Nocardia ignorata, a new agent of human nocardiosis isolated from respiratory specimens in Europe and soil samples from Kuwait

Nocardia ignorata is a recently described species identified on the basis of a single isolate of unknown origin. Here we describe the epidemiological, phenotypic, and phylogenetic characteristics of this new species, based on five new clinical and soil isolates.     

Tumor oxygenation and radiosensitization by pentoxifylline and a perflubron emulsion carbogen breathing

Oxygen tension measurements were made in three tumors: (i) the murine FSaII fibrosarcoma, (ii) the rat 9L gliosarcoma and (iii) the rat 13672 mammary adenocarcinoma using a pO2 histograph. Tumor oxygenation measurements were made while the animals breathed air or breathed carbogen (95% oxygen/5% carbon dioxide). Pentoxifylline or a perflubron emulsion was administered to the animals and tumor oxygen measurements were repeated under both breathing conditions. Both pentoxifylline and the perflubron emulsion improved the oxygenation of the FSaII fibrosarcoma under air breathing conditions but did not alter the oxygen profiles of either rat tumor compared with air breathing alone. Carbogen breathing increased the oxygenation of all tumors. Pentoxifylline administration did not change the oxygen profiles of the tumors under carbogen breathing conditions but administration of the perflubron emulsion increased the oxygenation of all three tumors under carbogen breathing conditions compared with carbogen breathing alone. Co-administration of pentoxifylline and the perflubron emulsion enhanced the radiation response of the Lewis lung tumor to daily fractionated radiation under air breathing conditions with a dose modifying factor of 1.65 and under carbogen breathing conditions with a dose modifying factor of 2.25. Over a range of perflubron emulsion doses, pentoxifylline increased the growth delay of the Lewis lung tumor in a constant manner. These results indicate that pentoxifylline and the perflubron emulsion have the largest impact on the oxygenation of more hypoxic tumors and that administration of the perflubron emulsion/carbogen breathing is the most effective means of increasing tumor oxygenation and radiation response.     

Tumor necrosis factor-{alpha} up-regulates Bcl-2 expression and decreases calcium-dependent apoptosis in human B cell lines

Group I and Epstein–Barr virus-negative Burkitt's lymphomacell lines and the B104 lymphoma cell line which expresses aphenotype of immature B cells undergo apoptosis after cross-linkingof their surface Ig receptors or after exposure to a calciumionophore. We show here that tumor necrosis factor (TNF)- protectsthese B cell lines against Ca²⁺-dependent apoptosis. Protectionwas associated with up-regulatlon of bcl-2 mRNA and proteinexpression. The increase of Bcl-2 expression induced by TNF-was inhibited by chelerythrine, a specific inhibitor of proteinkinase C (PKC), suggesting that Bcl-2 expression was dependenton PKC activation. Furthermore, we show that phorbol estersand cyclosporin A (CsA), which prevent Ca²⁺-dependent apoptosis,up-regulated Bcl-2 expression. The effect of CsA on Bcl-2 expressionis controlled by calcineurin since we have shown that FK506but not rapamycin had the same effect on Bcl-2 expression, whereasokadaic acid, an inhibitor of phosphatases 1, 2A and 2C, wasineffective. These data provide direct evidence that TNF- preventsCa²⁺-dependent apoptosis by a Bcl-2-dependent mechanism mediatedby PKC.     

Precentral cortex stimulation for the treatment of central neuropathic pain: results of a prospective study in a 20-patient series

The authors report a series of 23 patients with central neuropathic pain who were treated with the recently developed technique of precentral cortex stimulation (PCS). Of the 20 patients with a follow-up of more than 1 year (mean of 23 months) 25% had an excellent, 35% a good and 15% a fair relief of pain. In 25% the method failed. On the basis of these findings and the literature data (127 reported cases), the authors advocate PCS in patients with severe and medically refractory poststroke pain.     

Magnitude of 5-HT1B and 5-HT1A receptor activation in guinea-pig and rat brain: evidence from sumatriptan dimer-mediated [35S]GTPgammaS binding responses

The present study reports on G-protein activation by recombinant 5-HT receptors and by native 5-HT1A and 5-HT1B receptors in guinea-pig and rat brain using agonist-stimulated [35S]GTPgammaS binding responses mediated by a new 5-HT ligand, a dimer of sumatriptan. Dimerization of sumatriptan increased the binding affinity for h 5-HT1B (pKi: 9.22 vs. 7.79 for sumatriptan), h 5-HT1D (9.07 vs. 8.08) and also h 5-HT1A receptors (7.80 vs. 6.40), while the binding affinity for h 5-ht1E (6.67 vs. 6.19) and h 5-ht1F (7.37 vs. 7.78) receptors was not affected. Sumatriptan dimer (10 microM) stimulated [35S]GTPgammaS binding mainly in the superficial gray layer of the superior colliculi, hippocampus and substantia nigra of guinea-pig and rat coronal brain sections. This fits with the labelling by the 5-HT1B/1D receptor antagonist [3H] GR 125743. The observed [35S]GTPgammaS binding responses in the substantia nigra are likely to be mediated by stimulation of the 5-HT1B receptor subtype, since they were antagonized by the 5-HT1B inverse agonist SB 224289 (10 microM), and not by the 5-HT2A/1D antagonist ketanserin (10 microM). Quantitative assessment of the [35S]GTPgammaS binding responses in the substantia nigra of rat showed highly efficacious responses for both sumatriptan dimer and its monomer. In contrast, less efficacious agonist responses (51+/-10% and 35+/-13%, respectively) were measured in the guinea-pig substantia nigra. This may suggest that the G-protein coupling efficacy of 5-HT1B receptors is different between the substantia nigra of both species. In addition, the sumatriptan dimer also activated guinea-pig and rat hippocampal 5-HT1A receptors with high efficacy in contrast to sumatriptan. Therefore, dimerization of sumatriptan can be considered as a new approach to transform a partial 5-HT1A agonist into a more efficacious agonist. In conclusion, the sumatriptan dimer stimulates G-protein activation via 5-HT1B receptors besides 5-HT1A receptors in guinea-pig and rat brain. The magnitude of the 5-HT1B receptor responses is superior for sumatriptan and its dimer in rat compared to guinea-pig substantia nigra.     

Vasopressin V2 (SR121463A) and V1a (SR49059) receptor antagonists both inhibit desmopressin vasorelaxing activity

Although [Arg(8)]vasopressin is a potent vasoconstrictor, it possesses vasorelaxant properties manifested either after vasopressin V1 receptor blockade or directly in some vascular beds. The nature of the receptor involved in the vasorelaxant effect of [deamino-Cys(1) D-Arg(8)]vasopressin (desmopressin), a vasopressin V2 receptor agonist, was studied on rat precontracted aortic rings by the use of highly selective new non-peptide vasopressin receptor antagonists. The present study demonstrates for the first time that desmopressin relaxant effect is antagonized by the vasopressin V2 receptor antagonist SR121463A, but also by the vasopressin V1A receptor antagonist SR49059, suggesting that desmopressin-induced relaxation is mediated by a receptor subtype sharing both V1A and V2 pharmacological profiles.     

Modulation of 5-HT1A receptor signalling by point-mutation of cysteine351 in the rat Galpha(o) protein.

The activity state of G proteins is involved in the ligands' maximal responses that can be produced by activating the 5-HT1A receptor (Pauwels et al., 1997). The present study investigated the ligand responses at the recombinant h 5-HT1A receptor (RC: 2.1.5HT.01A) as mediated by the Galpha(o) protein. Therefore, a fusion protein was constructed between the 5-HT1A receptor and a pertussis toxin resistant rat Galpha(o)Cys351Gly mutant protein to define its pharmacological properties at a receptor: Galpha(o) protein density ratio of 1. Pertussis toxin treatment (100 ng/ml) affected neither the expression of the 5-HT1A receptor fusion protein as measured by [3H] MPPF (3.0+/-0.7 pmol/mg protein) nor the 5-HT-mediated [35S]GTPgammaS binding response (146+/-34 fmol/mg protein) in Cos-7 cells. 8-OH-DPAT (Emax: 55+/-7%) and buspirone (Emax: 22+/-4%) yielded partial agonist activity as compared to 5-HT, whereas WAY 100635 acted as a competitive antagonist (pK(B): 9.75+/-0.17). The magnitude of the 8-OH-DPAT response (Emax, %) was highly dependent on the nature of the amino acid 351 in the C-terminus of the Galpha(o) protein: Ile351 (93+/-4) > Cys351 (79+/-3) > Gly351 (55+/-7). The Emax values (%) of buspirone displayed the following gradient: 69+/-5 approximately/= 62+/-8 > 22+/-4. For comparison, maximal responses of 8-OH-DPAT and buspirone were enhanced versus 5-HT upon co-expression of the 5-HT1A receptor with the respective Galpha(o) proteins, probably due to an altered receptor: Galpha(o) protein density ratio. In conclusion, residue 351 of the rat Galpha(o) protein is involved in determining the magnitude of 5-HT1A receptor activation that ligands can produce at these receptors. Moreover, the fusion protein approach allows quantitative comparisons of the intrinsic activities of ligands between one single receptor subtype with different Galpha protein subtypes.