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Malgré l’importante prévalence de l’insuffisance mitrale primaire, les techniques et les résultats du traitement chirurgical restent hétérogènes. Le geste opératoire est essentiellement guidé par une évaluation morphologique (échocardiographique préopératoire et visuelle peropératoire) et le succès de la réparation valvulaire repose avant tout sur l’expertise du chirurgien. Certaines évolutions technologiques récentes nous permettent aujourd’hui de concevoir des outils innovants dédiés, permettant la mesure de paramètres physiques au cours de ces chirurgies. Au cours des procédures de réparation mitrale par implantation de néocordages par voie transapicale, à cœur battant et sans circulation extracorporelle, la tension exercée sur les néocordages implantés peut être mesurée. En plus d’améliorer notre compréhension de la physiopathologie mitrale, cette mesure permet d’adapter la traction afin d’obtenir une « réparation à bas-stress », faisant espérer des résultats à long terme optimaux. Une cartographie bidimensionnelle des forces de coaptation mitrale pourrait être réalisée lors des chirurgies mitrales conventionnelles (à « cœur ouvert » et sous circulation extracorporelle). Celle-ci pourrait permettre de mesurer de façon précise et en temps réel la surface de coaptation et d’évaluer la répartition des forces de coaptation valvulaire. Ces deux exemples illustrent le concept de chirurgies valvulaires guidées par des mesures physiques, en plus des mesures morphologiques habituelles. Néanmoins, si le concept de « réparation à bas-stress » est intuitivement attrayant, l’intérêt pronostique lié à l’utilisation de ces outils doit être évalué au travers d’études cliniques avec suivi prospectif à long terme.

Through high throughput screening of various libraries, substituted styryl naphthalene 6 was identified as an HCMV protease inhibitor. Optimization of various regions of the lead molecule using parallel synthesis resulted in 1,6-substituted naphthalenes 19d−i. These compounds displayed good potency and were selective over elastase, trypsin, and chymotrypsin. The optimization approach on lead compound 6 in three different regions of the molecule using parallel solution-phase synthesis and the corresponding SAR are discussed in detail.

OBJECTIVE: Extragonadal estrogen biosynthesis is relevant for the regulation of bone metabolism. The aims of this paper were: (i) to examine CYP19 (aromatase) gene expression in primary cultures of osteoblasts under several hormone and cytokine treatments and (ii) to study the promoter usage of CYP19 in these cells. METHODS: Primary cultures of osteoblasts were obtained from healthy donors. The effects of vitamin D and other factors on CYP19 expression were analysed by semiquantitative RT-PCR. Furthermore, CYP19 alternative promoter usage under the different treatments was characterized by RT-PCR. RESULTS: CYP19 transcripts were detected in cultured human osteoblasts in serum-free conditions. Vitamin D, dexamethasone, 17beta-estradiol and testosterone increased transcript levels of CYP19, whereas interleukin-1beta or tumor necrosis factor alpha decreased them. Aromatase mRNA produced under treatment with vitamin D was transcribed from promoters I.4 and I.3, while stimulation with dexamethasone or dexamethasone plus vitamin D also involved promoter I.2. Testosterone activated promoters I.2 and I.4. CONCLUSIONS: Our results suggested that vitamin D, testosterone, estrogens and glucocorticoids regulate CYP19 gene expression in human primary osteoblasts and the main promoter used appears to be promoter I.4. Promoters pII and I.3 seem to be related to basal transcription and may mediate estrogen stimulation, while promoter I.2 seems to play a role in the effect of glucocorticoids. These findings indicate that vitamin D and several hormones regulate local estrogen synthesis in human osteoblasts mainly through usage of promoters I.4 and I.3.

Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disease. To date, mutations in four members of the phototransduction cascade have been implicated in ARRP. Additionally, linkage of the disease to three loci on 1p, 1q, and 6p has been described. However, the majority of cases are still uncharacterised. We have performed linkage analysis in a large nuclear ARRP family with five affected sibs. After exclusion of several regions of the genome known to contain loci for retinal dystrophies, a genomic search for linkage to ARRP was undertaken. Positive lod scores were obtained with markers on 2q31-q33 (Ζmax at θ=0.00 of 4.03, 4.12, and 4.12 at D2S364, D2S118, and D2S389, respectively) defining an interval of about 7 cM for this new ARRP locus, between D2S148 and D2S161. Forty-four out of 47 additional ARRP families, tested with markers on 2q32, failed to show linkage, providing evidence of further genetic heterogeneity.

Mutations in the gene encoding β-glucocerebrosidase are the main cause of Gaucher disease. The identification of some of these mutations in prenatal tests is a good complement to enzymatic assay and allows diagnosis and, in some cases, prognosis of the disease to be made. DNA analysis is particularly useful for carrier detection since the results of biochemical analyses are often ambiguous. The main drawback of mutation analysis for prenatal diagnosis and carrier detection in Gaucher disease is that rare mutations account for more than 30 per cent of the mutant alleles in most populations. The individual detection of these mutations is too expensive and time-consuming for routine use. Here we present a diagnostic protocol based on co-segregation analysis, using highly polymorphic markers, to be applied when at least one disease allele does not correspond to the most common mutations. Because of the frequency of the N370S mutation and its relevance for prognosis, an improved PCR detection method is included. © 1998 John Wiley & Sons, Ltd.

Mutations in the gene encoding β‐glucocerebrosidase are the main cause of Gaucher disease. The identification of some of these mutations in prenatal tests is a good complement to enzymatic assay and allows diagnosis and, in some cases, prognosis of the disease to be made. DNA analysis is particularly useful for carrier detection since the results of biochemical analyses are often ambiguous. The main drawback of mutation analysis for prenatal diagnosis and carrier detection in Gaucher disease is that rare mutations account for more than 30 per cent of the mutant alleles in most populations. The individual detection of these mutations is too expensive and time‐consuming for routine use. Here we present a diagnostic protocol based on co‐segregation analysis, using highly polymorphic markers, to be applied when at least one disease allele does not correspond to the most common mutations. Because of the frequency of the N370S mutation and its relevance for prognosis, an improved PCR detection method is included. © 1998 John Wiley & Sons, Ltd.

Abstract: Mutations in the glucocerebrosidase (GBA) and prosaposin (PSAP) genes are responsible for Gaucher disease, the most prevalent sphingolipidosis. Somatic cell hybrid analysis and in situ hybridization experiments have localized the GBA gene to 1q21 and the PSAP gene to 10q21-q22. We performed pairwise and multi-point linkage analyses between the two genes and several highly polymorphic markers from the Généthon human linkage map. Our results show that six markers cosegregate with the GBA gene (Zmax = 8.73 at θ = 0.00 for marker D1S2714) and define a 3.2-cM interval between D1S305 and D1S2624 as the most probable location for the gene. Three of these markers (D1S2777, D1S303, and D1S2140), as well as the gene encoding pyruvate kinase (PKLR), are contained in a single YAC clone together with the GBA gene. A new polymorphism was identified within the PSAP gene (C16045T) and used for linkage studies. The multi-point analysis places the gene in a 9.8-cM interval between D10S1688 and D10S607. The fine localization of these genes provides a useful tool for cosegregation analysis, indirect molecular diagnosis, and population genetic studies.

Previous work on the thermal etching of (100) surfaces of NaCl single crystals is extended to the other surface orientations by using polycrystalline samples. The results obtained with (110), (111), (520) and (144) surfaces are used to corroborate the correctness of the mechanisms proposed in a previous paper to explain the thermal etching in air of (100) surfaces; it is also shown that these mechanisms are only dependent on crystal structure and not on the surface orientation.

Gaucher disease results, in most patients, from mutations in the gene encoding glucocerebrosidase. Mutation D409H is the third most frequent in Spanish patients, accounting for 5.7% of all mutated alleles. This allele is associated mainly with the neurological forms of the disease. Recently, homozygosity for the D409H mutation has been associated with a particular phenotype, including specific cardiovascular symptoms. Here we report a second Spanish patient bearing the D409H/D409H genotype with a very early manifestation of the disease. The patient started enzyme replacement therapy at 3 months of age. A common origin for the Spanish D409H alleles was ruled out by haplotype analysis using an internal polymorphism of the glucocerebrosidase gene and two external microsatellite markers.