Characterization of receptors for calcitonin gene-related peptide and adrenomedullin on the guinea-pig vas deferens

1. The receptors which mediate the effects of calcitonin gene-related peptide (CGRP), amylin and adrenomedullin on the guinea-pig vas deferens have been investigated. 2. All three peptides cause concentration dependant inhibitions of the electrically stimulated twitch response (pD 2s for CGRP, amylin and adrenomedullin of 7.90 ± 0.11, 7.70 ± 0.19 and 7.25 ± 0.10 respectively). 3. CGRP 8-37 (1 μM) and AC187 (10 μM) showed little antagonist activity against adrenomedullin. 4. Adrenomedullin 22-52 by itself inhibited the electrically stimulated contractions of the vas deferens and also antagonized the responses to CGRP, amylin and adrenomedullin. 5. [ 125I]-adrenomedullin labelled a single population of binding sites in vas deferens membranes with a pIC 50 of 8.91 and a capacity of 643 fmol mg -1. Its selectivity profile was adrenomedullin > AC187 > CGRP = amylin. It was clearly distinct from a site labelled by [ 125I]-CGRP (pIC 50 = 8.73, capacity = 114 fmol mg -1, selectivity CGRP > amylin = AC187 > adrenomedullin). [ 125I]-amylin bound to two sites with a total capacity of 882 fmol mg -1. 6. Although CGRP has been shown to act at a CGRP 2 receptor on the vas deferens with low sensitivity to CGRP 8-37, this antagonist displaced [ 125I]-CGRP with high affinity from vas deferens membranes. This affinity was unaltered by increasing the temperature from 4°C to 25°C, suggesting the anomalous behaviour of CGRP 8-37 is not due to temperature differences between binding and functional assays.

On-line learning in neural networks

On-line learning is one of the most powerful and commonly used techniques for training large layered networks and has been used successfully in many real-world applications. Traditional analytical methods have been recently complemented by ones from statistical physics and Bayesian statistics. This powerful combination of analytical methods provides more insight and deeper understanding of existing algorithms and leads to novel and principled proposals for their improvement. This book presents a coherent picture of the state-of-the-art in the theoretical analysis of on-line learning. An introduction relates the subject to other developments in neural networks and explains the overall picture. Surveys by leading experts in the field combine new and established material and enable non-experts to learn more about the techniques and methods used. This book, the first in the area, provides a comprehensive view of the subject and will be welcomed by mathematicians, scientists and engineers, whether in industry or academia.

Prophylactic ranitidine treatment in critically ill children - a population pharmacokinetic study

Aims - To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Methods - Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. Results - A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (−12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h−1 for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h−1 and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Conclusions - Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

JenPep : a novel computational information resource for immunobiology and vaccinology

JenPep is a relational database containing a compendium of thermodynamic binding data for the interaction of peptides with a range of important immunological molecules:  the major histocompatibility complex, TAP transporter, and T cell receptor. The database also includes annotated lists of B cell and T cell epitopes. Version 2.0 of the database is implemented in a bespoke postgreSQL database system and is fully searchable online via a perl/HTML interface (URL:  http://www.jenner.ac.uk/JenPep).