Search PubMed⌕ Search

Biomedical subjects

G Lenoir

Publications and source records attributed to G Lenoir.

At least 73 records · Page 4Linked to original sources
PubMed1996

Disturbed myeloperoxidase-dependent activity of neutrophils in cystic fibrosis homozygotes and heterozygotes, and its correction by amiloride.

The present study addresses the question of a possible linkage between the cystic fibrosis (CF) genetic autosomal recessive disorder and disturbance in neutrophil function. Neutrophil-dominated chronic airway inflammation is present at an early age in children with CF, even in the absence of detectable infection. As evidenced by extracellular superoxide anion release (measured by lucigenin luminescence) or intracellular hydrogen peroxide production (measured by 2',7'-dichlorofluorescein (DCF) fluorescence), no significant difference in the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity of isolated neutrophils was observed in noninfected CF children (homozygotes), their mothers or fathers (CF heterozygotes), and controls. In contrast, both myeloperoxidase (MPO)-dependent oxygenation activity (measured by luminol luminescence) and chloramine release were increased significantly in both CF homozygotes and heterozygotes as compared with controls. In the presence of either amiloride (a sodium channel inhibitor and sodium/proton antiport blocker) or EIPA (5-ethyl-N-isopropyl-amiloride, a specific inhibitor of the antiport), or choline buffer, intracellular MPO activity was decreased significantly in controls and in the CF homozygotes and heterozygotes, thus bringing intracellular MPO-dependent activity in CF subjects back to the level of controls. Extracellular release of MPO, measured by an ELISA to provide an activity-independent assessment of the enzyme, was increased only in CF homozygotes, and was decreased by amiloride and choline buffer, but not by EIPA. We conclude that a modification of intracellular pH and/or ionic concentrations may be related to the altered MPO enzymatic activity observed in CF neutrophils.

Adolescent↗
PubMed1996

BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes.

OBJECTIVES: To identify predictors of utilization of breast-ovarian cancer susceptibility (BRCA1 gene) testing and to evaluate outcomes of participation in a testing program. DESIGN: Prospective cohort study with baseline interview assessment of predictor variables (eg, sociodemographic factors, knowledge about hereditary cancer and genetic testing, perceptions of testing benefits, limitations, and risks). BRCA1 test results were offered after an education and counseling session in a research setting. Outcome variables (including depression, functional health status, and prophylactic surgery plans [follow-up only]) were assessed at baseline and 1-month follow-up interviews. PARTICIPANTS: Adult male and female members (n=279) of families with BRCA1-linked hereditary breast-ovarian cancer (HBOC). RESULTS: Of subjects who completed a baseline interview (n=192), 60% requested BRCA1 test results (43% of all study subjects requested results). Requests for results were more frequent for persons with health insurance (odds ration [OR], 3.74; 95% confidence interval [CI], 2.06-6.80); more first-degree relatives affected with breast cancer (OR, 1.59; 95% CI, 1.16-2.16); more knowledge about BRCA1 testing (OR, 1.85; 95% CI, 1.36-2.50); and indicating that test benefits are important (OR, 1.45; 95% CI, 1.13-1.86). At follow-up, noncarriers of BRCA1 mutations showed statistically significant reductions in depressive symptoms and functional impairment compared with carriers and nontested individuals. Individuals identified as mutation carriers did not exhibit increases in depression and functional impairment. Among unaffected women with no prior prophylactic surgery, 17% of carriers (2/12) intended to have mastectomies and 33% (4/12) to have oophorectomies. CONCLUSIONS: Only a subset of HBOC family members are likely to request BRCA1 testing when available. Rates of test use may be higher in persons of a higher socioeconomic status and those with more relatives affected with breast cancer. For some high-risk individuals who receive test results in a research setting that includes counseling, there may be psychological benefits. More research is needed to assess the generalizability of these results and evaluate the long-term consequences of BRCA1 testing.

Adult↗
PubMed1996

Predominance of null mutations in ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.

Amino Acid Sequence↗
PubMed1996

Evaluation of nasopharyngeal cultures for bacteriologic assessment of acute otitis media in children.

BACKGROUND: The recent emergence of penicillin-resistant Streptococcus pneumoniae, particularly in acute otitis media (AOM), has increased interest in the development of noninvasive procedures that might help to predict the bacterial etiology of this condition. We conducted an open multicenter study to evaluate the predictive value of the nasopharyngeal (NP) sampling in children with AOM by comparing the bacteriologic results of NP cultures with those of pus collected by myringotomy in the same patients. METHODS: The NP secretions and the pus obtained by myringotomy were collected concomitantly in 354 children younger than 6 years of age with clinical signs of AOM. The clinical usefulness of NP culture was determined by calculating its sensitivity and specificity, and especially its positive and negative predictive values for the three main pathogens responsible for AOM, Haemophilus influenzae, S. pneumoniae and Moraxella catarrhalis. RESULTS: A positive NP culture was found to have little predictive value for H. influenzae (52%), S. pneumoniae (43%) and M. catarrhalis (19%). In contrast the negative predictive value of NP cultures was much greater and was accompanied by negative middle ear fluid cultures in more than 95% of children, especially for S. pneumoniae. Furthermore the incidence of beta-lactamase-producing strains of H. influenzae at both sampling sites was similar (30 and 35%, respectively), as was the incidence of penicillin-resistant S. pneumoniae (50 and 54%). CONCLUSION: It appears that the correlation between results of NP and middle ear fluid cultures in children with AOM is too weak to allow NP culture to be recommended for the bacteriologic documentation of this disease. However, these results should not overshadow the considerable epidemiologic value of NP cultures, particularly with reference to the monitoring of pneumonococcal susceptibility in children. The collection of NP cultures should therefore be promoted for their collective epidemiologic value.

Bacterial Infections↗
PubMed1996

Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.

Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families. To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a set of 61 breast/ovarian cancer families selected for having one of six recurrent BRCA1 mutations. Tests of both mutations and family-specific differences in age at diagnosis were not significant. A comparison of the six mutations in the relative proportions of cases of breast and ovarian cancer was suggestive of an effect (P = .069), with 57% of women presumed affected because of the 1294 del 40 BRCA1 mutation having ovarian cancer, compared with 14% of affected women with the splice-site mutation in intron 5 of BRCA1. For the BRCA1 mutations studied here, the individual mutations are estimated to have arisen 9-170 generations ago. In general, a high degree of haplotype conservation across the region was observed, with haplotype differences most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. For several of the instances, there was evidence for multiple, independent, BRCA1 mutational events.

Alleles↗
PubMed1996

[Analysis of the RET gene and medullary cancer of the thyroid. Contribution to the diagnosis and treatment].

MTC occurs sporadically or as part of multiple endocrine neoplasia type 2 (MEN 2) syndromes or as familial MTC (FMTC). 97% of the patients affected with MEN 2B show a germline mutation in codon 918 (exon 16) within the tyrosine kinase domain of the RET protooncogene. In 97% of MEN 2A patients, the germline mutation affects one of five cysteine codons within exons 10 and 11 in the extracellular domain. Only 65% of FMTC patients are found to have a germline mutation of RET. These mutations affect either the cysteine rich domain (as MEN 2A mutations) or codons 768 (exon 13) or 804 (exon 14) within the tyrosine kinase domain. In families affected with hereditary form of MTC, mutation analysis is now commonly used to determine genetic status. Individuals without the mutation would be considered unaffected and would not require further biochemical screening. Individuals who inherit the MEN 2 mutation would undergo biochemical screening tests and have thyroidectomy as soon as these tests are abnormal. Risk of phaeochromocytoma in affected patients depends on the position of RET mutation. This risk is high if the patient has a codon 634 mutation and low if he has a mutation within exon 10, 13 or 14. Frequency of adrenal follow-up could so be adapted with regards to the localisation of RET germline mutation. When a new MTC case is diagnosed, the distinction between a true sporadic and a de novo hereditary case is important for future clinical management of both the patient and his family. The absence of RET exons 10, 11, 13, and 14 germline mutations appears to rule out MEN 2A to a high probability. However the presence of a familial form of MTC cannot be excluded conclusively. Since codon 918 somatic mutations are found in 25% of MTC from truly sporadic cases, mutation analysis of RET in tumour DNA may help in distinguishing the sporadic cases from those that are in fact heritable.

Carcinoma, Medullary↗
PubMed1996

[Neural crest and multiple endocrinopathies].

Multiple endocrine neoplasia type 2 (MEN 2) is a cancer syndrome which comprises three related disorders, MEN type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC), MEN 2A is characterized by the association of MTC, a tumour arising from thyroid C-cells, pheochromocytoma and parathyroid hyperplasia. In addition to the thyroid cancer, MEN 2B associates pheochromocytoma, mucosal neuromas, ganglioneuromatosis of the digestive tract and skeletal abnormalities. In FMTC, the MTC is the sole clinical manifestation. MEN 2 is a dominantly inherited neural crest disorder caused by germline mutations of the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase, which displays a cadherin-like domain and a cysteine rich motif in its extracellular part. Missense mutations at one of five cysteines clustered in the extra-cytoplasmic domain of RET have been identified in the majority of the MEN 2A families and in two-thirds of FMTC. A single point mutation leading to the replacement of a methionine by a threonine within the tyrosine kinase domain has been detected in almost all cases of MEN 2B. We have screened 170 french MEN 2 families and a germline mutations in the RET gene have been identified in 92% of cases. Moreover, we confirmed the significant correlation between the nature, the position of the RET mutations and the clinical phenotype. The accurate identification by DNA testing of individual predisposed to MEN 2 suggests new protocols of treatment. Thyroidectomy as early as 6 years of age in individuals with MEN 2 mutations has been recently advocated by clinicians. We further provide evidence that MEN 2A and MEN 2B mutations convert the RET proto-oncogene in a dominantly-acting transforming gene due to the ligand-independent constitutive activation of the tyrosine kinase. Finally, we have constructed transgenic mice carrying the RET gene carrying a MEN 2A mutation fused to the calcitonin gene related peptide/calcitonin promoter. Animals of three independent transgenic lines developed C-cell hyperplasia and subsequently MTC with a complete penetrance. Taken together, these findings indicate that MEN 2A form of RET is oncogenic in thyroid C-cells, and suggest that these transgenic animals should prove a valuable model for hereditary MTC. Future work should yield insights in the signaling pathways subverted by the RET-MEN 2 proteins.

Animals↗
PubMed1995

Risk modifiers in carriers of BRCA1 mutations.

The majority of, but not all, women with mutations in the BRCA1 gene will be affected with breast or ovarian cancer by the age of 70. To establish whether known risk factors modify susceptibility to cancer in these women, we have studied the reproductive histories of 333 North American women who were found by haplotype analysis to carry BRCA1 mutations. An increased risk for breast cancer was associated with low parity and with recent birth cohort. The risk of ovarian cancer decreased with increasing age at last childbirth; however, in contrast to the case for sporadic cancer, the risk of ovarian cancer in BRCA1 carriers was found to increase significantly with increasing parity.

Adult↗
PubMed1995

Mutations clustered in exon 5 of the p53 gene in primary nasopharyngeal carcinomas from southeastern Asia.

Mutations in the p53 tumor suppressor gene play an important role in the development of many common human malignancies. In nasopharyngeal carcinomas (NPC), p53 gene mutations were not detected in primary tumors, with one exception for a primary tumor displaying a p53 mutation at codon 280, whereas p53 mutations were identified in some metastatic and nude mouse-passaged NPC specimens. In the present report, 41 NPC primary tumors of the undifferentiated carcinoma nasopharyngeal type (UCNT; 21 from Hong Kong and 20 from Guangxi, southeastern China) were studied. Four point mutations that result in amino acid substitutions were identified by PCR amplification of exons 2-9 and direct DNA sequencing, combined with PCR-single-strand conformation polymorphism analysis. The 4 mutations detected were clustered within the DNA stretch from codon 175 to 177. Our data, taken together with those of others, suggest that mutation in p53 may occur in NPC at various points during tumorigenesis. Alternative mechanisms of p53 inactivation in NPC are also possible.

Animals↗
PubMed1995

Screening for germ-line mutations in the NF2 gene.

Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease that predisposes to the development of tumors of the nervous system, particularly meningiomas and schwannomas. The gene which, when altered, causes NF2, is localized on chromosome 22 and has recently been identified. The NF2 gene is also the site of somatic mutation in tumors, suggesting that it might have a tumor suppressor activity. We here report a screening method for the detection of point mutations in NF2 which takes advantage of denaturing gradient gel electrophoresis (DGGE). This method efficiently screens 95% of the coding sequence and 90% of intron/exon junctions. When applied to 91 unrelated NF2 patients, it enabled the identification of 32 germ-line mutations. Since mutations are found in only one third of the patients, it is expected that mutations or deletions affecting the promoter and/or intronic regions of the NF2 gene occur frequently. The characterized mutations are preferentially located within the 5' half of the gene. Most of them are predicted to lead to the synthesis of a truncated protein. A search for genotype/phenotype correlations showed that, at least in this series of patients, mild manifestations of the disease were associated with mutations which preserve the C-terminal end of the protein.

Base Sequence↗
PubMed1995

Detection of a germline mutation at codon 918 of the RET proto-oncogene in French MEN 2B families.

Multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC) are three dominantly inherited disorders linked to the same disease locus on chromosome 10. Two types of germline mutation of the RET proto-onco-gene, which codes for a transmembrane tyrosine kinase, are associated with MEN 2. Missense mutations at cysteine residues in the extra-cytoplasmic domain are exclusively associated with MEN 2A and FMTC. In MEN 2B patients, a single point mutation at codon 918 has recently been characterized, leading to the replacement of a methionine by a threonine within the RET tyrosine kinase domain. We now report the identification of a mutation at codon 918 in the germline of 16 patients out of 18 unrelated MEN 2B families analyzed. In these families we have been able to demonstrate that, in five cases, the mutation arose de novo, and that, in one kindred, it was coinherited with the disease. These results indicate that a unique mutation at codon 918 of the RET gene is the most prevalent genetic defect causing MEN 2B, but also that rare MEN 2B cases are associated with different mutations yet to be defined.

Adolescent↗
PubMed1995

Correlation between activity of beta-lactam agents in vitro and bacteriological outcome in acute pulmonary exacerbations of cystic fibrosis.

A study was conducted to determine whether a direct relationship exists between beta-lactam and/or aminoglycoside activity measured in vitro and bacteriological outcome in acute pulmonary exacerbations of cystic fibrosis. Twenty-seven patients, aged between 6 months and 24 years (mean age 10 1/2 years), were included in the study and received 41 i.v. courses of a beta-lactam agent combined with an aminoglycoside. A total of 63 Pseudomonas aeruginosa strains were found in sputum taken on admission at densities exceeding 10(6) cfu/g of sputum. For each episode, the serum inhibitory quotient (SIQ) and the serum bactericidal quotient (SBQ) of the beta-lactam agent and of the aminoglycoside administered were determined for the Pseudomonas aeruginosa isolate(s). The SIQs and SBQs were calculated by dividing the average peak serum levels achievable in the patients by the minimal inhibitory concentrations and minimal bactericidal concentrations, respectively. The SIQs and SBQs were compared to bacteriological outcome. Bacteriological success was defined as a decrease of 2 log10 counts or more in the Pseudomonas aeruginosa density in sputum between days 0 and 7 of therapy. The SIQ and SBQ of beta-lactam agents were good predictors of bacteriological outcome: SIQs of < 1:16 were 100% predictive of failure (chi 2 28; p < 0.001) and of > or = 1:64 were 92.9% predictive of success (chi 2 35.68; p < 0.001); SBQs of < 1:8 were 100% predictive of failure (chi 2 42.78; p < 0.001) and of > or = 1:32 were 95.8% predictive of success (chi 2 31.5; p < 0.001). Aminoglycoside SIQs and SBQs were not predictive of outcome.

Adolescent↗
PubMed1995

Multiple endocrine neoplasia type 1 in France: clinical and genetic studies.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by the involvement of several endocrine glands, including the parathyroid glands, the pancreatic islet cells, the anterior pituitary gland and other neuroendocrine tissues. In order to build up a French MEN1 register, a collaborative network was developed through the 'Groupe d'Etude des Néoplasies Endocriniennes Multiples de type 1' or GENEM 1. A 2-year follow-up in 40 medical and surgical units allowed the identification of more than 150 individual patients and 45 MEN1 families, and defined the major clinical features of the disease in our series. Multiple endocrine neoplasia type 1 is inherited as an autosomal dominant trait. The gene causing this syndrome has been localized to chromosome 11, band 11q13, and molecular genetic markers flanking the MEN1 locus are of use in identifying disease gene carriers in predisposed families. Selected data were presented in order to discuss the management of patients by combined clinical, biochemical and genetic screening. The set-up of a national register by a multi-disciplinary and collaborative medical and surgical network will facilitate further research on the clinical management of MEN1 patients and the basic physio-pathology of the disease.

Adolescent↗
PubMed1995

In vivo correlates for Streptococcus pneumoniae penicillin resistance in acute otitis media.

Eighty-four children suffering from acute otitis media caused by Streptococcus pneumoniae were treated prospectively with cefuroxime axetil suspension (30 mg/kg of body weight twice daily for 8 days). The high incidence of isolates with decreased susceptibilities to penicillin (42 of 84 isolates) allowed us to establish a relationship between clinical success and the penicillin MICs for pneumococcal isolates. It was found that cefuroxime axetil is clinically effective in the treatment of acute otitis media caused by penicillin-susceptible and penicillin-intermediate strains of S. pneumoniae. The results indicate that the risk of treatment failure with cefuroxime axetil was increased in children with otitis media caused by S. pneumoniae when the penicillin MIC were greater than or equal to 2 mg/liter.

Acute Disease↗
PubMed1995

Familial acromegaly: a specific clinical entity--further evidence from the genetic study of a three-generation family.

Familial acromegaly is a very rare inherited disorder, characterized by the clustering within a single family of several related cases with somatotroph adenomas and acromegaly. The causes of these dominantly inherited pituitary tumours remain unknown. Although these families have a clinical presentation distinct from that of multiple endocrine neoplasia type 1 (MEN-1), the question of this syndrome as being linked to the MEN-1 locus has remained open. Our aim was to study a three-generation family with cases of acromegaly in a mother and her son, to explore better the clinical presentation of the disease, its pattern of inheritance and to test the hypothesis of a genetic linkage to the MEN-1 locus using closely linked polymorphic genetic markers. The refined analysis of 15 unaffected relatives revealed miscellaneous non-specific endocrine dysfunctions and the presence of multiple lipomata, as noted previously in some cases. Moreover, the notion of acromegalo-gigantism in the maternal grandmother and an incomplete penetrance appeared even more typical, suggesting that familial acromegaly is a specific clinical entity. Finally, under the hypotheses assumed for segregation analysis, no clinical, biological or genetic evidence of linkage to the MEN-1 locus could be retained in this family. However, these conclusions were limited because of incomplete penetrance and uncertain definition of the carrier status. Therefore, we conclude that further identification of the genetic predisposition to familial acromegaly might be obtained from the combined molecular genetic analysis of several families presenting with the same clinical features.

Acromegaly↗
PubMed1995

[Pseudomonas aeruginosa and mucoviscidosis].

Pseudomonas aeruginosa causes episodes of infection which always have a deteriorating effect on the clinical course of cystic fibrosis. The factors and mechanisms involved were discussed on the basis of data in the literature and the experience at the Necker-Enfants-Malades hospital. Preventive measures and indications and modalities for treatment are also presented.

Anti-Bacterial Agents↗