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PubMed1994

[Molecular-genetic analysis of certain mutations of the "cystic fibrosis gene" in Moldavia. Characteristics of molecular markers and their linkage with various mutations].

Sixty-one patients with cystic fibrosis (CF) from Moldova were tested for mutations delta F508, G551D, and R553X. Frequencies of various alleles of the repeated GATT sequence in intron 6B of the CFTR gene, their linkage to other polymorphic markers, and various mutations were determined. The frequency of occurrence of mutation delta F508 was only 25%. An absolute majority of CF patients (80%) had pancreatic insufficiency. Mutations G551D and R553X were not found in our sample. Each of 31 chromosomes with mutation delta F508 carries the 6-GATT allele. Most "non delta F508" (78%) and normal (80%) chromosomes were marked by 7-GATT allele. Twenty-seven delta F508 chromosomes (96.4%) belong to haplotype B6, and only one to D6. Most chromosomes with "non delta F508" mutations are associated with haplotypes D7 (26.3%) and C7 (21%). In addition, a significant portion of chromosomes from this subgroup were associated with haplotypes A7 (23.7%), A6 (10.5%), and C6 (2.7%), which are not yet described for mutant chromosomes. The results obtained demonstrate that CF in Moldova is mainly associated with mutations other than delta F508, G551D, and R553X. Severe forms of the disease, with pancreatic insufficiency, are more frequently caused by these mutations; moreover, our data provides strong evidence about the presence of at least seven additional CF mutations in Moldova, apart from delta F508, G551D, and R553X. Some of these are probably not described.

Base Sequence↗
PubMed2004

Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-).

HCO(3)(-) secretion is a vital activity in cystic fibrosis transmembrane conductance regulator (CFTR)-expressing epithelia. However, the role of CFTR in this activity is not well understood. Simultaneous measurements of membrane potential and pH(i) and/or current in CFTRexpressing Xenopus oocytes revealed dynamic control of CFTR Cl(-)/HCO(3)(-) permeability ratio, which is regulated by external Cl(-) (Cl(-)(o)). Thus, reducing external Cl(-) from 110 to 0-10 mm resulted in the expected increase in membrane potential, but with no corresponding OH(-) or HCO(3)(-) influx. Approximately 3-4 min after reducing Cl(o)(-) to 0 mm, an abrupt switch in membrane potential occurs that coincided with an increased rates of OH(-) and HCO(3)(-) influx. The switch in membrane permeability to OH(-)/HCO(3)(-) can also be recorded as a leftward shift in the reversal potential. Furthermore, an increased rate of OH(-) influx in response to elevating pH(o) to 9.0 was observed only after the switch in membrane potential. The time to switch increased to 11 min at Cl(o)(-) of 5 mm. Conversely, re-addition of external Cl(-) after the switch in membrane potential did not stop HCO(3)(-) influx, which continued for about 3.9 min after Cl(-) addition. Importantly, addition of external Cl(-) to cells incubated in Cl(-)-free medium never resulted in HCO(3)(-) efflux. Voltage and current clamp experiments showed that the delayed HCO(3)(-) transport is electrogenic. These results indicate that CFTR exists in two conformations, a Cl(-) only and a Cl(-) and OH(-)/HCO(3)(-) permeable state. The switch between the states is controlled by external Cl(-). Accordingly, a different tryptic pattern of CFTR was found upon digestion in Cl(-)-containing and Cl(-)-free media. The physiological significance of these finding is discussed in the context of HCO(3)(-) secretion by tissues such as the pancreas and salivary glands.

Animals↗
PubMed2002

Faecal elastase-1 and fat-soluble vitamin profiles in patients with cystic fibrosis in Western Norway.

BACKGROUND: Exocrine pancreatic insufficiency is a major clinical manifestation of cystic fibrosis (CF). Almost nine of ten patients develop signs and symptoms of maldigestion and malabsorption, which often deteriorates nutritional status and therefore worsens the prognosis. Human faecal elastase-1 (FE-1) has shown promising results to assess exocrine pancreatic insufficiency, and this test has been used at Haukeland University Hospital since 1996. AIM OF THE STUDY: To evaluate FE-1 values and fat-soluble vitamin profiles in patients with CF and to correlate exocrine pancreatic function as measured as FE-1 to fat-soluble vitamin profiles. Moreover, we wanted to assess if there are differences between fat-soluble vitamin profiles in patients with impaired versus patent exocrine pancreatic function, and thirdly, if fat-soluble vitamin deficiency at diagnosis is effectively treated by supplementation. METHODS: Consecutive analyses (N = 212) of fat-soluble vitamin profiles and 35 analyses of FE-1 were investigated in 35 patients with CF. In 17 out of 35 patients fat-soluble vitamin profiles were also assessed at diagnosis. Results Mean value of FE-1 for all CF patients was 256.9 microg/g faeces (median 24.1 microg/g faeces). CF patients considered to have maldigestion (N=24) showed a mean value of 19.9 microg/g faeces (median 18.7 microg/g faeces), those without pancreas affection had a mean value of 773.9 microg/g faeces (median 728.9 microg/g faeces, p < 0.01). There was no difference in fat-soluble vitamin profiles among patients with or without exocrine pancreatic insufficiency while on appropriate supplementation. Median value for vitamin E in patients with exocrine pancreatic insufficiency at diagnosis was low (3.6 mg/L). Supplementation of pancreatic enzymes and vitamins normalised profiles in this group at follow-up. There was no significant correlation between exocrine pancreatic function as measured as FE-1 and fat-soluble vitamin profiles, neither in patients with impaired nor in those with patent pancreatic function. CONCLUSIONS: Severe degree of exocrine pancreatic insufficiency is common in patients with cystic fibrosis. There was no correlation of faecal elastase-1 levels to fat-soluble vitamin status. Fat-soluble vitamins (A, D, E) given in appropriate dosages combined with pancreatic enzymes ensured normal profiles in our patients with CF and malabsorption. Officially recommended supplementation of vitamin A and D in Norway during infancy and childhood may explain why so few patients had vitamin deficiencies at diagnosis.

Adolescent↗
PubMedDate not supplied

Biochemical analysis of meconium in fetuses presumed to have cystic fibrosis.

A series of proteins (albumin, transferrin, alpha 1-antitrypsin, alpha-fetoprotein and pancreatic oncofetal antigen) and enzymes (gamma-glutamyltranspeptidase, aminopeptidase M, alkaline phosphatase, alpha-glucosidase and protease) was measured in fetal meconium extracts. There were 19 fetuses thought to have cystic fibrosis (CF), 13 with neural tube defects, three with chromosome abnormalities and 19 normal controls, all with gestational ages between 18 and 21 weeks. With the exception of alpha-fetoprotein, all the proteins and enzymes were significantly elevated in the CF meconium extracts. The most definitive indicator of a CF fetus was the albumin concentration, where the mean level was five times that found in the control groups. However, five of 19 fetuses assumed to have CF had albumin in the normal range. In these cases the meconium protease levels were grossly elevated. Furthermore, in the same five fetuses meconium concentration of pancreatic oncofetal antigen, a protein synthesized in the fetal pancreas, was also greatly raised. We suggest that post-mortem examination of a fetus thought to have CF should include measurement of meconium albumin, protease and pancreatic oncofetal antigen.

Abortion, Induced↗
PubMed1998

Heparin accelerates the inhibition of cathepsin G by mucus proteinase inhibitor: potent effect of O-butyrylated heparin.

Heparin tightly binds cathepsin G and so protects the enzyme from inhibition by alpha1-antichymotrypsin, alpha1-proteinase inhibitor and eglin c, three proteins which do not bind heparin [Ermolieff J., Boudier C., Laine A., Meyer B. and Bieth J.G. (1994) J. Biol. Chem. 269, 29502-29508]. Here we show that heparin no longer protects cathepsin G from inhibition when the enzyme is reacted with mucus proteinase inhibitor (MPI), a heparin-binding protein. Heparin fragments of Mr=4500 and 8100 and O-butyrylated heparin of Mr=8000 form tight complexes with cathepsin G (Kd=0.5-2.2 nM) and MPI (Kd=0. 4-0.8 muM) and accelerate the MPI-promoted inhibition of cathepsin G by a factor of 17-26. They also accelerate the inhibition of neutrophil elastase and pancreatic chymotrypsin. The rate acceleration is due to the binding of heparin to MPI. Butyrylation of heparin slightly decreases its affinity for cathepsin G and MPI but sharply decreases the ionic interactions between the positively charged proteins and the negatively charged polyanion. The butyrylated heparin derivative is the best rate accelerator: it increases the rate constant for the MPI-induced inhibition of cathepsin G and elastase by factors of 26 and 23, respectively. This, together with the fact that it has a good bioavailability and a very low anticoagulant activity, suggests that it might be an adjuvant of MPI-based therapy of cystic fibrosis.

Animals↗
PubMed2006

Long-term docosahexaenoic acid therapy in a congenic murine model of cystic fibrosis.

We used a congenic C57Bl/6J cystic fibrosis transmembrane conductance regulator (Cftr)(-/-) mouse model, which develops cystic fibrosis (CF)-like pathology in all organs, to evaluate the short- and long-term therapeutic effects of dietary docosahexaenoic acid (DHA). Thirty-day-old Cftr(-/-) mice and wild-type littermates were randomized to receive a liquid diet with or without DHA (40 mg/day). Animals were killed for histological and lipid analysis after 7, 30, and 60 days of therapy. DHA had no significant therapeutic or harmful effect on the lung, pancreas, or ileum of the Cftr(-/-) mice or their wild-type littermates. In contrast, dietary DHA resulted in highly significant amelioration of the severity of liver disease in the Cftr(-/-) mice, primarily a reduction in the degree of peri-portal inflammation. Additionally, these detailed measurements confirm our previous findings that Cftr(-/-) mice have significant alterations in the pancreas (except external acinar diameter), ileum, liver, lung, and salivary (except sublingual) glands at all ages compared with their age-matched wild-type littermates. In conclusion, inhibition of cytokines and/or eicosanoid metabolism and release of endogenous inhibitors of inflammation by DHA may account for the anti-inflammatory effects in the liver of this congenic murine model of CF. The potential therapeutic benefits of DHA in severe CF-associated liver disease remain to be explored.

Administration, Oral↗
PubMed1982

Lingual lipase. Its role in lipid digestion in infants with low birthweight and/or pancreatic insufficiency.

At birth both pancreatic lipase and carboxylic ester hydrolase, two important lipolytic enzymes secreted by the pancreas, are present in duodenal contents but the activities of these enzymes are low. Another enzyme of possible importance in lipolysis is the lingual lipase which is secreted from serous glands present at the posterior part of the tongue. The enzyme is present already at birth and has been found in gastric contents from preterm infants in the 34th gestational week. The secretion of lingual lipase is stimulated by feeding and it is resistent against acid inactivation. The activity in gastric contents increases after feeding. This lipase hydrolyzes dietary triglycerides to mainly diglycerides and free fatty acids and may serve as a complement to the poorly developed pancreatic lipase activity. Furthermore, by the formation of polar lipolytic products the digestibility of dietary lipids in the duodenum may increase. Human milk lipase contributes to the lipolysis. It is inactive in the milk but becomes activated by the bile acids in the duodenum. Balance studies in preterm infants have shown that by pasteurization of human milk fat absorption decreases by one third.

Bile Acids and Salts↗
PubMed1987

Influence of antacid and formulation on effectiveness of pancreatic enzyme supplementation in cystic fibrosis.

A series of treatment trials, involving food balances based on determination of fat coefficient absorption, nitrogen faecal loss, and daily faecal weight, was performed in 82 patients with cystic fibrosis. Results showed that a conventional powdered pancreatic extract (Pancrex V) required a high dosage to achieve reasonable improvement in fat and nitrogen absorption (200 mg/kg body weight/day on average) and rarely restored digestion to normal. Bicarbonate (5.2 g/m2 body surface/day) slightly enhanced the enzymatic activity of the powdered extract, this being more apparent in those with more severe steatorrhoea. There was no advantage in providing the extract in microgranules protected by cellulose acetatephthalate. A product based on fungal lipase and protease (Krebsilasi) proved to be ineffective in correcting fat and protein absorption. The two recent products prepared in pH sensitive microspheres (Pancrex V microspheres and Pancreas-Prolipase) had similar advantages in digestive activity. Compared with the traditional preparations, they offered a number of practical advantages, including a smaller number of capsules (particularly Pancrex V microspheres) and improved palatability.

Antacids↗
PubMed1996

Inherited and congenital disorders of the exocrine pancreas.

The spectrum of inherited and congenital disorders of the exocrine pancreas is described. Although functional disturbances of the exocrine pancreas are less frequent in childhood than in adult life, there is a wide spectrum of causes, many of which are genetic or congenital in origin. Rarely, a disturbance of pancreatic function may arise as a result of disordered embryogenesis. More frequently, however, inherited disorders affecting multiple organs give rise to pancreatic dysfunction. Among Caucasian children, cystic fibrosis (CF) is, by far, the most common inherited disorder of disturbed pancreatic function. Examples of rarer, inherited causes of pancreatic dysfunction include Shwachman-Diamond syndrome, Johanson-Blizzard syndrome, Pearson's syndrome, pancreatic agenesis, and isolated enzyme deficiencies. Hereditary pancreatitis and several recently recognized metabolic causes of chronic pancreatitis can also produce severe pancreatic exocrine dysfunction.

Adolescent↗
PubMed1994

Adenovirus-mediated transfer of human lipase complementary DNA to the gallbladder.

BACKGROUND/AIMS: Despite many improvements in current therapy, exocrine pancreatic insufficiency remains a significant problem in cystic fibrosis. To establish a new therapy for exocrine pancreatic insufficiency, the feasibility of transferring the human pancreatic lipase complementary DNA to the gallbladder as a possible target using a recombinant adenovirus vector was evaluated. METHODS: The adenovirus vector AdCMV. Lip was constructed using the cytomegalovirus immediate early promoter to drive the human pancreatic lipase complementary DNA. In vitro infection of the human gallbladder epithelial cell line HS-181 and ex vivo infection of the sheep gallbladder with AdRSV. beta-gal (an adenovirus vector containing the Escherichia coli lacZ [(beta-galactosidase] gene) or AdCMV. Lip were evaluated. RESULTS: The supernatant from AdCMV. Lip-infected HS-181 showed the secretion of active lipase for at least 2 weeks in vitro. The epithelium of gallbladder infected with AdRSV.beta-gal ex vivo showed the expression of the beta-galactosidase. The fluid from the gallbladder lumen infected with AdCMV. Lip showed the increased lipase activity. CONCLUSIONS: These observations show that an adenovirus vector can transfer a human pancreatic enzyme in vitro and ex vivo, suggesting the feasibility of in vivo gene therapy for exocrine pancreatic insufficiency in cystic fibrosis.

Adenoviridae↗
PubMed2001

Pancreatic acinar cell dysfunction in CFTR(-/-) mice is associated with impairments in luminal pH and endocytosis.

BACKGROUND & AIMS: We have previously shown that endocytosis at the apical plasma membrane in pancreatic acinar cells is coupled to ductal bicarbonate secretion into the lumen. We hypothesized that decreased bicarbonate secretion in cystic fibrosis (CF) inhibits apical endocytosis. The aim of this study was to determine in cftr(-/-) mice (1) if the pH of the pancreatic juice is acidic compared with wild-type (WT) controls, (2) if there is a selective block in endocytosis, and (3) if alkalinization of the luminal fluid reverses this defect. METHODS: Fluid secretion and pH of pancreatic juice were measured. Exocytosis, endocytosis, and morphology were compared in pancreatic lobules from cftr(-/-) and WT mice. RESULTS: Pancreatic juice pH was 8.12 +/- 0.06 in WT mice compared with 6.60 +/- 0.04 in cftr(-/-) mice. Although cholecystokinin-stimulated amylase secretion was not significantly different, endocytosis was markedly inhibited in cftr(-/-) compared with WT mice. Cleavage of GP2, a GPI-anchored protein tightly associated with activation of endocytosis, was also decreased. Incubation of lobules from cftr(-/-) mice at pH 8.3 reversed the luminal dilatation. CONCLUSIONS: These data indicate that apical endocytosis is selectively impaired in cftr(-/-) mice, which explains, in part, the luminal dilatation observed at the apical plasma membrane. In vitro alkalinization of luminal fluid led to reversal of defects in membrane dynamics, restored coupled exocytosis and endocytosis, and abolished the luminal dilatation in this animal model of CF. Acidic pH changes in luminal secretions may play a role in the pancreatic membrane dysfunction observed in CF.

Amylases↗
PubMed1993

Genotype analysis of adult cystic fibrosis patients.

To assess the relationship between the genotype and phenotype of adult CF patients we have selected from a group of 512 CF patients attending centres in France, all these of greater than 35 years. We have analysed the entire coding sequence of their CFTR genes. The complete genotype was determined in 7 of the 8 patients and clinical data regarding pancreatic, respiratory and reproductive function were carefully evaluated. All these patients are compound heterozygote, seven carrying the delta F508 and one the G542X on one allele. The other allele carried is: (i) a missense mutation located in exons coding for transmembrane region in five patients [R334W (1); I336K (2); R117H (1); H1054D (1)]; (ii) a splice mutation in two patients [2789 + 5G-->A], (iii) an uncharacterised mutations in one patient. These results strongly suggest less severe CF phenotype to be associated with these mutations and strengthen the hypothesis that less severe phenotype are genetically determined.

Adult↗
PubMed2004

Genotype/phenotype correlation of the G85E mutation in a large cohort of cystic fibrosis patients.

In this European study, the phenotype in 68 patients, homozygous or compound heterozygous for the G85E mutation, was investigated. Each index case was compared with two cystic fibrosis (CF) patients from the same clinic, matched for age and sex: one with pancreatic sufficiency (PS) and one with pancreatic insufficiency (PI). When comparing 31 G85E/F508del and F508del/F508del patients, there were no differences in median age at diagnosis, mean sweat chloride value, most recent weight for height, most recent forced expiratory volume in one second % predicted, prevalence of chronic Pseudomonas aeruginosa colonisation and typical CF complications. However, PI was less frequent in the G85E/F508del group. Comparison of 55 G85E patients (with second mutation known and not classified as mild) with PS controls (n=44) showed that the G85E patients had a significantly higher sweat chloride, more often failure to thrive at diagnosis, higher prevalence of PI, worse current weight for height, higher prevalence of chronic P. aeruginosa colonisation and liver cirrhosis. Pulse-chase experiments revealed that G85E cystic fibrosis transmembrane conductance regulator failed to mature on a M470 as well as on a V470 background. Therefore, G85E is a class II mutation. Although there is variability in its clinical presentation, G85E mutation results in a severe phenotype.

Adolescent↗
PubMed2005

Cystic fibrosis in Korean children:a case report identified by a quantitative pilocarpine iontophoresis sweat test and genetic analysis.

Cystic fibrosis (CF) is inherited as an autosomal recessive trait, and the mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene contributes to the CF syndrome. Although CF is common in Caucasians, it is known to be rare in Asians. Recently, we experienced two cases of CF in Korean children. The patients were girls with chronic productive cough since early infancy. Chest computed tomography showed the diffuse bronchiectasis in both lungs, and their diagnosis was confirmed by the repeated analysis of a quantitative pilocarpine iontophoresis test (QPIT). The sweat chloride concentrations of the first patient were 108.1 mM/L and 96.7 mM/L. The genetic analysis revealed that she was the compound heterozygote of Q1291X and IVS8 T5-M470V. In the second case, the sweat chloride concentrations were 95.0 mM/L and 77.5 mM/L. Although we performed a comprehensive search for the coding regions and exon-intron splicing junctions of CFTR gene, no obvious disease-related mutations were detected in the second case. To our knowledge, this is the first report of CF in Korean children identified by a QPIT and genetic analysis. The possibility of CF should be suspected in those patients with chronic respiratory symptoms even in Korea.

Blood Pressure↗