Wegener's granulomatosis: Possible role of environmental agents in its pathogenesis. (41/212)

OBJECTIVE: To investigate the possibility that environmental agents contribute to the pathogenesis of Wegener's granulomatosis (WG). METHODS: We undertook an extensive search for possible environmental exposures by developing a comprehensive questionnaire that was administered by telephone interview to 53 patients with WG and 2 control groups: one with osteoarthritis and the other with gout. Questions focused on hobbies and vocations, work, home, and allergies. Exact logistic regression was used to calculate odds ratios and 95% confidence intervals after adjusting for potential confounders. After adjusting for age and sex, data are reported for all exposures with odds ratios >2.0 against either control group or for any allergic propensity. RESULTS: Results suggest that mercury and perhaps lead exposure were positively associated with WG as compared with either control group, although the number of patients exposed was small. A prior history of allergy was also associated with WG as compared with either control group. CONCLUSION: We conclude that heavy metal exposure and a prior history of allergy may play a role in the etiopathogenesis of Wegener's granulomatosis.  (+info)

New insights into the human 5-HT4 receptor binding site: exploration of a hydrophobic pocket. (42/212)

A body of evidences suggests that a hydrophobic pocket of the human 5-HT(4) receptor contributes to the high affinity of some bulky 5-HT(4) ligands. A thorough study of this pocket was performed using mutagenesis and molecular modeling. Ligand binding or competition studies with selected bulky ligands (RS39604, RS100235, [(3)H]GR113808 and ML11411) and small ligands (5-HT and ML10375) were carried out on wild-type and mutant receptors (W7.40A/F, Y7.43F, R3.28L) transiently transfected in COS-7 cells. The functional activity of the mutated receptors was evaluated by measuring the ability of 5-HT to stimulate adenylyl cyclase. For W7.40F mutation, no changes in the affinity of studied ligands and in the functional activity of the mutant receptor were observed, in contrary to W7.40A mutation, which abolished both binding of ligands and 5-HT-induced cAMP production. Mutation R3.28L revealed a totally silent receptor with a basal level of cAMP production similar to the mock control despite its ability to product cAMP in the presence of 5-HT. Moreover, a one order loss of affinity of RS39604 and a 45-fold increase of ML11411 affinity were observed. Mutation Y7.43F modified the affinity of GR113808, which displays a 13-fold lower affinity for the mutant than for the wild-type receptor. In conclusion, in the hydrophobic pocket, two polar amino acids are able to interact through hydrogen bonds with bulky ligands depending on their chemical properties. Moreover, these experimental data may validate the proposed new three-dimensional model of the human 5-HT(4) receptor.  (+info)

Effect of a trifluoromethyl ketone on the motility of proton pump-deleted mutant of Escherichia coli strain and its wild-type. (43/212)

We have recently found that 1-(2-benzoxazolyl)-3,3,3-trifluoro-2-propanone [TF18] exhibited the most potent antibacterial activity among 30 trifluoromethyl ketones against various prokaryotes, such as Escherichia coli (E. coli). In the present study, the inhibition of E. coli motility by TF18 was investigated. TF18 showed the lowest minimum inhibitory concentration (MIC) and highest inhibitory effect on the motility of E. coli strains. The wild-type E. coli was more sensitive to inhibition of motility than its proton pump-deleted mutant strain at subinhibitory concentrations. These data suggest that one of the targets of the antibacterial effect of the trifluoromethyl ketone is the proton pump system.  (+info)

The 5-hydroxytryptamine4 receptor exhibits frequency-dependent properties in synaptic plasticity and behavioural metaplasticity in the hippocampal CA1 region in vivo. (44/212)

Long-term plasticity, in the forms of long-term depression (LTD) and long-term potentiation (LTP), of synaptic transmission are thought to underlie memory. Biogenic amino acids modulate the expression of LTD and LTP. The serotonergic 5-hydroxytryptamine4 (5-HT4) receptor has been shown to influence learning and memory. However, little is known about the role of this receptor in synaptic plasticity. Here we show that although induction of LTP is unaffected by either pharmacological activation or inhibition of 5-HT4, application of the 5-HT4 receptor agonist, RS67333, completely blocks learning-induced depotentiation of LTP in the hippocampal CA1 region of freely moving rats, suggesting a role for 5-HT4 receptors in behavioural metaplasticity. In addition, the 5-HT4 antagonist RS39604 enhances the intermediate phase of LTD and converts short-term depression into persistent LTD (>24 h), suggesting a significant role for 5-HT4 receptors in the expression of LTD in CA1. Stimulation at 10 Hz causes transient synaptic depression. However, 5-HT4 antagonist application prior to 10 Hz stimulation leads to LTD, whereas agonist application leads to LTP expression. 5-HT4 receptors thus shift the frequency-response relationship for induction of plasticity. Together, these findings suggest a key role for 5-HT4 receptors in the regulation of synaptic plasticity and the determination of the particular properties of stored synaptic information.  (+info)

Involvement of a flavosemiquinone in the enzymatic oxidation of nitroalkanes catalyzed by 2-nitropropane dioxygenase. (45/212)

2-Nitropropane dioxygenase (EC 1.13.11.32) catalyzes the oxidation of nitroalkanes into their corresponding carbonyl compounds and nitrite. In this study, the ncd-2 gene encoding for the enzyme in Neurospora crassa was cloned, expressed in Escherichia coli, and the resulting enzyme was purified. Size exclusion chromatography, heat denaturation, and mass spectroscopic analyses showed that 2-nitropropane dioxygenase is a homodimer of 80 kDa, containing a mole of non-covalently bound FMN per mole of subunit, and is devoid of iron. With neutral nitroalkanes and anionic nitronates other than propyl-1- and propyl-2-nitronate, for which a non-enzymatic free radical reaction involving superoxide was established using superoxide dismutase, substrate oxidation occurs within the enzyme active site. The enzyme was more specific for nitronates than nitroalkanes, as suggested by the second order rate constant k(cat)/K(m) determined with 2-nitropropane and primary nitroalkanes with alkyl chain lengths between 2 and 6 carbons. The steady state kinetic mechanism with 2-nitropropane, nitroethane, nitrobutane, and nitrohexane, in either the neutral or anionic form, was determined to be sequential, consistent with oxygen reacting with a reduced form of enzyme before release of the carbonyl product. Enzyme-monitored turnover with ethyl nitronate as substrate indicated that the catalytically relevant reduced form of enzyme is an anionic flavin semiquinone, whose formation requires the substrate, but not molecular oxygen, as suggested by anaerobic substrate reduction with nitroethane or ethyl nitronate. Substrate deuterium kinetic isotope effects with 1,2-[(2)H(4)]nitroethane and 1,1,2-[(2)H(3) ethyl nitronate at pH 8 yielded normal and inverse effects on the k(cat)/K(m) value, respectively, and were negligible on the k(cat) value. The k(cat)/K(m) and k(cat) pH profiles with anionic nitronates showed the requirement of an acid, whereas those for neutral nitroalkanes were consistent with the involvement of both an acid and a base in catalysis. The kinetic data reported herein are consistent with an oxidasestyle catalytic mechanism for 2-nitropropane dioxygenase, in which the flavin-mediated oxidation of the anionic nitronates or neutral nitroalkanes and the subsequent oxidation of the enzyme-bound flavin occur in two independent steps.  (+info)

Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. III. Synthesis and antitumor activity of 3-phenylpiperazinyl-1-trans-propenes. (46/212)

A series of novel 3-[4-phenyl-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-pro penes and related compounds were synthesized and evaluated by their cytotoxic activity against several tumor cell lines in vitro and in vivo antitumor activity against some tumor models when administered both intraperitoneally and orally. Compounds with the 3-chloropyridin-2-yl group (9g) and the 3-fluoro-5-substituted phenylpiperazinyl group (29b, c, and e) showed significantly potent cytotoxicity by in vitro testing. Among them, the 3-cyano-5-fluorophenyl derivative (29b) exhibited potent antitumor activity against several tumor cells including human carcinoma without causing undesirable effects in mice.  (+info)

The number of functional olfactory receptor genes and the relative size of olfactory brain structures are poor predictors of olfactory discrimination performance with enantiomers. (47/212)

The ability of four squirrel monkeys and three pigtail macaques to distinguish between nine enantiomeric odor pairs sharing an isopropenyl group at the chiral center was investigated in terms of a conditioning paradigm. All animals from both species were able to discriminate between the optical isomers of limonene, carvone, dihydrocarvone, dihydrocarveole and dihydrocarvyl acetate, whereas they failed to distinguish between the (+)- and (-)-forms of perillaaldehyde and limonene oxide. The pigtail macaques, but not the squirrel monkeys, also discriminated between the antipodes of perillaalcohol and isopulegol. A comparison of the across-task patterns of discrimination performance shows a high degree of similarity among the two primate species and also between these nonhuman primates and human subjects tested in an earlier study on the same tasks. These findings suggest that between-species comparisons of the relative size of olfactory brain structures or of the number of functional olfactory receptor genes are poor predictors of olfactory discrimination performance with enantiomers.  (+info)

Enantio- and diastereoselective additions to aldehydes using the bifunctional reagent 2-(chloromethyl)-3-(tributylstannyl)propene: application to a synthesis of the C16-C27 segment of bryostatin 1. (48/212)

[reaction: see text] Reactions of the bifunctional allylstannane 2-(chloromethyl)-3-(tributylstannyl)propene with aldehydes have been examined. These generally occur in high yields using Lewis acid promoters and the products can be isolated and purified without incident. Good yields and high enantioselectivities are also realized in catalytic asymmetric allylations (CAA reactions) using the previously described BITIP catalyst system. Protection of the free hydroxyl can be accomplished without cyclization to the derived tetrahydrofuran, although this transformation is also facile. The utility of the incorporated allyl chloride functionality allows for the obvious use of such products in reactions with nucleophiles. Use of these products in a less obvious connective strategy is demonstrated in the synthesis of the C12-C27 segment of bryostatin 1 where a connective, or "lynchpin", double-allylation process was employed. The beta-hydroxy allyl chloride obtained from an initial chelation-controlled allylation of aldehyde 16 was converted to allylstannane 19 and applied in a second allylation reaction, thus allowing for a highly convergent synthesis of the bryostatin C ring backbone in a stereoselective fashion.  (+info)