Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy

The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.     

Septins: a ring to part mother and daughter

The septins are well conserved GTPases found in animals and fungi. In yeast, they are required for the formation of 10-nm filaments, with which they co-localize at the bud neck. Therefore, septins have been proposed to be components of the neck filaments and to have polymerization properties. In support of this hypothesis, septin complexes purified from yeast and flies form filaments in vitro. However, recent studies have questioned the relevance of septin filament formation for septin function. Particularly, septin polymerization may not be required for their function in cytokinesis. New septin functions have also been recently uncovered: in budding yeast, the septin ring is required for the maintenance of cell polarity. It forms a cortical barrier that prevents lateral diffusion of membrane-associated proteins through the bud neck. Here, we review the most recent functional and biochemical data, to discuss whether there is a link between septin polymerization properties and septin function.     

Genetic polymorphism of cytomegalovirus strains responsible of congenital infections

OBJECTIVES: Congenital Cytomegalovirus (CMV) infection is the main cause of neurological handicap in young children. The objective for studying genetic polymorphism of strains responsible for congenital infection is to identify CMV strains or groups of strains which would be more frequent in this context and/or which would be responsible for more severe congenital infection. METHODS: In this paper, we report and analyze the literature concerning the genetic polymorphism of CMV strains responsible of congenital infection, in the genes coding for the envelop protein B and the non structural UL144 protein and in the CMV short tandem repeats. RESULTS AND CONCLUSION: All UL144 and gB genotypes can be vertically transmitted from mothers to fetuses, none of these studies has shown any link between the genotypes and the severity of congenital disease. Moreover, no link between short tandem repeats polymorphism and severity of congenital disease has been demonstrated. However, short tandem repeats analysis may be a powerful tool to study the epidemiology of CMV congenital infections.     

Culture of epithelial cells derived from the oviduct of different species

This study proposes a procedure for the isolation and cultureof oviduct epithelial cells of several species. In-vitro cultureon such a feeder seems to allow full embryonic development andviability. The inner linings of Fallopian tubes from mouse,rabbit, cow and human were trypsinized and the epithelial cellswere enriched with Percoll gradient. Isolated cells, obtainedin high yield with good viability, were maintained in monolayerculture in B2-Menezo medium supplemented with serum, which alsosupports early embryonic development in vitro. The plated primarycultures reached confluence within 8 days, producting a monolayerof cohesive polygonalcells. Associated with this large epithelialcall population, ciliated cells as wellas polykaryotic cellsand few fibroblastic nestswere observed. After the first sub-culture,the ciliated cells disappeared and the epithelial cell monolayergrew rapidly to confluence with in 3 days and displayed contactinhibition. No epithelial cell growth could be obtained inculturein the absence of serum. The addition of oestrogens had no effecton any of the cultured oviductal epithelial cells. A sponotaneousalteration was observed in morphology and growth after severalpassages, the number of which depends mainly upon the species     

Application of the Electrotopological State Index to QSAR Analysis of Flavone Derivatives as HIV-1 Integrase Inhibitors

Purpose. A QSAR study based on electrotopological state (E-state) indices was conducted for a series of flavone HIV-1 integrase inhibitors to guide drug design. Methods. E-state indices formulated to encode electronic and topological information for each skeletal atom in a molecule (Kier and Hall Pharm. Res. 7:801–807 (1990)) were calculated using the Molconn-X program, and partial least squares (PLS) multivariate regression was used to derive QSAR models. Results. Predictive models with correlation coefficients (r²) of 0.98 (3 PLS components) and 0.99 (5 PLS components) and corresponding cross-validated correlation coefficients (c.v. r²) of 0.51 and 0.73, were obtained for inhibition of cleavage and integration, respectively, with one molecule omitted from the analysis. Conclusions. E-state indices at C6, C3, C5, C5, and O4 were found to be more important for prediction of activity than those for any of the other 12 flavone skeletal atoms that are common to the molecules in the data set.     

Cancer chemotherapy in the elderly: a series of 51 patients aged>70 years

Summary A total of 2,238 new cancer patients were treated in our institution in 1988; among the 423 (18.9%) who were>70 years old, 51 underwent chemotherapy. The median age was 75.8 years, and the Karnofsky performance status (KPS) was 70% for 40 patients. Malignancies were hematopoietic in 24 cases (47%) and digestive in 15 patients (29%), and 12 subjects (24%) had other types of cancers. The first chemotherapy course was given at the full dose to 23/51 (45.1%) patients. The drug dose was reduced for 28/51 (54.9%) patients, due in 25 cases to the subjects being>70 years old. Neither age, KPS, pretreatment assessment, nor cancer extent was correlated with the modifications made to the first cycle. An overall toxicity of grade 3+4 (WHO grading scale) was noted in 10 subjects (19.6%). Although these elderly patients were probably selected, analysis of their charts did not evidence an increase in chemotherapy toxicity, regardless of the dose they received.Presented at the EORTC Pharmacokinetics and Metabolism Group Meeting, Bordeaux, November 1990     

Induction of partial protection in mice after oral administration of Lactococcus lactis producing Brucella abortus L7/L12 antigen.

The Brucella abortus ribosomal protein L7/L12 is an immunodominant antigen and an interesting candidate for the development of oral live vaccines against brucellosis. Here, a recombinant Lactococcus lactis strain producing L7/L12 under the control of nisin inducible promoter was orally administered to BALB/c mice. Significant levels of anti-L7/L12 specific IgA detected in feces revealed an induced local humoral immune response. However, serum analysis did not reveal any anti-L7/L12 antibodies suggesting the absence of a systemic response. Nevertheless, the vaccinated mice showed a partial protective immunity against B. abortus virulent strain (S2308) challenged by intraperitoneal inoculation.     

Localized pelvic neuroblastoma: excellent survival and low morbidity with tailored therapy--the 10-year experience of the French Society of Pediatric Oncology.

PURPOSE: To assess the results and morbidity of treatment of children with localized pelvic neuroblastoma (NB). PATIENTS AND METHODS: All consecutive cases of localized pelvic NB registered in the French multicenter prospective studies NBL90 and NBL94 between 1990 and 1999 were reviewed. Resectability was decided on the basis of clinical and radiologic evaluation. In unresectable tumors, primary chemotherapy (combinations of carboplatin-etoposide and vincristine-cyclophosphamide-doxorubicine) was administered before surgery. RESULTS: Forty-seven children (with 26 resectable tumors and 21 unresectable) were included in this study. At the end of treatment, 31 children were in complete remission (66%). Long-term neurologic sequelae were observed in seven patients (15%), directly attributable to surgery in three cases. After a median follow-up of 48 months (range, 13 to 129 months), 44 patients are alive. Six children experienced local relapse; four of these children achieved subsequent remission. The projected overall survival and event-free survival (EFS) rates at 5 years are, respectively, 93% +/- 4% and 84% +/- 5%. Survival of children treated with preoperative chemotherapy are similar to those treated by primary surgery (80% and 88% respectively). The extent of surgical resection seemed to have no influence on the outcome (EFS rates 76% and 89% in case of gross residue and complete resection or microscopic residue, respectively). CONCLUSION: Our data confirm the excellent survival of localized pelvic NBs. Considering the efficacy of preoperative chemotherapy, patients with pelvic NB should be carefully screened for primary surgery. The risk of neurologic impairment during radical excision should be balanced with the good survival of children with minimal residual disease.