Uncertainty in Fitted Estimates of Apparent in Vivo Metabolic Constants for Chloroform

It has become common practice to rely on fitted estimates ofapparent in vivo metabolic constants (e.g., V_max and K_M) inparameterization of PBPK models. Yet, quantitative estimatesof precision in these fitted parameters are not routinely reported.Such information is needed to assess the reliability of modelpredictions. The purpose of this study was to assess the precisionin estimates of V_max and K_M for chloroform, accounting for boththe statistical uncertainties in parameter estimates from individualdata sets and any additional uncertainty due to differencesin the parameter estimates derived from various experiments.Joint confidence regions for V_max and K_M from each experiment,generated using maximum likelihood techniques, were used toevaluate these questions. Three previously published data setswere considered. Estimates of V_max and K_M obtained from thesedata sets differed more than could be explained as a consequenceof a limited number of observations, measurement error, or stochasticerror. Issues associated with the use of maximum likelihoodtechniques to estimate joint confidence regions, the estimationof metabolic constants from individual experiments within agas uptake study versus the full data set, the degree of overlapin the joint confidence regions for metabolic constants obtainedfrom separate data sets, and the implications for risk assessmentare discussed.     

Online Medical Database Searching

A wide range of databases and databanks are presently availableto medical researchers. This paper outlines the scope of thedatabases available through a commercial host system and describesthe procedures required for their access and use. A discussionof some of the limitations and likely future developments ispresented in the context of our experience of their use. Requests for reprints should be addressed to: Dr N. Wood, Department of Epidemiology and Community Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK     

Collagenous colitis: Clinical and histological spectrum in ten patients

Collagenous colitis is characterized by the presence of a thick subepithelial collagen band in the colonic mucosa. The condition was diagnosed on rectal biopsy in 10 patients (one male, nine females) who presented with watery diarrhoea. Although rectal mucosal erythema was present in three and ulceration in two, the mucosa was of normal endoscopic appearance in five of the patients. There was marked variability in the thickness of the submucosal collagen band, both between and within individuals. Empirical drug therapy included sulphasalazine, glucocorticoids and antidiarrhoeals. All patients reported symptomatic improvement.     

Preservation of All Chordae Tendineae and Papillary Muscle During Mitral Valve Replacement with a Tilting Disc Valve

Mitral valve replacement was performed in 21 patients using a surgical technique that preserves the entire papillary muscle and chordal apparatus. With this technique, the anterior mitral leaflet is split from the center of the free edge toward the annulus. Bilateral incisions are made from the proximal end of this split to the two mitral commissures, detaching the anterior leaflet from the annulus. These two halves of the leaflet, with all chordae intact (corresponding to the anterolateral and posteromedial papillary muscles), are judiciously trimmed to remove areas of leaflet untethered by chordae tendineae and (when necessary) fibrous thickening; then swung posteriorly and sutured to the posterior mitral annulus using mattress sutures with pledgets. This surgical technique is expected to favor the preservation of left ventricular function and avoid occurrence of irreversible left ventricular dilation/dysfunction, and has been used successfully for calcific and degenerative etiologies, using both tilting disc valves and porcine bioprostheses. It is especially useful in the implantation of tilting disc and bileaflet mechanical prostheses because anterior subvalvular chordae tissue may interfere with the disc excursion and relocated to the posterior leaflet annulus.     

Do Electrode and Lead Design Differences for Permanent Cardiac Pacing Translate into Clinically Demonstrable Differences? (Comparison of Sintered Platinum and Activated Vitreous and Porous Carbon Electrodes)

A randomized prospective study was undertaken to compare the electrical performances of three permanent, endocardial, tined pacing leads with different electrode designs--sintered platinum, vitreous carbon, and porous carbon. Ninety-nine patients received one of the leads (S80 31; 423S 32; S100 36). Acute R wave amplitude and ST elevation of the native endocardial electrogram, voltage threshold, impedance, and current flow at four pulse durations (0.25-1.0 msec) were measured. Voltage thresholds were measured noninvasively at each of four pulse durations at 2 days and 1, 3, and 6 months after implantation. No significant differences were found in sensing properties, or current flow at threshold at 0.5 msec pulse duration. The 423S lead had a significantly higher impedance at threshold and both a higher impedance and lower current flow at 5 V. No significant differences in threshold voltages were found between the three leads at any pulse duration, at any of the assessed times after implantation. Six-month thresholds for the S80, 423S, and S100 leads were 1.18 +/- 0.35, 1.17 +/- 0.29, and 1.06 +/- 0.38 V respectively at 0.5 msec pulse duration. Differences between 'high performance' pacing leads need to be of a greater order of magnitude before they can be exploited to give any real clinical advantage to patients.     

Symposium on glial interfaces in the nervous system: development and repair

This Anatomical Society symposium, held at University College, Cork in September 1995 was the first of its kind. The objective was to stimulate and facilitate constructive interaction between experts on topics relating to the various types of glial barrier which form partitions within the nervous system. Some of these barriers are transient and are found only during development, for example, those which define the limits of developing nuclei or fibre bundles. Others are permanent, such as those at the transitional zones which separate the CNS and PNS milieux at nerve root attachments to the neuraxis. Still others, such as glial scars, are seen only following injury when they tend to inhibit neurite regeneration. In experimental circumstances, for example following irradiation or chemical damage, glial barriers may be broken down and even relocated. This may be associated with Schwann cell invasion of the CNS and, experimentally, with Schwann cell and glial cell transplantation into demyelinated areas. Such transplantation studies are in turn related to remyelination and CNS axon regeneration and the factors which facilitate these. Twelve review lectures were given on these topics. Five articles based on these communications are reproduced here. The underlying theme was the relationship between advances in the understanding of fundamental nervous tissue biology, especially as related to glial cells, and potential developments aimed at treating CNS demyelinating diseases and achieving CNS regeneration.     

Establishment of a liaison service for pregnant opiate-dependent women

A pregnancy liaison and outreach service was developed as part of a community drug team to attract pregnant drug-dependent women into treatment. Women were provided with information on harm reduction, safer drug use and offered treatment for drug dependence. In total, 43 women (45 pregnancies) presented to the service over a 30-month period. Thirty-four women began out-patient treatment of opiate dependence. There was a significant reduction in maternal methadone dose by delivery. Of the 45 pregnancies, four women had therapeutic abortions, two first trimester and two second trimester spontaneous abortions and 34 live births (three women remained untraceable). All the pregnancies that continued to the third trimester proceeded uneventfully with a consequent live birth. Mean gestational age was 37.9 ±3.7 weeks, mean birth weight was 2863 ± 526 g, 10 of the babies were small for gestational age. Fifteen babies required medication for neonatal withdrawal symptoms; mothers whose babies exhibited withdrawal symptoms were using significantly higher doses of methadone at delivery than mothers whose babies did not withdraw. The importance of providing this type of service for women drug users in the 1990s is discussed.