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Biomedical subjects

D Hubert

Publications and source records attributed to D Hubert.

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

High susceptibility for cystic fibrosis human airway gland cells to produce IL-8 through the I kappa B kinase alpha pathway in response to extracellular NaCl content.

Increasing evidence suggests that in airways from cystic fibrosis (CF) patients, inflammation may precede bacterial infection and be related to an endogenous dysregulation of proinflammatory cytokines in airway epithelial cells. Several investigators have reported that, in CF airway fluids, elevated NaCl concentrations may also contribute to the diseased state by inhibiting the bactericidal properties of airway fluid. Because many proinflammatory cytokines are transcriptionally regulated by the NF-kappa B, we investigated whether an elevated extracellular NaCl content in airway fluids significantly impaired the regulation of the NF-kappa B/I kappa B alpha complex and the chemokine IL-8 production in primary non-CF and CF human bronchial gland epithelial cells. Exposure of non-CF gland cells to hypotonic (85 mM) NaCl solution, compared with isotonic (115 mM) NaCl and hypertonic (170 mM) NaCl solutions, resulted in a significant decrease in IL-8 production that was paralleled by a strong inhibition of activated NF-kappa B associated with an increased cytosolic expression of I kappa B alpha and a decrease in the I kappa B kinase alpha protein level. In CF gland cells, we demonstrated that, compared with the high IL-8 in an hypertonic solution, the release of IL-8 was significantly reduced 2-fold in an isotonic solution and 5-fold in a hypotonic solution. Strikingly, exposure of CF bronchial gland cells to either hypotonic or isotonic milieu did not result in a marked inhibition of the activated NF-kappa B/I kappa B alpha system. This is the first demonstration that primary human CF bronchial gland cells exhibit abnormally high IL-8 production through constitutively activated NF-kappa B and high I kappa B kinase alpha level, whatever the hypo-, iso-, and hypertonic NaCl milieu.

Adolescent↗
PubMed2000

[Characteristics and specificities of cystic fibrosis in adults: evolutive disease of childhood or recently diagnosed disease?].

We have studied the characteristics of 202 cystic fibrosis adult patients, all with chronic respiratory symptoms, with a median age of 27 yrs (18 to 55 yrs) and a male predominance (56%). At genetic analysis, delta F508 homozygotes were 41%, delta F508 heterozygotes 42% and 17% had no delta F508. The respiratory disease was more severe and complications were more frequent in adults: hemoptysis in 14%, pneumothorax in 15%, lung transplantation in 25 patients. Chronic bronchial colonisation with Pseudomonas aeruginosa, in 76% of patients, contributed to making treatments more severe because of antibiotic i.v. courses and nebulised antibiotics. Respiratory function showed a mean FVC of 62 +/- 22% and a mean FEVI of 48 +/- 94%. External pancreatic insufficiency was found in 83%, diabetes in 14%. Intestinal occlusion syndromes were observed in 11% of patients and hepatic cirrhosis in 8%. In spite of the severity of the respiratory disease, theses patients succeeded in social and occupational insertion; 62% were independent, 18% had children and 77% were working or studying. Analysis of the patients according to age at diagnosis showed that, in 38 patients diagnosed after the age of 18 yrs, the respiratory disease was less severe, pancreatic insufficiency and non-respiratory complications were less frequent (34% had pancreatic insufficiency, 5% had diabetes and none had cirrhosis). This may partly be due to the presence of milder CFTR mutations. In conclusion, cystic fibrosis in adulthood frequently looks like an evolutive form of cystic fibrosis in childhood. Nevertheless, some late diagnosed forms in adults, with better prognosis, have been recently identified.

Adolescent↗
PubMed2000

[Specific aspects and care of lung involvement in adults with cystic fibrosis].

Respiratory impairment is present in almost all adult cystic fibrosis patients and makes the prognosis. Viscous, infected and abundant secretions, inflammation and bronchial oedema, bronchoconstriction and respiratory muscle fatigue lead to airway obstruction, bronchiectasis and respiratory failure. The disease is preferentially located in the upper lobes. Exacerbations of the disease are due to bronchial infections and are often responsible for drops of the respiratory function. Regular spirometric surveillance is fundamental for the prognosis and the assessment of the effects of the treatment. Among adult patients chronic colonisation with mucoid and often multiresistant strains of Pseudomonas Aeruginosa are common. It is treated with i.v. high doses antibiotic courses and nebulized antibiotics between i.v. courses. Respiratory failure may require long term oxygen and non invasive mechanical ventilation. Systemic hypervascularization around the bronchiectasis may lead to moderate to severe hemoptysis, which may require embolization. Pneumothorax are associated with poor prognosis and are treated by pleural drainage and if failure by thoracoscopy.

Adrenal Cortex Hormones↗
PubMed1999

Genistein inhibits constitutive and inducible NFkappaB activation and decreases IL-8 production by human cystic fibrosis bronchial gland cells.

The inflammatory pathogenesis in airways of patients with cystic fibrosis (CF) is still unresolved. We demonstrate here that in in situ human DeltaF508 homozygous CF bronchial tissues, submucosal gland cells exhibit an absence of inhibitor factor kappaBalpha (IkappaBalpha) and high levels of chemokine interleukin-8 (IL-8) expression. These results were confirmed by cultured human CF bronchial gland cells in which a lack of cytosolic IkappaBalpha and high levels of constitutively activated nuclear factor kappaB (NFkappaB) associated with an up-regulation of IL-8 production (13-fold increase) were found when compared to non-CF (control) disease bronchial gland cells. We also demonstrated that the isoflavone genistein, a well known CFTR mutant Cl(-) channel stimulator, significantly reduces the endogenous and Pseudomonas aeruginosa lipopolysaccharide-induced IL-8 production in cultured CF bronchial gland cells by increasing cytosolic IkappaBalpha protein levels. Overall, results show that genistein is a potent inhibitor of the activated NFkappaB identified in CF gland cells. This strong inhibition of constitutively activated NFkappaB and the resulting down-regulation of IL-8 production by genistein in the CF gland cells highlights the key role played by cytosolic IkappaBalpha in the regulation of inflammatory processes in CF human airway cells.

Adolescent↗
PubMed1999

HLA class II polymorphism in cystic fibrosis. A possible modifier of pulmonary phenotype.

Evolution of lung damage is highly variable in cystic fibrosis (CF) even in patients with the same cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The analysis of genetic factors other than CFTR may help our understanding of genotype-phenotype relationships in CF. As human leukocyte antigen (HLA) class II polymorphism has been associated with a number of diseases including autoimmune and inflammatory diseases, asthma, and allergy, we investigated the possibility that HLA polymorphism contributes to CF-associated pulmonary inflammation. Among the 98 adult CF patients tested, the genotypic frequencies of DR4 and DR7 alleles (serologic group DR53) and DR7/ DQA*0201 haplotype were higher than in 39 selected control subjects without atopy (p </= 10(-)6, relative risk [RR] = 22, and p </= 5.10(-)4, RR = 27, respectively) and in a random population. No significant difference of these allelic distributions was found according to the CFTR genotype. In the CF patients, the DR7 allele was significantly associated with an increase in total IgE and with chronic Pseudomonas aeruginosa colonization (100% of DR7 versus 83% of non-DR7 patients being colonized, p < 0.05). Our results suggest that genetic factors known to modulate the immune response might contribute to chronic infection with Pseudomonas, increased total IgE, and pulmonary outcome in CF.

Adult↗
PubMed1999

Increased frequency of cystic fibrosis deltaF508 mutation in bronchiectasis associated with rheumatoid arthritis.

This study investigated the clinical characteristics and the possible involvement of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients with symptomatic diffuse bronchiectasis (DB) associated with rheumatoid arthritis (RA). Twenty-six patients with both RA and DB (group RA+DB) and control groups of 29 consecutive patients with RA but no bronchiectasis (group RA) and 29 patients with symptomatic DB of unknown origin (group DB) were prospectively studied. Among the patients of the RA+DB group, four (15.4%) were heterozygous for the CFTR gene deltaF508 mutation, whereas no deltaF508 mutation was found in patients of the RA and the DB groups (both, p<0.05). This frequency of deltaF508 mutation was also higher than the expected frequency (2.8%) in the general European population (p<0.04). Sweat chloride values and nasal potential differences were normal in three out of four patients carrying the deltaF508 mutation. In the RA+DB group, those with deltaF508 mutation had more frequent chronic sinusitis (p<0.05), a trend toward a more severe pulmonary involvement, and a lower value of nasal potential differences (p<0.01) whereas their rheumatic features had no particularity. In the RA+DB group, patients with adult-onset bronchiectasis (including two with deltaF508 mutation) had a greater reduction in total lung capacity (p<0.05) and lower nasal potential differences (p<0.005) than those with childhood-onset bronchiectasis. This study suggests a possible deleterious effect of the cystic fibrosis transmembrane conductance regulator mutated protein in the airways which may predispose to the development and severity of bronchiectasis in patients suffering from rheumatoid arthritis.

Adult↗
PubMed1998

Relationships between nasal potential difference and respiratory function in adults with cystic fibrosis.

This study investigated the relations between nasal transepithelial electric potential difference (PD) and the phenotype and genotype of cystic fibrosis (CF) adult patients. Basal nasal PD was measured in 95 adult CF patients who were classified into three groups of nasal PD (expressed as absolute values) according to the 10th and the 90th percentiles (28.3 and 49.2 mV, respectively), which defined group 1 (nasal PD < or =28.3 mV), group 2 (nasal PD 28.3-49.2 mV) and group 3 (nasal PD > or =49.2 mV). Patients from group 1 had a higher forced vital capacity (FVC) than patients from groups 2 and 3 (76.5+/-22.4 versus 57.4+/-21.2 and 55.7+/-21.1% predicted, respectively, p<0.05) and a higher forced expiratory volume in one second (FEV1) (69.3+/-24.0 versus 42.5+/-22.4 and 42.2+/-21.4% pred, respectively, p<0.01). Among patients with severe mutations (deltaF508 homozygotes, or one deltaF508 mutation plus another "severe" mutation, or two "severe" mutations), patients from group 1 had a higher FVC, FEV1 and arterial oxygen tension than patients from groups 2 and 3 (p<0.05 for each comparison). The results show that in adult cystic fibrosis patients a normal basal nasal potential difference is related to milder respiratory disease, irrespective of the severity of the genotype.

Adolescent↗
PubMed1998

A novel missense mutation D513G in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified in a French CBAVD patient. Mutations in brief no. 175. Online.

Congenital bilateal absence of the vas deferens (CBAVD) with obstructive azoospermia is a congenital reproductive disorder that affects one in 10000 male individuals. The observation that many men presenting with CBAVD have mutations in their CFTR genes had led to the proposal that CBAVD may be a primary genital form of cystic fibrosis. We report here one novel mutation located in exon 10 of the CFTR gene. This mutation, named D513G (A-->G at position 1670), has been found in one of 83 patients with CBAVD from France, the analysis of exon 10 using a chemical clamp DGGE assay allowed us to identify three CF mutations AEF508 (37/166; 22%), AE1507 (1/166; 0/6%) and D513G (1/166; 0.6%), and two variants M470V and E528E (1716 G>A). The novel D513G mutation has not been found in more than 200 non-CF chromosomes and in a sample of 300 CF chromosomes from French classical CF patients.

Animals↗
PubMed1997

Molecular diagnosis of congenital bilateral absence of the vas deferens: analyses of the CFTR gene in 64 French patients.

Congenital bilateral absence of the vas deferens is a congenital reproductive disorder that affects about one in 1000 male individuals. Screening of the entire coding and flanking sequences of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 64 males with CBAVD revealed that in only 23% CBAVD was caused by two CFTR mutations. The 5T allele in one copy, that causes reduced levels of the normal CFTR protein, in combination with a CFTR mutation in the other copy, was one of the most common causes of CBAVD. Twenty six per cent of men with CBAVD had the 5T allele. The presence of only one CFTR mutation or the 5T allele in 34% of patients suggests that undetected changes in CFTR may be involved in CBAVD. These molecular defects are probably mutations with partial penetrance. Moreover, the high proportion (20%) of patients with CBAVD who did not have CFTR mutations or the 5T allele allows to propose that another gene or genes could be responsible for CBAVD. In these cases, in vitro fertilization may be required and the genetic counselling appears to be very complex and additional studies, including CFTR mRNA and linkage analyses, are required to resolve these questions.

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed1996

Analysis of alternative splicing patterns in the cystic fibrosis transmembrane conductance regulator gene using mRNA derived from lymphoblastoid cells of cystic fibrosis patients.

Using in vitro amplification of cDNA by the polymerase chain reaction, we analyzed alternatively spliced events of cystic fibrosis transmembrane conductance regulator gene in lymphoblastoid cells. Ten alternatively spliced transcripts were identified using analysis of 6 overlapping segments of amplified cDNA, 4 of which have not been described previously. These include transcripts lacking exon 16, 17b, 22 and a transcript resulting from the use of a cryptic acceptor and donor splice sites. Moreover, in 2 cystic fibrosis (CF) patients bearing nonsense mutations E60X or W1282X, we observed that nonsense mutations are associated with an alteration of splice site selection in vivo resulting in exon skipping of constitutive exons or in the use of cryptic splice sites. In addition, even though lymphoblastoid cells are not the relevant tissue to address the question of the relationship between clinical respiratory phenotype and genotype, our results concerning adult CF patients (delta F508/ delta F508) suggest that individual-specific RNA splicing patterns could influence the severity of the CF pulmonary disease. If this phenomenon of alternative splicing events proves to be significant in CF and to be a common feature of disease genes, the study of RNA splicing could become an important tool for the analysis of the genotype-phenotype relationship in many inherited disorders.

Adult↗
PubMed1996

Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients.

In cystic fibrosis (CF), relationships between genotype and phenotype have been shown for pancreatic status but not for pulmonary disease. One hundred and ten adult CF patients were classified according to the expected effect of their mutations on cystic fibrosis transmembrane conductance regulator (CFTR) protein: Group 1 (n=48) included deltaF508 homozygotes; Group 2 (n=26), patients with two "severe" mutations and no expected CFTR production; Group 3 (n=17), patients with expected partly functional CFTR corresponding to at least one "mild" mutation; Group 4 (n=19), patients with no mutation identified or only one identified "severe" mutation. As compared to Groups 1 and 2: patients from Groups 3 and 4 had higher arterial oxygen tension (Pa,O2) (9.5+/-1.9 and 9.9+/-1.5 vs 8.8+/-1.5 and 8.3+/-1.7 kPa, respectively p<0.02); and a slower decline in their pulmonary function, estimated by the mean annual loss in forced vital capacity (FVC) (1.2+/-1.0 and 1.5+/-1.1 vs 2.0+/-0.9 and 2.2+/-1.0%, respectively; p<0.01) and in forced expiratory volume in one second (FEV1) (1.7+/-1.1 and 1.9+/-1.3 vs 2.6+/-1.0 and 2.8+/-1.0%, respectively; p<0.005). They had fewer episodes of colonization of the airways by Pseudomonas aeruginosa, and colonization occurred at a more advanced age (median age 25 and 19 vs 15 and 17 yrs, respectively; p<0.01) and required fewer intravenous antibiotic courses (p<0.01). Pancreatic insufficiency was less frequent in Groups 3 (23%) and 4 (63%) than in Groups 1 (100%) and 2 (96%). This study suggests that the phenotype of adult cystic fibrosis patients, including the severity of the lung disease, is related to the severity of the cystic fibrosis transmembrane conductance regulator mutations.

Adolescent↗
PubMed1995

[Is the nuclear center a risk for the population and workers during usual operation?].

Radioactive material is formed in nuclear power plants during normal operation but adequate shielding insulate them from the outside. Population receive very low radiation doses from nuclear plants releases, insignificant in comparison with natural radiation. Epidemiological studies which were conducted in populations living near nuclear power plants have shown excess leukaemia in children in the United Kingdom but were negative in other countries. The hypothesis of a genetic effect of radiation on the leukaemic children's fathers who were working in nuclear plants has been rejected. Nuclear workers receive higher doses than population, but much lower than the regular standards. At the moment, it is not possible to take into account any increase of diseases, especially of specific cancers, in the workers, even if a few isolated increases have been noted. A slight increase in leukemia is possible in workers who have received the highest doses but the margin of uncertainties is large.

Adolescent↗