The discovery of a potent Nav1.3 inhibitor with good oral pharmacokinetics.

In this article, we describe the discovery of an aryl ether series of potent and selective Nav1.3 inhibitors. Based on structural analogy to a similar series of compounds we have previously shown bind to the domain IV voltage sensor region of Nav channels, we propose this series binds in the same location. We describe the development of this series from a published starting point, highlighting key selectivity and potency data, and several studies designed to validate Nav1.3 as a target for pain.

The development of the EASE model.

The estimation and assessment of substance exposure (EASE) model has been under development and in use since the early 1990s. It is a general model that can be used to predict workplace exposure to any substance hazardous to health. The current EASE model (version 2.0) has been used widely in the risk assessment of new and existing chemicals by the UK Health and Safety Executive (HSE) and other regulatory agencies. EASE has also been distributed globally to over 200 users and therefore may have been used for many other purposes. Despite widespread use of the model, neither the development of its structure nor its underlying concepts and principles have been published in the open literature. Using surviving documentary evidence and discussions with key personnel, the creation and development of the model from 1992 to 2002 is described. The role of the HSE's National Exposure Database (NEDB) as the principal data source for the development of the model output exposure ranges is described. A number of problems and limitations of the model have been identified and the description of the model's development provides some explanation of their presence.

Evaluation and further development of EASE model 2.0.

EASE (Estimation and Assessment of Substance Exposure) is a general model that may be used to predict workplace exposure to a wide range of substances hazardous to health. First developed in the early 1990s, it is now in its second Windows version. This paper provides a critical assessment of the utility and performance of the EASE model, and on the basis of this review, recommendations for the structure of a revised model are outlined. Twenty-seven stakeholders were interviewed about their previous use of EASE, perceived advantages and limitations of the model and suggestions for improvement. A subset of stakeholders was contacted on a second occasion to determine their views on the preferred outputs for an ideal exposure assessment model. Overall, stakeholders felt that the model should be updated to provide more accurate and precise exposure assessments. However, users also expressed the view that the simplicity and usability of the software model should not be compromised. Six studies investigating the validity of the inhalation exposure assessment section of EASE were identified. These showed that the model generally either predicted close to the measured exposures or overestimated exposure; though performance was highly variable. Two studies investigated the validity of the dermal exposure assessment and found that EASE produced considerable overestimates of actual dermal exposure (the amount of a substance that actually lands on the skin). A conceptual model of exposure was developed to investigate whether the structure of the EASE model is appropriate. Although EASE has a number of characteristics that describe exposure, it is a greatly simplified model and does not include all the important exposure determinants. More importantly, EASE can produce estimates of exposure that are ambiguous or incomplete. Our conceptual model may provide a rational basis for developing an improved version of EASE but further consultation is needed to decide the purpose and intended use of any successor to EASE.

Sonographic examination of lateral epicondylitis.

OBJECTIVE: The purpose of this study was to describe the sonographic appearance of the common extensor origin in cadavers and asymptomatic volunteers, and to relate this appearance to the findings in patients with lateral epicondylitis. SUBJECTS AND METHODS: Seventy-two elbows in 71 patients with lateral epicondylitis were examined on sonography. Most of the patients (60/71) gave a history of repetitive microtrauma. The injuries were evaluated with respect to location and severity. Focal areas of degeneration, discrete cleavage tears, and involvement of the lateral collateral ligament were identified. Calcification and bony changes were noted. The appearance of the normal common extensor tendon was described, and cadaveric specimens were dissected. Twenty-one patients subsequently underwent surgery. RESULTS: The normal common extensor origin is composed of longitudinal fibrils bound closely with the extensor carpi radialis brevis constituting most of the deep fibers, with the extensor digitorum making up the superficial part. The lateral collateral ligament can be identified as a discrete and separate band. The most common appearance of lateral epicondylitis is a focal hypoechoic area in the deep part of the tendon (46/72). These focal areas were identified at surgery and corresponded histologically to collagen degeneration with fibroblastic proliferation. Often discrete cleavage planes traversing the tendon were manifest as partial (18/72) and complete (2/72) tears. The lateral collateral ligament was involved in eight of 72 elbows. CONCLUSION: Sonography of the common extensor origin can be used to confirm lateral epicondylitis in patients with lateral elbow pain and provide information about the severity of the disease.

Computed tomographic and ultrasound appearances of focal spared areas in fatty infiltration of the liver.

Computed tomography (CT) and ultrasound (US) appearances of diffuse and focal fatty infiltration of the liver (FIL) are well recognized. We have recently seen 10 cases with "fat spared" areas in FIL presenting as pseudo tumours of the liver. Characteristic appearances of fat free areas in FIL which help differentiate these areas from other focal liver lesions include (i) location in the medial segment of the left lobe of the liver, (ii) absence of mass effect on surrounding vessels and liver tissue, and (iii) presence of typical changes of FIL elsewhere in the liver on CT or US examination.

Improved gas chromatographic method for quantitation of deoxynivalenol in wheat, corn, and feed.

A gas chromatographic (GC) method is described to determine deoxynivalenol in wheat and corn at levels as low as 20 ppb. Ground samples are extracted with water, adsorbed onto a Clin Elut column, extracted with ethyl acetate, and passed through a silica gel Sep-Pak cartridge. The final extract is then derivatized with N-heptafluorobutyrylimidazole and quantitated by GC using an electron capture detector. Recoveries are greater than 85% for spiked samples at levels of 50-1000 ppb. Results for wheat, corn, and mixed feed samples are given as well as the results of an interlaboratory study on a naturally contaminated wheat sample.

Specific method for determining uric acid in serum using high-performance liquid chromatography and gas chromatography-mass spectropmetry.

A method using a combination of high-performance liquid chromatography and stable-isotope dilution-mass spectrometry is described for the specific quantitation of uric acid in serum. The procedure involves addition of a known amount of [1,3,9-15n]uric acid, as intenral standard, to the serum sample followed by equilibration with the endogenous analyte. After separation from serum proteins, cationic and neutral compounds by anion-exchange chromatography, the purified uric acid is converted into its tetraethyl derivatives. High-performance liquid chromatography is used to isolate the three major isomeric derivatives for measurement of the isotope ratio m/e 280 to m/e 283. This ratio gives the relative abundances of the molecular ions of natural and of labelled tetraethyluric acid, and from it the amount of uric acid in the original serum specimen is determined. Effective separation of tetraethyluric acid isomers can be achieved by adsorption or reversed-phase high-performance liquid chromatography using n-heptane-isopropanol (80:1, v/v) and methanol-water (3:2, v/v), respectively, as solvent systems.