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Biomedical subjects

G Lenoir

Publications and source records attributed to G Lenoir.

At least 37 records · Page 2Linked to original sources
PubMed2000

French multicenter randomized double-blind placebo-controlled trial on nebulized amiloride in cystic fibrosis patients. The Amiloride-AFLM Collaborative Study Group.

The effect of amiloride, a sodium channel blocker, has been evaluated in a multicenter randomized double-blind placebo-controlled trial in cystic fibrosis patients more than 5-years-old (n = 137) whose forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV(1)), and forced mid-expiratory flow (FEF(25-75)) were not below 50%, 50%, and 30% of reference values, respectively. Patients were randomly allocated to two parallel groups. Sixty-four patients were chronically colonized with Pseudomonas aeruginosa; they received either amiloride or placebo as a nebulized solution three times daily for 6 months. Routine treatments were continued. Patients chronically colonized with Pseudomonas received nebulized colimycine twice a day for a month during the third and sixth months of treatment. Bronchopulmonary exacerbations were treated in the usual way. The effects of the amiloride treatment were assessed at the end of the 6-month treatment period. The effects on FVC and secondarily on FEV(1), FEF(25-75), the number of days on antibiotic therapy, the Shwachman score, a nutritional index (weight/height(2)), the change in sputum bacterial flora, and nocturnal cough were assessed. For the patients not chronically colonized with Pseudomonas, the effect of the treatment was also evaluated by counting chronic colonizations with pathogens appearing during the trial period. The present study failed to demonstrate any significant benefit of amiloride over placebo on FVC, FEV(1), and the other secondary endpoints in the studied population. Neither the chronically colonized, nor the noncolonized patients benefited. The confidence intervals of the differences between treatment groups indicated small differences that were most likely of no clinical significance. Complementary analyses taking into account the gender, the type of mutation, the subpopulations whose FVC and FEV(1) were below 80% of normal values at the beginning of the study, and also patients less than 10 years old, did not show any statistically or clinically significant improvements following amiloride therapy.

Administration, Inhalation↗
PubMed2000

[Antibiotic therapy in cystic fibrosis. II Antibiotic strategy].

Antibiotherapy is one of the main treatments of cystic fibrosis, contributing to a better nutritional and respiratory status and a prolonged survival. The choice of antibiotics depends on quantitative and qualitative analysis of sputum, bacteria resistance phenotypes and severity of infection. Haemophilus influenzae infection can be treated orally with the association of amoxicillin-clavulanic acid or a cephalosporin. Staphylococcus aureus generally remains sensitive to usual antibiotics; in case of a methicillin-resistant strain, an oral bitherapy or a parenteral cure can be proposed. Treatment of Pseudomonas aeruginosa is different in case of first colonization or chronic infection: in first colonization, parenteral antibiotherapy (beta-lactams-aminoglycosids) followed by inhaled antibiotherapy may eradicate the bacteria; in chronic infections, exacerbations require parenteral bi-antibiotherapy (beta-lactams or quinolons and aminoglycosids) for 15 to 21 days, inhaled antibiotics between the cures being useful to decrease the number of exacerbation. A careful monitoring of antibiotherapy is necessary because of possible induction of bacterial resistance, nephrotoxicity and ototoxicity of aminosids and allergy to beta-lactams.

Anti-Bacterial Agents↗
PubMed2000

[Antibiotic therapy in cystic fibrosis. I. Pharmacologic specifics of antibiotics].

Antibiotherapy is one of the main treatment in cystic fibrosis. Antibiotic administration schedules are different from normal patients because of pharmacokinetic and pharmacodynamic particularities. In moderate disease, the digestive resorption of antibiotics is delayed and their half-life is reduced due to an increase in total clearance. In severe disease, the volume of distribution of antibiotics is increased due to the higher proportion of lean mass in these malnourished patients. Other particularities limit the action of antibiotics such as thick sputum, which limits drug penetration; the property of Pseudomonas aeruginosa to be surrounded by a biofilm; alteration of local antibacterial defense; and inhibition of antibiotics by local factors. Systematic prescription of a biotherapy beta-lactam-aminoglycoside and obtaining high antibiotic concentration in situ might limit this antagonism. In spite of particular therapeutic schedules such as single daily dose for aminoglycoside and continuous infusion for beta-lactams, the intervals between administrations must be narrowed for time-dependent antibiotics, and the total daily dose increased by 20 to 30% for concentration-dependent antibiotics.

Absorption↗
PubMed2000

Characterization of inflammatory reaction in upper airways of cystic fibrosis patients.

Inflammatory cell populations have not been yet precisely evaluated in cystic fibrosis (CF) airways. We intended to characterize morphological modifications, inflammatory cell infiltration and cell proliferation in nasal tissues obtained from 15 CF patients and from 6 non-CF patients with nasal polyposis. Morphological analysis showed an intense inflammatory infiltration in CF and non-CF tissues with only few modifications in the epithelium from CF tissues. Inflammatory cell populations characterized by specific immunolabeling were quantified, showing a predominance of macrophages and T- and B-lymphocytes and only moderate numbers of neutrophils in CF tissues; in non-CF polyps, lymphocytes and eosinophils were abundant. Proliferating cell percentages quantified after proliferating cell nuclear antigen immunolabeling were 5.3+/-4.1% (mean +/- SD) in CF polyps and 3.1+/-1.2% in non-CF polyps in epithelium but were very low in lamina propria. Intense inflammation in nasal tissues from CF patients is therefore dominated by macrophages and lymphocytes rather than by neutrophils. While morphology is preserved, proliferation is high in epithelium from CF polyps. These findings should be regarded in the future for a better understanding of inflammation in CF airway disease.

Adolescent↗
PubMed2000

Localization of the gene for fibrodysplasia ossificans progressiva (FOP) to chromosome 17q21-22.

Fibrodysplasia ossificans progressiva (FOP) is a very rare disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of muscles. To identify the chromosomal localization of the FOP gene, we conducted a genomewide linkage analysis using seven affected families. The FOP phenotype is linked to markers located in the 17q21-22 region (LOD score of 3.41 at the recombination fraction theta = 0). Crossover events localize the putative FOP gene within a 12cM interval, bordered proximally by D17S809 and distally by D17S1838. Noggin (NOG) gene, located in 17q22, is an excellent candidate gene for FOP.

Chromosome Mapping↗
PubMed1999

Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2.

There is now evidence to suggest that BRCA1 and BRCA2 are involved in the response of cells to DNA damage and cell cycle checkpoint control. This report examines the death pathways of human cells with various BRCA1 and BRCA2 genotypes after exposure to gamma-rays. A lack of functional BRCA1 and BRCA2 led to defective repair of DNA double-strand breaks in irradiated cells. This impairment resulted in a relaxation of cell cycle checkpoints, production of micronuclei, and a loss of proliferative capacity. Heterozygous BRCA1 and BRCA2 mutations also led to enhanced radiosensitivity, with an impaired proliferative capacity after irradiation. The existence of a phenotype related to radiosensitivity in BRCA1+/- and BRCA2+/- cells raises the question of the response of heterozygous women to radiation.

BRCA1 Protein↗
PubMed1999

Cryptic exons as a source of increased diversity of Ewing tumor-associated EWS-FLI1 chimeric products.

In the Ewing family of tumors (EFT), the EWS gene is rearranged with members of the ets oncogene family. Variability in genomic breakpoint locations is the source of significant heterogeneity in fusion product structure. As a consequence of variably included exon sequences from the two partner genes, a variable amount of additional peptide sequence is inserted in between the minimal transforming domains. Some of this molecular diversity has recently been correlated with disparate clinical outcome. Here we report on cryptic exons found in the chimeric RNA of three EFT with different EWS-FLI1 fusions. In two tumors, the emergence of a cryptic exon from FLI1 intron 5 in the chimeric RNA was apparently unrelated to the genomic rearrangement that occurred in FLI1 introns 4 and 5, respectively. In one case, a novel exon was generated through the creation of an artificial splice acceptor site in FLI1 intron 6 by the genomic rearrangement that occurred in EWS intron 8. These results further extend the spectrum of molecular diversity in EFT.

Adolescent↗
PubMed1999

Characterisation of 16 polymorphic markers in the NF2 gene: application to hemizygosity detection.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder that predisposes to nervous system tumors. Point mutations are evidenced in about 50% of the NF2 patients and large genomic deletions account for approximately 33% of the NF2 gene alterations. To facilitate the deletion screening, 16 polymorphic markers were identified in the NF2 genomic sequence enabling an hemizygosity test in familial studies.

DNA Primers↗
PubMed1999

Rapid improvement of intracranial tuberculomas after addition of ofloxacin to first-line antituberculosis treatment.

Reported here is the case of a 9-year-old girl presenting with disseminated tuberculosis, the manifestations of which included mediastinal adenopathy, an osteolytic parietal lesion with a large associated scalp abscess, cerebral empyema, meningoencephalitis, and tuberculomas. No clear improvement was observed after 4 weeks of first-line antituberculosis treatment (10 mg/kg rifampin, 15 mg/kg isoniazid, 30 mg/kg ethambutol, 30 mg/kg pyrazinamide). The isolation of an isoniazid-resistant organism prompted institution of ofloxacin. Introduction of this drug was associated with dramatic improvement. Its good penetration into the central nervous system and its distribution into macrophages suggest that this drug may be of interest for the treatment of intracranial tuberculomas, particularly those due to isoniazid-resistant strains.

Anti-Infective Agents↗
PubMed1999

An update on DNA-based BRCA1/BRCA2 genetic counseling in hereditary breast cancer.

The identification of BRCA1 and BRCA2 mutations has enabled physicians to identify persons at high risk for carcinoma of the breast and ovary in hereditary breast-ovarian cancer (HBOC) families. Many physicians have limited knowledge about the effective translation of these new discoveries into clinical practice settings. This problem is further confounded by the limited number of genetic counselors who have experience with cancer genetics. Genetic counseling about DNA test results was provided to 420 patients from 37 HBC/HBOC families. Descriptive data were collected and recorded about their responses to questions posed immediately before and after test results were disclosed. Findings disclosed a significant tendency of patients to overestimate rather than underestimate their risk (P < .001) prior to receiving results. The chief reason for declining to receive results was fear of insurance discrimination. The primary reason that patients sought test results was for their children. Most women reported that, if testing identified them as mutation carriers, they would consider lifetime surveillance and prophylactic surgery. Responses to DNA test results were varied and often unpredictable. Counseling by an appropriately educated and skilled professional is essential to assist people in making decisions regarding testing and health management.

Adult↗
PubMed1999

Inflammation and CFTR: might neutrophils be the key in cystic fibrosis?

The aim of this hypothesis is to provide new insights into the still unclear mechanisms governing airway inflammation in cystic fibrosis. Although the genetic basis of cystic fibrosis as well as the molecular structure of cystic fibrosis transmembrane regulator (CFTR), the mutated protein which causes the disease, have been well defined, a clear relationship between the genetic defect and the pulmonary pathophysiology, especially chronic infections and neutrophil-dominated airway inflammation has not been established. Cystic fibrosis is thus a unique pathological situation in that neutrophils can be depicted as both an antiinfectious and a proinflammatory cell. In cystic fibrosis there is an emerging picture of an imbalance between these two roles with both a reduction in the antiinfectious efficacy and an augmentation of the proinflammatory functions. Better knowledge of fundamental defects in neutrophil function in cystic fibrosis as well as a novel cellular function of CFTR, which will be reviewed, will allow identification of potentially new clinical targets and aid selective therapeutic action aimed at counteracting the lethal neutrophil-induced airway inflammation. The rationale for colchicine therapy is a significant example of a drug which might act both at the molecular levels on CFTR expression in epithelial cells and on neutrophils to mediate antiinflammatory effects. Preliminary results are presented in this issue (Med Inflamm 1999; 8: 13-15).

Anti-Inflammatory Agents↗
PubMed1999

Interest of colchicine for the treatment of cystic fibrosis patients. Preliminary report.

Cystic fibrosis (CF) lung disease is characterized by persistent inflammation. Antiinflammatory drugs, such as corticosteroids and ibuprofen, have proved to slow the decline of pulmonary function although their use is limited because of frequent adverse events. We hypothesized that colchicine could be an alternative treatment because of its antiinflammatory properties and upregulatory effect on cystic fibrosis transmembrane regulator (CFTR) closely related proteins. We herein present results obtained in an open study of eight CF children treated with colchicine for at least 6 months. Clinical status was better in all patients and respiratory function tests significantly improved in five. Median duration of antibiotherapy decreased significantly. These preliminary results support our hypothesis of a beneficial effect of colchicine in CF patients and stress the need for a controlled therapeutic trial.

Adolescent↗
PubMed1999

Priming of blood neutrophils in children with cystic fibrosis: correlation between functional and phenotypic expression of opsonin receptors before and after platelet-activating factor priming.

Blood phagocyte opsonin receptor CR1 (CD35) and CR3 (CD11b) functions were examined in cystic fibrosis (CF) patients with endobronchial Staphylococcus aureus or Pseudomonas aeruginosa chronic infection, CF patients without infection, heterozygous, non-CF patients with chronic pulmonary infection, and healthy controls. Circulating and platelet-activating factor (PAF)-primed phagocyte luminol luminescence responses to complement-opsonized zymosan were increased in both groups of infected CF and non-CF children relative to uninfected CF children and healthy control children and adults. The ratio between circulating and PAF-primed phagocyte responses was significantly elevated in all children with CF, and in these, the ratio could serve as an indicator of response to antibiotic treatment. The ratios of circulating and PAF-primed phenotypic expression for CR1, CR3, and FcgammaRIII (CD16), but not FcgammaRII (CD32), correlated with the functional ratios. Phagocyte opsonin receptor response capacity might be used for evaluation of inflammation and infection in CF patients.

Adolescent↗
PubMed1999

Proteinase 3, a potent secretagogue in airways, is present in cystic fibrosis sputum.

We evaluated the roles of proteinase 3 (PR3) and human neutrophil elastase (HNE), two neutrophil serine proteinases in the mechanisms leading to airway inflammation and hypersecretion in cystic fibrosis (CF). Using specific enzyme-linked immunosorbent assay (ELISA), we found higher levels of PR3 than HNE in sputum from CF patients. Using two inhibitors, ICI (Imperial Chemical Industries) 200,355 (which inhibits both HNE and PR3) and secretory leukoproteinase inhibitor (SLPI) (which inhibits only HNE), we showed that PR3 was enzymatically active in sputum, and its activity, as assessed by SLPI-resistant serine proteinase activity, correlated highly with its antigenic concentration measured by ELISA. Interestingly, sputum pellet-associated serine proteinase activity was mostly due to HNE. PR3 purified from neutrophil azurophil granules triggered airway gland secretion, as measured by the release of radiolabeled molecules from cultured bovine tracheal serous cells pulse-labeled with Na235SO4. This secretory activity was inhibited by ICI 200,355. PR3 concentration in CF sputum was highly correlated with taurine concentration, a reliable marker of airway inflammation and respiratory scores (e.g., FEV1%), whereas no significant correlation was observed with HNE. We verified that Pseudomonas aeruginosa proteinases did not interfere with the assessment of PR3 and HNE. Indeed, the PR3/HNE ratio was greatest in patients chronically infected by P. aeruginosa. We suggest that PR3 may play a role in the hypersecretory process that is characteristic of CF.

Adolescent↗