearly as a function of increasing temperature, suggestive of a significant conformational change. However, while NMR spectra of CsA confirmed the previously predicted presence of multiple conformers in aqueous solution, the equilibrium between the two major species was not affected by changes in temperature. These NMR data indicated that the observed temperature-dependent changes in the membrane permeability of CsA do not originate from changes in the peptide backbone conformation. Sedimentation equilibrium analysis revealed that CsA behaves in a highly nonideal manner over the temperature range tested. We interpret this behavior as a change in the hydration state with a smaller (or weaker) hydration shell surrounding the peptide at higher temperatures. Such a change would result in lower peptide desolvation energy, thereby promoting partitioning into cellular membranes. We contend that changes in membrane penetration result from alterations in the hydration state of CsA and are not related to the interconversion of the defined conformations.
Summary:Purpose: To determine whether repeat boluses of diazepam (DZP) lead to significant accumulation in the central nervous system and/or peripheral compartments, as repeat intravenous boluses of diazepam are commonly used in the treatment of status epilepticus (SE).Methods: In a rat model that permits simultaneous serum and cerebrospinal fluid (CSF) sampling, we characterized the pharmacokinetics of DZP and its metabolite, desmethyldiazepam, in CSF and blood using HPLC. DZP was administered by intraperitoneal injection as either a single dose (20 or 30 mg/ kg) or repeat doses (10 or 20 mgkg x 3, 1 h apart).Results: After a single intraperitoneal dose, DZP was rapidly absorbed with a time to maximum concentration of 10 min. The serum concentrations then declined biexponentially. DZP rapidly entered the CSF; the CSF to serum ratio reached equilibrium within 10 min, and was equivalent to the ratio of free to total serum concentration. Repeated DZP dosing resulted in a threefold decrease in volume of distribution and clearance (p < 0.001). This was reflected in the CSF concentration data; however, after the third dose, the ratio of CSF to serum concentration, also increased greatly, representing further persistence of DZP in the CSF compartment.Conclusions: Repeat dosing of DZP leads to substantial accumulation, and high, persistent serum and CSF concentrations, which may explain the toxic effects of repeat DZP dosing. Repeat dosing of DZP using a tapering protocol, however, may increase the effectiveness of DZP in treating SE by preventing relapses without substantially increasing toxicity.
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