morphine and Pseudomonas-Infections

The existence of pleiotropy in disorders with multi-organ involvement can suggest therapeutic targets that could ameliorate overall disease severity. Here we assessed pleiotropy of modifier genes in cystic fibrosis (CF). CF, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects the lungs, liver, pancreas and intestines. However, modifier genes contribute to variable disease severity across affected organs, even in individuals with the same CFTR genotype. We sought to determine whether SLC26A9, SLC9A3 and SLC6A14, that contribute to meconium ileus in CF, are pleiotropic for other early-affecting CF co-morbidities. In the Canadian CF population, we assessed evidence for pleiotropic effects on (1) pediatric lung disease severity (n = 815), (2) age at first acquisition of Pseudomonas aeruginosa (P. aeruginosa) (n = 730), and (3) prenatal pancreatic damage measured by immunoreactive trypsinogen (n = 126). A multiple-phenotype analytic strategy assessed evidence for pleiotropy in the presence of phenotypic correlation. We required the same alleles to be associated with detrimental effects. SLC26A9 was pleiotropic for meconium ileus and pancreatic damage (p = 0.002 at rs7512462), SLC9A3 for meconium ileus and lung disease (p = 1.5 × 10(-6) at rs17563161), and SLC6A14 for meconium ileus and both lung disease and age at first P. aeruginosa infection (p = 0.0002 and p = 0.006 at rs3788766, respectively). The meconium ileus risk alleles in SLC26A9, SLC9A3 and SLC6A14 are pleiotropic, increasing risk for other early CF co-morbidities. Furthermore, co-morbidities affecting the same organ tended to associate with the same genes. The existence of pleiotropy within this single disorder suggests that complementary therapeutic strategies to augment solute transport will benefit multiple CF-associated tissues.

Topics: Alleles; Amino Acid Transport Systems; Amino Acid Transport Systems, Neutral; Antiporters; Canada; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genes, Modifier; Genetic Pleiotropy; Genotype; Humans; Ileus; Infant, Newborn; Male; Meconium; Models, Genetic; Morbidity; Mutation; Polymorphism, Single Nucleotide; Pseudomonas aeruginosa; Pseudomonas Infections; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sulfate Transporters

Previous studies of risk factors for progression of lung disease in cystic fibrosis (CF) have suffered from limitations that preclude a comprehensive understanding of the determinants of CF lung disease throughout childhood. The epidemiologic component of the 27-year Wisconsin Randomized Clinical Trial of CF Neonatal Screening Project (WI RCT) afforded us a unique opportunity to evaluate the significance of potential intrinsic and extrinsic risk factors for lung disease in children with CF.. Describe the most important intrinsic and extrinsic risk factors for progression of lung disease in children with CF.. Variables hypothesized at the onset of the WI RCT study to be determinants of the progression of lung disease and potential risk factors previously identified in the WI RCT study were assessed with multivariable generalized estimating equation models for repeated measures of chest radiograph scores and pulmonary function tests in the WI RCT cohort.. Combining all patients in the WI RCT, 132 subjects were observed for a mean of 16 years and contributed 1,579 chest radiographs, and 1,792 pulmonary function tests. The significant determinants of lung disease include genotype, poor growth, hospitalizations, meconium ileus, and infection with mucoid Pseudomonas aeruginosa. The previously described negative effect of female sex was not seen.. Modifiable extrinsic risk factors are the major determinants of progression of lung disease in children with CF. Better interventions to prevent or treat these risk factors may lead to improvements in lung health for children with CF.

Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Progression; Female; Genotype; Hospitalization; Humans; Ileus; Infant; Infant, Newborn; Longitudinal Studies; Lung; Male; Meconium; Neonatal Screening; Nutrition Disorders; Oligopeptides; Pseudomonas aeruginosa; Pseudomonas Infections; Radiography; Respiratory Function Tests; Risk Factors; Young Adult

This matched case-control study compared the nutritional and the pulmonary long-term outcomes of cystic fibrosis (CF) patients presenting a history of meconium ileus (MI) with early-diagnosed symptomatic CF without MI (non-MI).. Twenty-six patients with CF treated for MI between 1980 and 1997 have been matched for sex, birth date, and earliest CF symptomatic diagnosis for the children with non-MI CF. Clinical characteristics, genotype and complications were evaluated as well as the progression of the CF disease from infancy to 15 years old by nutritional status (z score weight, z score height), pulmonary function tests (PFTs) (FVC and FEV1), and Pseudomonas aeruginosa acquisition.. Median duration of the follow-up was 12.5 years (range, 10-17 years). Genotype identification showed no significant difference. Further on, the rate of complications and the occurrence of chronic P. aeruginosa colonization did not differ. At age of 15 years (n = 13), nutritional status and PFTs did not demonstrate any significant difference.. These results suggest that adequate initial nutritional and medical management of MI allows further similar nutritional status and PFTs compared with other early-diagnosed symptomatic CF patients. In this study, MI did not represent an additional risk factor for the patient's life.

Topics: Adolescent; Case-Control Studies; Cathartics; Child; Child, Preschool; Cohort Studies; Cystic Fibrosis; Diatrizoate Meglumine; Digestive System Surgical Procedures; Enema; Female; Humans; Ileus; Infant; Intestinal Obstruction; Male; Meconium; Nutrition Assessment; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests; Treatment Outcome

We studied the intestinal flora of 23 newborns, whose meconium had yielded a pure culture of Pseudomonas aeruginosa on blood agar medium. Twelve infants had a single serotype of P. aeruginosa in their meconium, 10 had a second serotype and the last infant was carrying three distinct ones. The maximum levels of P. aeruginosa observed during the first week of life were variable among the infants: 1 x 10(3) to 1 x 10(10) CFU/g of stools. The levels diminished progressively afterwards, and after 1 year of age only 1 of the 13 infants examined remained a carrier of P. aeruginosa. In 11 infants a second or a third serotype occurred during the course of the study. The serotypes that appeared secondarily always disappeared before the initial ones. Antibiotics: ampicillin + gentamicin or cefotaxime + netilmicin and colistin which were given to 8 infants had no clear effect on P. aeruginosa levels. Four infants had delayed colonization by Escherichia coli of greater than or equal to 10 days. All 4 had high levels of P. aeruginosa: 1 x 10(7) to 1 x 10(10) CFU/g stool, and antibiotic therapy, rendering it impossible to assess which was the cause of this delay. This colonization by P. aeruginosa did not lead to any clinical trouble.

Topics: Cefotaxime; Colistin; Drug Therapy, Combination; Escherichia coli; Feces; Female; Gentamicins; Humans; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Intestinal Diseases; Male; Meconium; Netilmicin; Pseudomonas aeruginosa; Pseudomonas Infections; Serotyping; Ticarcillin; Time Factors

Azlocillin, an acylureido penicillin with bactericidal activity, is particularly effective against Pseudomonas, enterococci and Haemophilus influenzae. It is also very active against E. coli, various Proteus species and Bacteroides. Pharmacokinetic studies were carried out in 138 children of various ages (prematures, newborns, infants, schoolchildren) after administering 50-75-100 mg/kg/ body weight azlocillin via the i.v. or i.m. routes; The constant of elimination and the distribution volumes were calculated besides the serum levels. In prematures and newborns, therapeutically effective serum levels were obtained on administering 50 or 100 mg/kg body weight twice daily. Infants and older children required 100 or 75 mg/kg body weight t.i.d. Determination of azlocillin in the bronchial secretion after i.v. doses of 75 mg/kg body weight showed good elimination. Azlocillin was always identified up to the 5th hour post injectionem. Inspite of parenteral administration, azlocillin was identified in different concentrations in the meconium as well. 39 children were treated with azlocillin, 35 of whom had Pseudomonas infection. Very good results were obtained in infections of the urinary tract, wound infections, conjunctivitis, dacryocystitis and in one case of meningitis. Bronchopulmonary diseases did not take an equally good course, but in these cases the conditions had not been favourable. No serious side effects were revealed by testing several laboratory parameters.

Topics: Azlocillin; Child; Child, Preschool; Conjunctivitis; Dacryocystitis; Humans; Infant; Infant, Newborn; Kinetics; Meconium; Meningitis; Penicillins; Pseudomonas Infections; Respiratory Tract Infections; Surgical Wound Infection; Urinary Tract Infections

Topics: Humans; Infant, Newborn; Infant, Newborn, Diseases; Intestinal Obstruction; Intestinal Perforation; Liver Diseases; Meconium; Megacolon; Peritonitis; Pseudomonas Infections; Radiography; Sepsis