Organophosphorus compounds (OPs) interfere with the catalytic mechanism of acetylcholinesterase (AChE) by rapidly phosphorylating the catalytic serine residue. The inhibited enzyme can at least partly be reactivated with nucleophilic reactivators such as oximes. The covalently attached OP conjugate may undergo further intramolecular dealkylation or deamidation reactions, a process termed "aging" that results in an enzyme considered completely resistant to reactivation. Of particular interest is the inhibition and aging reaction of the OP compound tabun since tabun conjugates display an extraordinary resistance toward most reactivators of today. To investigate the structural basis for this resistance, we determined the crystal structures of Mus musculus AChE (mAChE) inhibited by tabun prior to and after the aging reaction. The nonaged tabun conjugate induces a structural change of the side chain of His447 that uncouples the catalytic triad and positions the imidazole ring of His447 in a conformation where it may form a hydrogen bond to a water molecule. Moreover, an unexpected displacement of the side chain of Phe338 narrows the active site gorge. In the crystal structure of the aged tabun conjugate, the side chains of His447 and Phe338 are reversed to the conformation found in the apo structure of mAChE. A hydrogen bond between the imidazole ring of His447 and the ethoxy oxygen of the aged tabun conjugate stabilizes the side chain of His447. The displacement of the side chain of Phe338 into the active site gorge of the nonaged tabun conjugate may interfere with the accessibility of reactivators and thereby contribute to the high resistance of tabun conjugates toward reactivation.

A world-wide comparative study of the frequency and characteristics of latent carcinoma of the prostate was undertaken in seven areas, using standardized methods and "blind" microscopic evaluation in order to reduce selection and observer bias. The morphological features of 350 latent carcinomas found in 1,327 prostates were examined. Two Chinese populations, from Hong Kong and Singapore, showed a low frequency of latent carcinoma in comparison with western Europeans in Sweden and the Federal Republic of Germany and negroes from Jamaica; an intermediate position was found for Israelis and black Ugandans. The frequency of small latent carcinomas was about 12% in all the areas investigated and did not vary with age. Rates for larger latent carcinomas increased sharply with age ans showed an area-to-area variation resembling that of clinical carcinoma of prostate. The small carcinomas were almost exclusively situated in the outer half of the prostate and latent carcinomas of all sizes were evenly distributed between the anterior and posterior halves of the prostate and the right and left sides of the outer prostatic shell. Certain disagreements in diagnosis were noted when the sections from each area were evaluated independently by a different pathologist. Most of these disagreements were resolved by re-reading the sections; their occurrence had no significant effect on the geographical comparisons.

Objective To describe the outcome, assessed as the level of prostate specific antigen (PSA), of a mature (more than half the events recorded) prospective randomized study with a median follow-up of 82 months of neoadjuvant hormonal therapy before radical prostatectomy, as this has been suggested to decrease the rate of positive surgical margins (i.e. provide greater potential to completely excise the tumour). Patient and methods From December 1991 to March1994, 126 patients with clinically localized prostate cancer were randomized between direct radical prostatectomy or a 3-month course of a gonadotrophinreleasing hormone analogue before surgery. The patients were followed by PSA determinations and a value of > 0.5 ng/mL used to define progression. ResultsThe incidence of positive surgical margins decreased from 45.5% to 23.6% ( P = 0.016) with hormone treatment. Despite this there was no difference in PSA progression-free survival at the last follow-up; it was 51.5% for those undergoing radical prostatectomy only and 49.8% for those who received hormonal pretreatment ( P = 0.588). Conclusions Three months of neoadjuvant hormonal therapy before radical prostatectomy offers no benefit to the patient and cannot be recommended for routine clinical use.

The bacterial pathogen Yersinia pestis expresses a potential adhesin, the pH6 antigen (pH6-Ag), which appears as fimbria-like structures after exposure of the bacteria to low pH. pH6-Ag was previously shown to agglutinate erythrocytes and to bind to certain galactocerebrosides. We demonstrate that purified pH6-Ag selectively binds to apolipoprotein B (apoB)-containing lipoproteins in human plasma, mainly LDL.

Chemotactic motility has previously been shown to be essential for the virulence of Vibrio anguillarum in waterborne infections of fish. To investigate the mechanisms by which chemotaxis may function during infection, mucus was isolated from the intestinal and skin epithelial surfaces of rainbow trout. Chemotaxis assays revealed that V. anguillarum swims towards both types of mucus, with a higher chemotactic response being observed for intestinal mucus. Work was performed to examine the basis, in terms of mucus composition, of this chemotactic response. Intestinal mucus was analyzed by using chromatographic and mass spectrometric techniques, and the compounds identified were tested in a chemotaxis assay to determine the attractants present. A number of mucus-associated components, in particular, amino acids and carbohydrates, acted as chemoattractants for V. anguillarum. Importantly, only upon combination of these attractants into a single mixture were levels of chemotactic activity similar to those of intestinal mucus generated. A comparative analysis of skin mucus revealed its free amino acid and carbohydrate content to be considerably lower than that of the more chemotactically active intestinal mucus. To study whether host specificity exists in relation to vibrio chemotaxis towards mucus, comparisons with a human Vibrio pathogen were made. AcheR mutant of a Vibrio cholerae El Tor strain was constructed, and it was found that V. cholerae andV. anguillarum exhibit a chemotactic response to mucus from several animal sources in addition to that from the human jejunum and fish epithelium, respectively.

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Although hormonal pretreatment significantly decreased the positive margin rate, it did not result in any difference in progression-free survival when followup exceeded 3 years. Thus, our current results do not support the routine administration of hormonal treatment before radical prostatectomy.