The Perseus Exobiology mission on MIR: behaviour of amino acids and peptides in Earth orbit.

Leucine, alpha-methyl leucine and two peptides were exposed to space conditions on board the MIR station during the Perseus-Exobiology mission. This long duration space mission was aimed at testing the delivery of prebiotic building blocks. During this mission, two amino acids (leucine and alpha-methyl leucine) and two peptides (leucine-diketopiperazine and trileucine thioethylester) were exposed in Earth orbit for three months. Basalt, clay and meteorite powder were also mixed with the samples in order to simulate the effects of potential meteorite protection. Analysis of the material after the flight did not reveal any racemization or polymerisation but did provide information regarding photochemical pathways for the degradation of leucine and of the tripeptide. Amino acids appeared to be more sensitive to UV radiation than peptides, the cyclic dipeptide being found to be as particularly resistant. Meteorite powder which exhibits the highest absorption in Vacuum UltraViolet (VUV) afforded the best protection to the organic molecules whereas montmorillonite clay, almost transparent in VUV, was the least efficient. By varying the thickness of the meteorite, we found that the threshold for efficient protection against radiation was about 5 microm. The possible exogenous origin of biological building blocks is discussed with respect to the stability to the molecules and the nature of the associated minerals.

Inhibition of all-TRANS-retinoic acid metabolism by R116010 induces antitumour activity.

All-trans-retinoic acid is a potent inhibitor of cell proliferation and inducer of differentiation. However, the clinical use of all-trans-retinoic acid in the treatment of cancer is significantly hampered by its toxicity and the prompt emergence of resistance, believed to be caused by increased all-trans-retinoic acid metabolism. Inhibitors of all-trans-retinoic acid metabolism may therefore prove valuable in the treatment of cancer. In this study, we characterize R116010 as a new anticancer drug that is a potent inhibitor of all-trans-retinoic acid metabolism. In vitro, R116010 potently inhibits all-trans-retinoic acid metabolism in intact T47D cells with an IC(50)-value of 8.7 nM. In addition, R116010 is a selective inhibitor as indicated by its inhibition profile for several other cytochrome P450-mediated reactions. In T47D cell proliferation assays, R116010 by itself has no effect on cell proliferation. However, in combination with all-trans-retinoic acid, R116010 enhances the all-trans-retinoic acid-mediated antiproliferative activity in a concentration-dependent manner. In vivo, the growth of murine oestrogen-independent TA3-Ha mammary tumours is significantly inhibited by R116010 at doses as low as 0.16 mg kg(-1). In conclusion, R116010 is a highly potent and selective inhibitor of all-trans-retinoic acid metabolism, which is able to enhance the biological activity of all-trans-retinoic acid, thereby exhibiting antitumour activity. R116010 represents a novel and promising anticancer drug with an unique mechanism of action.

Acquired alexia in multilingual aphasia and computer-assisted treatment in both languages: issues of generalisation and transfer.

This single-subject study addresses the issue of investigation and remediation of an acquired reading impairment observed in a Spanish-English bilingual speaker. Detailed bilingual reading testing showed parallel disturbances in the two languages, both from a qualitative and a quantitative point of view, with characteristics of letter-by-letter and aphasic alexia. On the basis of this mixed pattern, common to both languages, a two-step computer-assisted remediation programme was designed for English, then for Spanish, using a crossover AB-AB design. Therapy A consisted of tasks aimed at the inhibition of letter-by-letter reading. This was alternated with therapy B, which was designed to address phonological assembly. Results on therapy reveal transfer of gains when common reading processing are involved and language-specific gains with a greater benefit on the mother tongue when phonological representations are required in therapy and assessment. Consequences for language choice in bilingual aphasia therapy are discussed on the basis of these results.

Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro.

R115777 [(B)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)-methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone] is a potent and selective inhibitor of farnesyl protein transferase with significant antitumor effects in vivo subsequent to oral administration in mice. In vitro, using isolated human farnesyl protein transferase, R115777 competitively inhibited the farnesylation of lamin B and K-RasB peptide substrates, with IC50s of 0.86 nM and 7.9 nM, respectively. In a panel of 53 human tumor cell lines tested for growth inhibition, approximately 75% were found to be sensitive to R115777. The majority of sensitive cell lines had a wild-type ras gene. Tumor cell lines bearing H-ras or N-ras mutations were among the most sensitive of the cell lines tested, with responses observed at nanomolar concentrations of R115777. Tumor cell lines bearing mutant K-ras genes required higher concentrations for inhibition of cell growth, with 50% of the cell lines resistant to R115777 up to concentrations of 500 nM. Inhibition of H-Ras, N-Ras, and lamin B protein processing was observed at concentrations of R115777 that inhibited cell proliferation. However, inhibition of K-RasB protein-processing could not be detected. Oral administration b.i.d. of R115777 to nude mice bearing s.c. tumors at doses ranging from 6.25-100 mg/kg inhibited the growth of tumors bearing mutant H-ras, mutant K-ras, and wild-type ras genes. Histological evaluations revealed heterogeneity in tumor responses to R115777. In LoVo human colon tumors, treatment with R115777 produced a prominent antiangiogenic response. In CAPAN-2 human pancreatic tumors, an antiproilferative response predominated, whereas in C32 human melanoma, marked induction of apoptosis was observed. The heterogeneity of histological changes associated with antitumor effects suggested that R115777, and possibly farnesyl protein transferase inhibitors as a class, alter processes of transformation related to tumor-host interactions in addition to inhibiting tumor-cell proliferation.

R115866 inhibits all-trans-retinoic acid metabolism and exerts retinoidal effects in rodents.

All-trans-retinoic acid (RA) regulates epithelial differentiation and growth through activation of specific nuclear RA receptors (RARs). Because high-rate metabolism largely impairs the biological efficacy of RA, we have sought for compounds capable of inhibiting the metabolic breakdown of the retinoid. This study identifies R115866 as a novel inhibitor of the cytochrome P450 (CYP)-mediated metabolism of RA. In vitro, nanomolar concentrations of R115866 inhibited the conversion of RA by CYP26, a RA-inducible RA metabolizing enzyme. In vivo, oral administration of R115866 (2.5 mg/kg) to rats induced marked and transient increases of endogenous RA levels in plasma, skin, fat, kidney, and testis. Consistent with its ability to enhance endogenous RA content in tissues, R115866 was found to exert retinoidal activities. Like RA, the title compound: 1) inhibited vaginal keratinization in estrogen-stimulated rats; 2) induced epidermal hyperplasia in mouse ear skin; 3) transformed mouse tail epidermis from a para- to an orthokeratotic skin type; and 4) up-regulated the CYP26 mRNA expression in rat liver. Furthermore, we found that the keratinization-suppressive and CYP26-inducing activities of R115866 could be reversed by concomitant administration of the RAR antagonist, AGN193109. Our data characterize R115866 as a potent, orally active inhibitor of RA metabolism, capable of enhancing RA levels and displaying retinoidal actions. These activities are reversed by RAR antagonism, supporting the idea that the actions of R115866 result from increased availability of endogenous RA and improved RAR triggering.

The development of conditional reasoning and the structure of semantic memory.

The present article examines 2 predictions concerning conditional reasoning in children derived from a revised version of Markovits's model of conditional reasoning. The first study examined the prediction that younger children (8 years of age) would have greater difficulty in responding correctly to premises where the antecedent was strongly associated with the consequent than to premises where the association was weaker; for example, "If something is a car, then it has a motor" should be more difficult than "If something is a refrigerator, then it has a motor." A total of 55 children in grades 2 and 3 (average age: 8 years) and 49 children in grades 5 and 6 (average age: 11 years) were given either 2 strongly associated problems or weakly associated counterparts. Results indicated that 8-year-olds did better on the weakly associated problems than on the strongly associated problems, but there was no difference among the 11-year-olds. The second study examined the prediction that younger children (8 years of age) would have greater difficulty in responding correctly to causal premises ("If a rock is thrown at a window, the window will break") than to corresponding ad hoc premises ("A rock is something that can be used to break a window"). A total of 53 children in grades 2 and 3 (average age: 8 years) and 49 children in grades 5 and 6 (average age: 11 years) were given either 2 causal problems or ad hoc counterparts. Results indicated that 8-year-old did better on the ad hoc problems than on the causal problems, but there was no difference among the 11-year-olds. These studies are interpreted as consistent with the idea that 1 major factor in the development of reasoning in this age level is the development of children's ability to explore their own knowledge base.

Synthesis of LIAZAL, a retinoic acid metabolism blocking agent (RAMBA) with potential clinical applications in oncology and dermatology.

The synthesis of LIAZAL (compound 9, R085246) is described. LIAZAL inhibits all-trans-retinoic acid metabolism and thereby exerts retinoid-like effects in vivo.

Technical evolutions of the French multipurpose instruments for Cognitive Neurosciences.

Since the first French flight in space in 1982, the CNES has developed a wide range of instruments, especially in the field of Neurosciences. The design of these instruments has considerably evolved from rather simple equipment up to much more sophisticated tools that are being specially tailored for these missions. Four major phases can be identified: -a simple adaptation of an echographe leading to the first neurosciences experiments (the ARAGATZ'88 mission), -the ILLUSIONS and VIMINAL instruments used during the ANTARES'92 and ALTAIR'93 missions, -the COGNILAB instrument developed for the CASSIOPEE'96 mission, to be re-used in 1997 and in 1999, -a preliminary design of the 1999 mission payload, including virtual reality concepts, in a modular design to adapt to the European COF. Aside from the evolution of scientific requirements, the experience gained during the flights led to progressive improvements in the different technical parts, including visual system, body restraint systems, accessories, such as a force feedback joystick, computer and software, etc. This paper describes the technical evolutions in the CNES Neurosciences program.

The Kinelite Project: a new powerful motion analyser for Spacelab and space station.

The goal of the Kinelite Project is to develop a space qualified motion analysis system to be used in space by the scientific community, mainly to support neuroscience protocols. The measurement principle of the Kinelite is to determine, by triangulation mean, the 3D position of small, lightweight, reflective markers positioned at the different points of interest. The scene is illuminated by Infra Red flashes and the reflected light is acquired by up to 8 precalibrated and synchronized CCD cameras. The main characteristics of the system are: Camera field of view: 45 degrees; Number of cameras: 2 to 8; Acquisition frequency: 25, 50, 100, or 200 Hz; CCD format: 256 x 256; Number of markers: up to 64; 3D accuracy: 2mm; Main dimensions: 45 cm x 45 cm x 30 cm; Mass: 23 kg; Power consumption: less than 200 W. The Kinelite will first fly aboard the NASA Spacelab; it will be used, during the NEUROLAB mission (4/98), to support the "Frames of References and Internal Models" (Principal Investigator: Pr. A. Berthoz, Co Investigators: J. McIntyre, F. Lacquaniti).

[Comparative evaluation of maternity hospitals in Auvergne: from planning to contracting]. / Evaluation comparative des maternités en Auvergne: de la planification à la contractualisation.

Two reforms of public hospitals have been launched by the French government in 1991 and 1996 aimed at lowering costs and increasing the quality of services and ultimately the safety of patients. As concerns maternity hospitals, several new rules have been imposed upon. For example, those who performed less than 300 births a year should be closed. The basic idea was to concentrate technical resources and human skills in middle-size and important hospitals for saving money, and simultaneously, raising the safety level for mothers and babies. However, negative adverse effects fastly appeared: to avoid closure, some small maternity homes tried to convince future mothers not to go to well-equipped hospitals, even if their cases appeared complex and their health at risk. An experience of partnership between maternity hospitals (care providers), the Sickness Insurance Fund (the financing body) and the Administration was carried out in the Auvergne region. It was based on the observation of a large number of indicators concerning the activity of hospitals, the size and quality of their equipment, the satisfaction of their patients ... etc ... for designing the rights and duties of each partner. Instead of planning from the summit, a process of mutually-agreed contract was established.

Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat. The American PKD1 Consortium (APKD1 Consortium).

The complete genomic sequence of the gene responsible for the predominant form of polycystic kidney disease, PKD1, was determined to provide a framework for understanding the biology and evolution of the gene, and to aid in the development of molecular diagnostics. The DNA sequence of a 54 kb interval immediately upstream of the poly(A) addition signal sequence of the PKD1 transcript was determined, and then analyzed using computer methods. A leucine-rich repeat (LRR) motif was identified within the resulting predicted protein sequence of the PKD1 gene. By analogy with other LRR-containing proteins, this may explain some of the disease-related renal alterations such as mislocalization of membrane protein constituents and changes in the extracellular matrix organization. Finally, comparison of the genomic sequence and the published partial cDNA sequence showed several differences between the two sequences. The most significant difference detected predicts a novel carboxy-terminus for the PKD1 gene product.

Comparative effects of the aromatase inhibitor R76713 and of its enantiomers R83839 and R83842 on steroid biosynthesis in vitro and in vivo.

R76713 (6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H- benzotriazole) is a selective, non-steroidal aromatase inhibitor containing an asymmetric carbon atom. In this paper, we compare the effects of R76713 (racemate) with its enantiomers R83839 (the levo-isomer) and R83842 (the dextro-isomer) on steroid biosynthesis in rat cells in vitro and in the rat in vivo. In rat granulosa cells, aromatase activity was inhibited by 50% at concentrations of 0.93 nM of R76713, 240 nM of R83839 and 0.44 nM of R83842, revealing a 545-fold difference in activity between both enantiomers. Up to 1 microM, none of the compounds had any effect on steroid production in primary cultures of rat testicular cells. Above this concentration all three compounds showed a similar slight inhibition of androgen synthesis with a concomitant increase in the precursor progestins, indicative for some effect on the 17-hydroxylase/17,20-lyase enzyme. In rat adrenal cells none of the compounds showed any effect on corticosterone synthesis. At concentrations above 1 microM there was an increase in the levels of 11-deoxycorticosterone pointing towards an inhibition of the 11-hydroxylase enzyme. This increase was more pronounced for R83839 than for R76713 and R83842. In vivo, in PMSG-primed rats, R83842 reduced plasma estradiol by 50%. 2 h after oral administration of 0.0034 mg/kg, whereas 0.011 mg/kg of R76713 and 0.25 mg/kg of R83839 were needed to obtain the same result. Oral administration of up to 20 mg/kg of the compounds did not significantly affect plasma levels of adrenal steroids in LHRH/ACTH-injected rats. Plasma testosterone was lowered at 10 and 20 mg/kg of R83842 and at the highest dose (20 mg/kg) of R76713 and R83839. In conclusion, the present study shows that the aromatase inhibitory activity of R76713 resides almost exclusively in its dextro-isomer R83842. R83842 exhibits a specificity for aromatase as compared to other enzymes involved in steroid biosynthesis of at least a 1000-fold in vitro as well as in vivo. This confirms the extreme selectivity previously found for the racemate.

R 76713, a new specific non-steroidal aromatase inhibitor.

The effects of R 76713, a new triazole derivative, on rat ovarian, testicular and adrenal steroidogenesis were investigated both in vitro and in vivo. In vitro R 76713 is a very potent inhibitor of the aromatase enzyme in rat granulosa cells, showing an IC50-value of 3.0 +/- 0.2 nM. The compound is about 1000 times more active than aminoglutethimide which shows an IC50-value of 3900 +/- 2800 nM in the same system. R 76713 is also a highly selective aromatase inhibitor. In cultures of ovarian, testicular and adrenal cells, formation of progesterone, androgens and glucocorticoids was only affected by drug concentrations higher than 1 microM. In vivo, single oral drug doses of 0.05 mg/kg lowered plasma estradiol levels of PMSG-primed female rats by more than 90%. An ED50-value of 0.005 mg/kg could be calculated. A single oral dose of 1 mg/kg suppressed plasma estradiol levels almost completely for 24 h. A dose of 0.1 mg/kg lowered plasma estradiol by more than 90% for 8 h. In vivo, R 76713 also showed a highly selective profile. In LHRH/ACTH-injected rats, plasma levels of testicular and adrenal steroids remained unchanged after administration of a drug dose of 20 mg/kg. R 76713 at drug concentrations of 10 microM, showed no interaction in vitro with estrogen-, progestin-, androgen- and glucocorticoid-receptors. Given orally at 20 mg/kg for 3 days the compound also showed no estrogen or androgen agonistic or antagonistic effects.

Synthesis, affinity and specificity of 18F-setoperone, a potential ligand for in-vivo imaging of cortical serotonin receptors.

Setoperone, a piperidine derivative known for its potent serotonin and moderate dopamine receptor blocking properties was labelled with the positron emitter 18F using a nucleophilic substitution on the nitro derivative. The general pattern of the in-vivo and in-vitro rat brain distribution of this new radioligand was consistent with the mapping of serotonin (5HT2) and dopamine (D2) receptors. The cortical binding of 18F-setoperone was selectively inhibited by ketanserin and not by sulpiride. The affinity of the radiofluorinated ligand for the serotonin receptors was in the nanomolar range (Kd = 0.7 nM).