Limitations in the use of gamma-glutamyl transferase estimations in alcohol-dependent subjects.

This paper studies a cohort of randomly selected attenders at a district alcohol treatment service and examines the relationship between clinical assessments and laboratory markers currently in use in the unit. It measures in particular the rate of change of serial gamma-glutamyl transferase (GGT) during abstinence throughout an alcohol treatment programme in alcohol-dependent subjects. The results show that GGT is less often elevated in alcohol-dependent patients than was previously thought. Its predictive value changes little with respect to the age of the subject and length of drinking history. Measurement of GGT adds little to the diagnostic sensitivity of careful history taking. In the alcohol-dependent population, GGT estimation is of little value and a normal GGT does not exclude chronic alcohol dependence.

PRO_SELECT: combining structure-based drug design and combinatorial chemistry for rapid lead discovery. 1. Technology.

This paper describes a novel methodology, PRO_SELECT, which combines elements of structure-based drug design and combinatorial chemistry to create a new paradigm for accelerated lead discovery. Starting with a synthetically accessible template positioned in the active site of the target of interest, PRO_SELECT employs database searching to generate lists of potential substituents for each substituent position on the template. These substituents are selected on the basis of their being able to couple to the template using known synthetic routes and their possession of the correct functionality to interact with specified residues in the active site. The lists of potential substituents are then screened computationally against the active site using rapid algorithms. An empirical scoring function, correlated to binding free energy, is used to rank the substituents at each position. The highest scoring substituents at each position can then be examined using a variety of techniques and a final selection is made. Combinatorial enumeration of the final lists generates a library of synthetically accessible molecules, which may then be prioritized for synthesis and assay. The results obtained using PRO_SELECT to design thrombin inhibitors are briefly discussed.

Active-site-directed 3D database searching: pharmacophore extraction and validation of hits.

Two new computational tools, PRO_PHARMEX and PRO_SCOPE, for use in active-site-directed searching of 3D databases are described. PRO_PHARMEX is a flexible, graphics-based program facilitating the extraction of pharmacophores from the active site of a target macromolecule. These pharmacophores can then be used to search a variety of databases for novel lead compounds. Such searches can often generate many 'hits' of varying quality. To aid the user in setting priorities for purchase, synthesis or testing, PRO_SCOPE can be used to dock molecules rapidly back into the active site and to assign them a score using an empirical scoring function correlated to the free energy of binding. To illustrate how these tools can add value to existing 3D database software, their use in the design of novel thrombin inhibitors is described.

A psychiatric study of idiopathic oedema.

Twenty-five women with idiopathic oedema and twenty-five women attending gynaecology clinics were assessed by means of a standardised psychiatric interview, an interview on dietary habits, and a specially designed interview on current health. The patients with idiopathic oedema were significantly more depressed and anxious, with a trend towards widespread neurotic symptoms. There was no evidence that diuretic or laxative abuse is an important aetiological factor. In many patients with idiopathic oedema excessive fluid retention may be related to the neuroendocrine abnormalities associated with psychiatric illness.

Chemical burns: retrospective review.

The records of 51 patients with chemical burns were reviewed to identify demographics, mechanism and place of injury, cause, distribution, initial management, and outcome of treatment. Patients were classified as having received adequate (immediate dilution or neutralization of the chemical treatment--group A, or inadequate (delayed or inappropriate) treatment--group B. Inpatient mortality for chemical burns was 13% compared to 15% overall burn center mortality. Of the burns, 79% occurred in the 21-50 age group; 69% of burns were work-related in men and 17% in women. In group A, 19% required skin grafting (mortality 9.5%); in group B, 36% required grafting (mortality 21%). Alkali were the most frequent cause of burns, followed by sulfuric acid and, less often, gasoline, anhydrous ammonia, white phosphorus, and hydrofluoric acid.