A simple tool to evoke physicians' real training needs.

Commonly used methods for identifying the training needs of general practitioners do not enable the real needs felt during interviews with patients during office visits to be detected. In this study, the authors evaluate how physicians' use of a personal-office-visit diary affects the level of specificity of their expressed training needs. In 1999, the authors carried out a controlled intervention trial using a random sample of 1,038 general practitioners from a region of France, randomized to intervention and control groups. The practitioners in the intervention group were asked to identify their training needs using a personal-office-visit diary. The level of specificity for their expressed needs was compared with that of the expressed needs of the practitioners in the control group. The use of the diary was associated with a significantly higher level of specificity in the training needs identified by the general practitioners who participated. Independent of the intervention, practitioners under 40 years of age, those in urban practice, and those who were members of a continuing medical education (CME) association expressed their training needs with higher specificity. The personal-office-visit diary would seem to be a simple, inexpensive, and useful tool for more specifically identifying training needs, which could help establish more appropriate and better-targeted training programs. However, it should be assessed further by those involved in CME for general practitioners.     

3H]-flunitrazepam binding after morphine treatment and under abstinence syndrome.

Chronic morphine treatment produced increases in [3H]-flunitrazepam binding in some hippocampal areas of the rat brain. The differences in binding were statistically significant in some cases. Both morphine-dependent and morphine-deprived (abstinence syndrome) animals showed an identical response in binding, which confirms a real, although small, increase in benzodiazepine binding sites in the hippocampus after morphine treatment, that is not affected by a naloxone-induced abstinence syndrome under the conditions studied. These findings support the hypothesis of a morphine-induced up-regulation of benzodiazepine binding sites in the hippocampus. A possible different response in benzodiazepine binding sites 1 and 2 could explain the different findings reported in the literature. Our data suggest that the detected increase in benzodiazepine binding would be mainly due to type 2 binding sites, since the hippocampus has a higher density of this type of benzodiazepine binding sites.     

The plasminogen-activation system in ovarian tumors

We studied the plasminogen activation system in tumor tissue by measuring the antigen level of the 2 plasminogen activators, tissue-type (t-PA) and urokinase-type (U-PA) and their inhibitors, plasminogen-activator inhibitors type-1 (PAI-1) and type-2 (PAI-2) in the tissue extracts of 43 human benign and malignant ovarian tumors. U-PA levels were significantly higher in malignant than in benign tumors. In addition, U-PA antigen levels were higher in the metastatic tissue of advanced disease (FIGO stage III) than in the primary localized tumor (FIGO stage I/II). Also PAI-1 concentrations tended to be higher in malignant than in benign tumors, but this difference was not statistically significant. In contrast, t-PA levels were lower in metastatic than in non-metastatic tumors, whereas PAI-2 levels were unrelated to the stage of ovarian malignancy. These results were integrated in a plasminogen-activation-dependent malignancy index (U-PA × PAI-1/t-PA). This index distinguished the different groups of benign ovarian tumors, localized and metastatic ovarian carcinomas better than U-PA levels. It could be useful as a prognostic indicator in ovarian cancer © 1993 Wiley-Liss, Inc.     

B-B10 (anti-CD25)-saporin immunotoxin--a possible tool in graft-versus-host disease treatment.

An immunotoxin containing the B-B10 MoAb, directed against the CD25 determinant, and the ribosome-inactivating protein saporin, inhibits 3H-TdR incorporation in phytohemagglutin, allogeneic-stimulated lymphocytes (primary and secondary mixed-lymphocyte reaction), and in an alloreactive T cell clone. A lower degree of inhibition was obtained with the B-B10 MoAb, which is known to inhibit IL-2 activity, as well as with the unconjugated compounds. These results suggest that the in vivo administration of the conjugate might be a more effective tool in the treatment of patients affected by graft-versus-host disease than B-B10 alone, by inducing an efficient killing of allogeneic-reacting T lymphocytes.     

A comprehensive survey for polymorphisms in the bovine IFN-gamma gene reveals a highly polymorphic intronic DNA sequence allowing improved genotyping of Bovinae.

This study aimed to identify interferon-gamma (IFN-gamma) gene variants in cattle for diagnostic purposes. Therefore, the entire bovine IFN-gamma gene (BoIFNG) and 2605 bp of its promoter DNA were sequenced. The BoIFNG DNA sequence conforms to the published part of Bo-IFN-gamma cDNA. Primer extension experiments show the presence of a 5' extension of exon 1 by 42 nucleotides (nt). One SINE element (Bov-A2) is located in the 5'-region, and two SINE elements (Bov-tA, Bov-B) are contained in the 3'-region of BoIFNG. The variants were detected by comparative sequence analysis of PCR amplicons from different bovine species. Four polymorphic mononucleotide repeats are situated in the promoter and in intron 1. Four distinct series of single nucleotide polymorphisms (SNP) were found in functionally important regions of BoIFNG. The region between the two intron 1 microsatellites contains the highest density of SNPs in Bos taurus breeds. One G-T transversion in the coding region of exon 1 causes a Gly(14) to Val(14) exchange in the BoIFNG signal peptide of different bovine species. A G-A transition in exon 2 encodes a Ser(19) to Asn(19) change in the mature protein of the Tibetan yak. Genotyping of randomly sampled Holstein Friesian cows at selected SNPs and of both intron 1 microsatellites revealed two dominant BoIFNG microhaplotypes. The detected SNPs improve the recently reported genotyping system of cattle.     

New Potent Azomethine Prodrugs of the Histamine H3-Receptor Agonist (R)-α-Methylhistamine Containing a Heteroarylphenyl Partial Structure

The therapeutic value of histamine H₃-receptor ligands is under current investigation. On the basis of recently described diaryl imine prodrugs of the histamine H₃-receptor agonist (R)-α-methyl-histamine ( 1 ) a series of new azomethine prodrugs containing five- and six-membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vitro activity after oral application. It was found that electron-deficient six-membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five-membered heterocycles appeared to be highly effective for the CNS delivery of 1 , and a remarkable correlation between chemical structure and pharmacokinetic profile was observed. Particularly (R)-4-fluoro-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino](1H-pyrrol-2-yl)methyl]phenol ( 8c ), the 2-furanyl analogue 8d , and its 3-furanyl isomer 8e proved to be equipotent to the most potent of recently described halogenated diaryl imine prodrugs of 1. However, in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1 in the CNS and can thus be regarded as a ‘retard’ prodrug. Assuming that a therapeutic indication of histamine H₃-receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use.     

Direct syncytial assay for the quantitation of bovine leukemia virus.

A direct in vitro tissue culture method is described for the quantitation of bovine leukemia virus, utlizing a feline S+L-- cell line.