Phenotypic heterogeneity in cystic fibrosis

Sing, Charles F.; Risser, David R.; Howatt, William F.; Erickson, Robert P.

doi:10.1002/ajmg.1320130209

Cited by 15 publications

(10 citation statements)

References 11 publications

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“…An example of a Southern blot with several HLA-DR types patterns is shown in Figure 1. Eleven different HLA-DR haplotypes were recognized among these individuals, and the distribution of all of them between clusters 1 + 2 and 3 + 4, constructed according to Sing et al [1982], was evaluated (Table V). The distribution of HLA-DR types in the sample studied (66 haplotypes) is not different from a random distribution among the cluster subgroup.…”

Section: Resultsmentioning

confidence: 99%

Correlation of phenotypic and genetic heterogeneity in cystic fibrosis: Variability in sweat electrolyte levels contributes to heterogeneity and is increased with the XV‐2c/KM19 B haplotype

et al. 1991

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We have reinvestigated a classification of clinical heterogeneity among cystic fibrosis (CF) patients that we previously reported and investigated the possible relationship of the identified CF subgroups to haplotypes around the CF gene and to HLA-DR haplotypes. Age-corrected values for sweat electrolytes, rate of progression of lung disease as assessed by Brasfield chest x-ray scores, and severity of pancreatic insufficiency as assessed by daily supplemented enzyme dosage were obtained for 55, 59, and 59 patients, respectively. XV-2c and KM19 RFLPs were determined by hybridization to TaqI and PstI digests of human genomic DNA, respectively, and analysis of mutations by PCR amplification followed by allele-specific oligo-deoxynucleotide hybridization was performed for 29 patients. HLA-DR restriction fragment length polymorphisms (RFLPs) were determined by hybridization of cDNA beta 1 and genomic DQ alpha probes to TaqI digests of human genomic DNA. The results show that the previous subdivision on the basis of age-corrected levels of sweat electrolytes, as well as measures of severity of lung disease and pancreatic disease, is valid. In addition, the C and D haplotypes are associated with lower age-corrected sweat sodium level. No significant relationship between CF haplotypes and the other two disease variables or between HLA-DR haplotypes and any of the clinical variables was found.

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Section: Resultsmentioning

confidence: 99%

Correlation of phenotypic and genetic heterogeneity in cystic fibrosis: Variability in sweat electrolyte levels contributes to heterogeneity and is increased with the XV‐2c/KM19 B haplotype

et al. 1991

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“…Heterogeneity increases as disease progresses so that there are diverse pheno-and genotypes that are heterogeneously resistant in parallel within one patient. Furthermore, it has been demonstrated that there is considerable within-patient diversity per time point (82)(83)(84)(85)(86)(87). Consequently, the geno-and phenotypes of strains isolated from CF patients vary both within an individual patient per time point and with time as the disease progresses.…”

Section: Heteroresistance a Resistance Reservoir Without Selective Pmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Dalhoff¹

2014

Clin Microbiol Rev

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SUMMARY Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced.

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“…Two general explanations for the different mean activities of the two CF subpopulations can be considered. Heterogeneity within CF is well recognized (44) and genetic polymorphism in the CaATPase may be intrinsic to the differences in pancreatic status. Perhaps more likely, the maldigestion and malabsorption accompanying pancreatic deficiency may affect the Ca-ATPase activity through nutritional alterations.…”

Section: Discussionmentioning

confidence: 99%

Calcium-ATPase Activity in Cystic Fibrosis Erythrocyte Membranes: Decreased Activity in Patients with Pancreatic Insufficiency

et al. 1984

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Summary modulin, of the pancreatic sufficient patients (34.3 f 4.2 and 75.9 f 6.9 nmol/min/mg) was indistinguishable from that of The activity of Ca-ATPase (Ca2+,Mg2+-ATPase, ATP phos-controls (35.8 2.6 and 84.3 f 4.7 nmol/min/mg), while both phohydrolase, EC 3.6.1.3) was measured in erythrocyte mem-activities of patients with pancreatic insufficiency were signifibrane preparations from 37 cystic fibrosis patients, 27 with cantly decreased (28.9 + 1.3, < 0.02; 65.2 + 3.0, < 0.001) pancreatic insufficiency and 10 with pancreatic sufficiency, and to the control group. Similarly, the mean erythrocyte from 24 healthy controls. The mean maximal calcium-stimulated membrane (Na + K)ATPase activity was decreased only for specific activities, in the absence and presence of purified cal-those patients with a history of steatorrhea and who clinically Received August 18, 1983; accepted March 12, 1984. required pancreatic enzyme therapy and had low immunoreactive

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Phenotypic heterogeneity in cystic fibrosis

Cited by 15 publications

References 11 publications

Correlation of phenotypic and genetic heterogeneity in cystic fibrosis: Variability in sweat electrolyte levels contributes to heterogeneity and is increased with the XV‐2c/KM19 B haplotype

Correlation of phenotypic and genetic heterogeneity in cystic fibrosis: Variability in sweat electrolyte levels contributes to heterogeneity and is increased with the XV‐2c/KM19 B haplotype

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

Calcium-ATPase Activity in Cystic Fibrosis Erythrocyte Membranes: Decreased Activity in Patients with Pancreatic Insufficiency

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