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PubMed2000

Challenges in the dietary treatment of cystic fibrosis related diabetes mellitus.

Cystic fibrosis related diabetes mellitus is an increasingly recognized problem as survival in patients with cystic fibrosis improves. In a 5 year retrospective study of 627 children and adults attending Toronto cystic fibrosis clinics, we identified 57 (9%) patients with cystic fibrosis related diabetes mellitus; four (1.3%) of 301 children (<18 years) and 53 (16%) of 326 adults. The development of this complication of cystic fibrosis is associated with increased mortality, deteriorations in both respiratory and nutritional status, and the development of late microvascular, but not macrovascular, diabetic complications. Unfortunately, systematic review of the literature provides few well designed studies that provide sound evidence for clinical practice. Recommendations are therefore often based on anecdote, rather than physiological or outcomes research. Dietary therapy combines the principles of the dietary management of both cystic fibrosis and diabetes mellitus, but emphasizes the need for a high energy diet (> 100% of recommended daily intake) in patients with cystic fibrosis related diabetes mellitus. The importance of calories from fat is emphasized, with no restriction on total carbohydrate intake. Insulin intake mirrors carbohydrate intake. Routine dietary therapy is straightforward, but challenges occur due to both complications of cystic fibrosis and advancing disease. If a patient with cystic fibrosis related diabetes mellitus is malnourished, overnight enteral tube feeding is often used, with an adjusted insulin regimen. There is a great need for both physiological and outcomes research to provide sound scientific evidence for the dietary treatment of cystic fibrosis related diabetes mellitus.

Cystic Fibrosis↗
PubMed1991

In vivo evidence of altered chloride but not potassium secretion in cystic fibrosis rectal mucosa.

In cystic fibrosis, cyclic adenosine monophosphate-mediated chloride secretion is abnormal in respiratory, small intestinal, and rectal mucosa. Calcium-mediated chloride secretion is also aberrant in CF small intestinal mucosa in cystic fibrosis, in contrast to the respiratory epithelia, where it appears to be normal. To determine whether this disparity between calcium- and cyclic adenosine monophosphate-mediated chloride secretion exists in cystic fibrosis rectal mucosa in vivo, transrectal potential difference was measured in age-matched adult cystic fibrosis subjects (n = 8) and control subjects (n = 9) in response to 10-minute luminal perfusions of bethanechol (1 mmol/L) or theophylline (5 mmol/L). In response to bethanechol, an initial (1-minute) negative change in potential difference (-1.4 +/- 1.1 mV; mean +/- SEM) was seen in control subjects, in contrast to a positive change in mean potential difference (+2.5 +/- 1.0 mV) in cystic fibrosis subjects (control vs. cystic fibrosis, P less than 0.05). After 1 minute, mean potential differences changes in both control and cystic fibrosis subjects were positive. Theophylline perfusion resulted in a significant (P less than 0.01) difference in potential difference response between groups; at 10 minutes, the potential difference became more negative (-3.6 +/- 1.4 mV) in control subjects and more positive in cystic fibrosis subjects (+3.9 +/- 1.4 mV). To determine whether second messenger-mediated potassium secretion contributed to the observed potential difference changes in response to bethanechol and theophylline, studies were repeated in the presence of barium chloride, a known blocker of potassium conductance. In the control group, barium chloride significantly enhanced the theophylline-induced negative potential difference change (P less than 0.05) and reduced the positive potential difference change seen with bethanechol alone. In subjects with cystic fibrosis, barium chloride completely abolished the previously seen positive potential difference change in response to either bethanechol or theophylline alone. These in vivo studies suggest that there is active potassium secretion in both control and cystic fibrosis rectal mucosa in response to cyclic adenosine monophosphate- and calcium-dependent secretagogues and that the magnitude of the potential difference changes attributable to barium-inhibitable potassium secretion is the same in cystic fibrosis and control subjects. In contrast, it appears that in cystic fibrosis rectal mucosa in vivo, calcium- as well as cyclic adenosine monophosphate-dependent chloride secretion is aberrant.

Adult↗
PubMed1991

[Allele polymorphism of the DNA loci MET, D7S8, D7S23, linked to the cystic fibrosis gene in some populations of the USSR, in high risk families and in cystic fibrosis patients].

RELP analysis of DNA loci MET, D7S8 and D7S23 was carried out in Leningrad population and partially in populations of Moscow, Azerbaijan, Ukraine, Buryatia as well as in individuals from high risk families and in cystic fibrosis (CF) patients by means of blot hybridization and polymerase chain reaction. Allelic polymorphism of all loci studied in these three groups was found to be quite similar to that in the North-Western Europe and in whites of the North America. Linkage disequilibrium of the alleles studied with the CF gene was especially pronounced for alleles of the D7S23 locus and gradually decreases from KM-19 through CS-7 to XV-2c DNA probes. The data witness genetic homogeneity of the CF mutation in European populations of the USSR and its similarity to this mutation in Western Europe. The significance of these data for potential diagnosis of CF and for heterozygous carrier detection is discussed.

Alleles↗
PubMed1976

Studies on cystic fibrosis using isoelectric focusing. II. Demonstration of deficient proteolytic cleavage of alpha2-macroglobulin in cystic fibrosis plasma.

A protein with an isoelectric point (pI) of 5.48 was found to be deficient in plasma from most cystic fibrosis (CF) homozygotes and obligate heterozygote carriers of CF as compared with normal control plasma. Purification of the protein with a pI of 5.48 from normal plasma was performed using ammonium sulfate precipitation, DEAE-cellulose and CM-cellulose chromatography, Sephadex G-200- gel filtration, starch block electrophoresis, and Sepharose 4B gel filtration. The purified protein migrated as a single band on polyacrylamide gel electrophoresis, and displayed a single arc on immunoelectrophoresis against polyvalent antiserum to whole human serum. Results from various techniques used in its characterization indicate that this protein is a fragment of alpha2-macroglobulin (alpha2M) which is derived from alpha2M by proteolytic cleavage of intact alpha2M subunits. Quantitation of alpha2M levels in plasma indicated no significant differences between levels of alpha2M in CF homozygote, obligate heterozygote carrier, or normal control plasma samples. Quantitation of arginine esterase activity in plasma treated with cloroform and ellagic acid indicated that both the total arginine esterase activity and that fraction of arginine esterase activity inhibited by soybean trypsin inhibitor (SBTI) were decreased in most CF homozygote and obligate heterozygote plasma samples relative to normal control values. The results of this study indicate that plasma samples from CF homozygotes and obligate heterozygote carriers for CF show deficient proteolytic cleavage of alpha2M as compared with normal control plasma, and suggest that a structural abnormality in alpha2M or a deficiency in plasma proteolytic activity may be responsible for this deficiency in proteolysis.

Arginase↗
PubMed1992

The spectrum of CFTR mutations in south-west German cystic fibrosis patients.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene of 110 cystic fibrosis (CF) patients from the south-west of Germany was screened for 12 different mutations. This analysis resulted in an identification of 79% of all CF mutations and a complete genotype in 66% of the families. The most common mutation found was delta F508 (67%). Another 5 mutations accounted for a further 12.5% (4% G542X; 3% R553X; 3% N1303K; 2% 1717-1 G-->A; 0.5% G551D) whereas 6 mutations (R117H, A455E, delta I507, S549I, S549N, and R1162X) were not found. Fifty-four (49%) patients were delta F508 homozygotes and 18 (16.5%) were compound heterozygotes for delta F508 and one of the rarer mutations. These frequencies differ slightly from those found in the north of Germany and considerably from those reported from the south of Europe, which seems to be consistent with a north to south decline of the relative abundance of delta F508. Two patients, age 6 and 25 years, were compound heterozygotes for G542X and N1303K. The clinical features of the 6 year old were characterised by severe gastrointestinal and as yet only mild pulmonary complications whereas the 25 year old manifested severe pulmonary and gastrointestinal symptoms indicating that the N1303K mutation of the C-terminal CFTR nucleotide binding fold significantly impairs protein function in both the pancreas and the lungs.

Adolescent↗
PubMed1994

Mutation analysis in 600 French cystic fibrosis patients.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene of 600 unrelated cystic fibrosis (CF) patients living in France (excluding Brittany) was screened for 105 different mutations. This analysis resulted in the identification of 86% of the CF alleles and complete genotyping of 76% of the patients. The most frequent mutations in this population after delta F508 (69% of the CF chromosomes) are G542X (3.3%), N1303K (1.8%), W1282X (1.5%), 1717-1G-->A (1.3%), 2184delA + 2183 A-->G (0.9%), and R553X (0.8%).

Alleles↗
PubMed2004

CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.

BACKGROUND & AIMS: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype-phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl- channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. METHODS: To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)-mediated Cl- secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non-DeltaF508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR-mediated Cl- secretion with patients in whom Cl- secretion was absent. RESULTS: Residual anion secretion was detected in 40% of CF patients, and was associated with later disease onset (P < 0.0001), higher frequency of PS (P < 0.0001), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of approximately 12%-54% of controls. CONCLUSIONS: Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR-mediated Cl- secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity.

Adolescent↗
PubMed1999

[Physiopathology of cystic fibrosis lung disease].

Cystic fibrosis is a common genetic disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although the link between the mutations of the CFTR gene and the progressive lung disease is not completely understood, noteworthy advances have been made in the understanding of the mechanisms underlying lung injury in CF. The pathophysiologic cascade starts with CFTR dysfunction resulting from mutations of the CFTR gene, and leading to abnormal ion and water transport across airway epithelia. Abnormal airway surface liquid may in turn lead to impairment of mucociliary clearance, airway mucosal anti-microbial defenses, chronic bacterial infection and inflammation. Each of these steps has been elucidated in more detail in the recent years. This is of relevance from a therapeutic viewpoint. New therapeutic interventions include gene therapy, agents that may circumvent the defect in intracellular processing of mutated CFTR, agents that may modulate defects in epithelial ion transport, and anti-inflammatory agents.

Anti-Inflammatory Agents↗
PubMed1978

Calcium and sodium transport processes in patients with cystic fibrosis. I. A specific decrease in Mg2+-dependent, Ca2+-adenosine triphosphatase activity in erythrocyte membranes from cystic fibrosis patients.

Calcium-ATPase activity (Mg2+-dependent Ca2+-ATPase, ATP phosphohydrolase, EC 3.6.1.3) in erythrocyte membrane preparations from cystic fibrosis (CF) patients was greatly reduced compared to erythrocyte membranes from control subjects. The Km for calcium was found to be similar in the two groups; however, the Vmax, the maximal rate of activation of the Ca2+-ATPase, is reduced by 50% in the erythrocyte membrane preparations of the CF patients (P less than 0.001). In contrast, the Mg2+-ATPase activity of erythrocyte membranes from CF patients was unchanged compared to the control subjects. No difference in the Na+,K+-ATPase activity in erythrocyte membranes from CF patients compared to control patients could be observed. This indicates that the Ca2+-ATPase activity noted in CF erythrocytes is not part of a generalized membrane or membrane-bound enzyme alteration. It remains to be determined whether this alteration in Ca2+-ATPase activity is directly related to a defect in calcium transport in these cells and is a generalized phenomenon in CF present in cell types more directly involved in secretion.

Adolescent↗
PubMed2001

Radioisotopic imaging allows optimization of adenovirus lung deposition for cystic fibrosis gene therapy.

Cystic fibrosis is a common, heriditary disease resulting from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Airway transfer of the CFTR gene is a potential strategy to treat or prevent the lung pathology that is the main cause of morbidity and mortality. Among the vectors used for gene therapy, adenoviruses have shown their ability to transfer the CFTR gene to respiratory epithelial cells, using either instillation or nebulization. Our objective was to characterize the lung deposition of aerosolized adenovirus by quantitative radioisotopic imaging, the only noninvasive technique allowing in vivo quantitation of inhaled drugs. We first labeled an adenovirus expressing human CFTR with the gamma-emitting radioisotope, technetium 99m (99mTc), and determined the best labeling conditions to allow preservation of virus bioactivity. We then administered the radioaerosol to baboons, determined lung regional deposition of 99mTc-labeled adenovirus, and compared the expression of CFTR transcripts 3 and 21 days after inhalation. The expression of vector-encoded mRNA ranged from 4 to 22% with respect to the endogenous CFTR mRNA depending on the lung segments. Moreover, we have developed a model using 99mTc-DTPA (diethylenetriamine pentaacetic acid), which can be used, as an alternative to adenovirus, to determine the profile of lung deposition of the vector. This study demonstrates that scintigraphy is a useful technique to achieve optimization of gene administration to the airways.

Adenoviridae↗
PubMed1996

Gastrointestinal manifestations in cystic fibrosis.

CFTR, or cystic fibrosis transmembrane conductance regulator, the gene product that is defective in cystic fibrosis, is present in the apical membrane of the epithelial cells from the stomach to the colon. In the foregut, the clinical manifestations are not directly related to the primary defect of the CFTR chloride channel. The most troublesome complaints and symptoms originate from the oesophagus as peptic oesophagitis or oesophageal varices. In the small intestinal wall, the clinical expression of CF depends largely on the decreased secretion of fluid and chloride ions, the increased permeability of the paracellular space between adjacent enterocytes and the sticky mucous cover over the enterocytes. As a rule, the brush border enzyme activities are normal and there is some enhanced active transport as shown for glucose and alanine. The results of continuous enteral feeding of CF patients clearly show that the small intestinal mucosa, in the daily situation, is not functioning at maximal capacity. Although CFTR expression in the colon is lower, the large intestine may be the site of several serious complications such as rectal prolapse, meconium ileus equivalent, intussusception, volvulus and silent appendicitis. In recent years colonic strictures, after the use of high-dose pancreatic enzymes, are being increasingly reported; the condition has recently been called CF fibrosing colonopathy. The CF gastrointestinal content itself differs mainly from the normal condition by the lower acidity in the foregut and the accretion of mucins and proteins, eventually resulting in intestinal obstruction, in the ileum and colon. Better understanding of the CF gastrointestinal phenotype may contribute to improvement of the overall wellbeing of these patients.

Colonic Diseases↗
PubMed1996

Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double-blind multicenter trial. The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis.

Liver disease is increasingly recognized as a major cause of morbidity in cystic fibrosis (CF). Preliminary data suggest that ursodeoxycholic acid (UDCA) may be beneficial for treatment of this manifestation. We performed a double-blind, multicenter trial in these patients to establish efficacy and safety of UDCA in terms of the improvement of clinical and nutritional indicators besides standard liver function tests. We also intended to establish whether taurine supplementation has a beneficial effect in patients receiving UDCA. From June to December 1990, we enrolled in 12 centers 55 CF patients with liver disease (39 male subjects; median age, 13.8 years). They were randomly assigned to receive for 1 year one of the following treatments: UDCA (15 mg/kg body weight daily) plus taurine (30 mg/kg body weight daily), UDCA plus placebo, placebo plus taurine, or double placebo. Clinical and laboratory evaluations were performed every 3 months. After 1 year, deterioration of overall clinical conditions, as indicated by the Shwachman-Kulczycki score (SKS), occurred in patients who received placebo but not in those who received UDCA (P = .025). Patients treated with UDCA also showed an improvement in gamma-glutamyl transpeptidase (GGT) (P = .004) and 5'-nucleotidase (P = .006) levels. Treatment with taurine was followed by a significant increase in serum prealbumin levels (P = .053), a trend toward a reduction in fat malabsorption, and no effect on the biochemical profile. No severe side effects occurred with any treatment. Thus, we concluded that UDCA administration improves clinical and biochemical parameters in CF patients with liver disease. Taurine supplementation may be indicated in patients with severe pancreatic insufficiency and poor nutritional status.

5'-Nucleotidase↗
PubMed1996

Preimplantation genetic diagnosis of cystic fibrosis (delta F508).

Cystic fibrosis is a common autosomal recessive condition caused by mutations in the cystic fibrosis transmembrane regulator gene. The major mutation is a three base pair deletion (delta F508). If both partners carry this deletion, the chance of having an affected child is 1 in 4. In vitro fertilization (IVF) with preimplantation genetic diagnosis allows the selection of the unaffected embryos only to be returned to the uterus. Preimplantation genetic diagnosis was attempted in 14 couples in which both partners carry the delta F508 deletion. A total of 22 cycles resulted in 170 normally fertilized embryos of which, 145 embryos were successfully biopsied and in 18 cycles, one or two unaffected embryos were transferred. A total of five clinical pregnancies established and at birth all five singletons have been confirmed as homozygous for the normal allele. From our experience, cleavage stage biopsy after in vitro fertilization provides sufficient embryos diagnosed as unaffected for transfer in this autosomal recessive disease. Also, pregnancy rates after the preimplantation diagnosis are similar to those with infertile couples. Prospects for applying preimplantation genetic diagnosis to autosomal dominant conditions, where incidences of having affected embryos would be higher, therefore, appear good.

Cystic Fibrosis↗
PubMed1989

Analysis of DNA polymorphism haplotypes linked to the cystic fibrosis locus in North American black and Caucasian families supports the existence of multiple mutations of the cystic fibrosis gene.

Strong linkage disequilibrium (LD) was found between DNA marker XV2c and the cystic fibrosis (CF) locus (delta = 0.46) and between DNA marker KM19 and CF (delta = 0.67) in 157 CF and 138 normal chromosomes from U.S. Caucasians. DNA haplotypes with nine polymorphic sites were created in 54 Caucasian families. There is a strong LD between the haplotypes and the presence of the mutant CF genes. This implies that the DNA polymorphisms examined are close to the CF gene and that one mutation of the CF gene predominates in the Caucasian population. Haplotype analysis can also be used to refine estimates of CF carrier risk in Caucasians. Data for XV2c and MET markers in 16 American black patients and their families revealed a different haplotype distribution and LD pattern with the CF locus. These data suggest that racial admixture alone does not explain the occurrence of CF in American blacks and that multiple alleles of the CF gene may exist in this population.

Black People↗
PubMed2005

[Cystic fibrosis modifying genes].

Cystic fibrosis is a common autosomal recessive disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes a membrane-bound chloride ion channel. CFTR gene mutations cause alterations in fluid and salt secretion of various tissues. The CF phenotype is highly variable even in siblings and twins carrying the same CFTR mutations. The course of CF pulmonary disease is modulated by both environmental and genetic factors independent of CFTR. This review summarises association studies that focused on disease modifier genes in CF. Understanding the molecular and cellular basis of the genotype-phenotype associations will help to better understand the disease and to identify new targets for therapeutic interventions in CF.

Cystic Fibrosis↗
PubMed1983

Meconium ileus equivalent in children with cystic fibrosis.

Children with cystic fibrosis may develop intestinal obstruction later in life due to inspissation of small bowel content. Two children with cystic fibrosis who developed intestinal obstruction at the age of 5 and 14 years respectively are reported. The condition may be precipitated by reduction or stopping pancreatic supplement, dehydration or intercurrent chest infection. The intensive therapy of chest complications has improved the survival of children with cystic fibrosis, so that it is likely that in future more cases of meconium ileus equivalent will present in later childhood and in adulthood.

Adolescent↗
PubMed1994

The substituted benzimidazolone NS004 is an opener of the cystic fibrosis chloride channel.

Cystic fibrosis is a major inherited disorder involving abnormalities of fluid and electrolyte transport in a number of different organs. Epithelial cells of cystic fibrosis patients have a decreased capacity to secrete chloride in response to cAMP-mobilizing agents because of the mutation of a single gene. The gene product, the cystic fibrosis transmembrane conductance regulator or CFTR, is a chloride channel. The most frequent mutation is a deletion of phenylalanine in position 508 (delta F508-CFTR) that reduces both the expression of the CFTR protein at the cell surface, and the activity of the Cl- channel. This work presents the properties of NS004, a substituted benzimidazolone, which is the first activator of normal and mutant CFTR-associated chloride channels to be described. NS004 activated CFTR and delta F508-CFTR Cl- channels expressed in Xenopus oocytes, and increased 125I efflux (via the Cl- channel) from Vero cells expressing CFTR and delta F508-CFTR. Application of NS004 to the external side of outside-out patches excised from these CFTR- and delta F508-CFTR-expressing cells induced a marked and reversible increase in channel activity.

1-Methyl-3-isobutylxanthine↗