Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021843 (bowel obstruction)
 9,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over 90% of untreated CFTR S489X homozygous (CF) mutant mice reportedly die of intestinal obstruction by 40 days of age, significantly limiting their usefulness as a model for the human disease. Because the period of highest mortality is during the week after weaning, we hypothesized that providing a low-residue liquid diet would improve survival and growth. When 99 CF mice that survived to 10 days of age were fed Peptamen (Clintec Nutrition), an elemental liquid diet, and housed on corn-cob bedding, 88% of them survived to maturity (50 days). The diet causes only minor histologic and ion transport changes in the intestines of normal mice and does not reduce growth rate or size. CF mice raised on Peptamen continue to display severe pathological changes in the intestine and completely lack a adenosine 3',5'-cyclic monophosphate-inducible chloride current in the cecum. This combination of dietary and bedding changes provides a reliable method for keeping CF mice alive well into adulthood and will be useful for the evaluation of the effect and duration of potential therapies for CF.
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PMID:Dietary changes improve survival of CFTR S489X homozygous mutant mouse. 749 81

Recently we have created a mouse model of cystic fibrosis (CF) by insertional gene targeting to exon 10. In common with CF subjects, this model displays a low incidence of meconium ileus. This contrasts strikingly with the very high level of fatal intestinal obstruction in the three other CF mouse models so far described. We investigate here the molecular basis of this difference in phenotype. We show that the partial duplication consequent upon insertional gene targeting allows exon skipping and aberrant splicing to produce normal Cftr mRNA, but at levels greatly reduced compared with wild-type mice. Furthermore, instead of the predicted mutant Cftr transcript, a novel mRNA is produced that utilizes cryptic splice sites in the disrupting plasmid sequence. However, we have previously shown that these mice display the ion transport defect characteristic of CF, and mutant animals can be distinguished from their normal littermates on this basis. Consistent with this, residual CFTR function has recently been observed for several "mild" mutations in CF individuals who display pancreatic sufficiency but still develop lung disease. We conclude that (i) residual wild-type mRNA in the exon 10 insertional mutant mouse ameliorates the severity of the intestinal phenotype observed in the absolute "null" CF mice, (ii) the presence of low-level residual wild-type Cftr mRNA does not correct the CF ion transport defect, and (iii) the long-term survival of this insertional mutant mouse provides the opportunity to address the factors important in development of lung disease.
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PMID:Long-term survival of the exon 10 insertional cystic fibrosis mutant mouse is a consequence of low level residual wild-type Cftr gene expression. 794 29

Mouse models for cystic fibrosis (CF) with no CFTR function (Cftr-/-) have the disadvantage that most animals die of intestinal obstruction shortly after weaning. The objective of this research was to extend the lifespan of CF mice and characterize their phenotype. Weanlings were placed on a nutrient liquid diet, and histologic and functional aspects of organs implicated in the disease were subsequently examined. Approximately 90% of Cftr-/- mice survived to 60 d, the majority beyond 100 d. Cftr-/- mice were underweight and had markedly abnormal intestinal histology. The intestinal epithelia did not respond to challenges with agents that raised intracellular cAMP, consistent with the absence of functional CFTR. No lesions or functional abnormalities were evident in the lungs. Liquid-fed Cftr-/- mice were infertile, although some males weaned to a solid diet were fertile before they died. Thus, we have succeeded in using dietary means to prolong the lives of Cftr-/- mice.
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PMID:Phenotypic abnormalities in long-term surviving cystic fibrosis mice. 882 71

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.
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PMID:Gastrointestinal manifestations in cystic fibrosis. 886 67

Mouse models of cystic fibrosis that are generated by targeted disruption (knockout) of the cystic fibrosis transmembrane conductance regulator gene, cftr(-/-), typically die shortly after weaning, from intestinal obstruction/rupture caused by an inability to secrete fluid into the bowel lumen. We investigated the use of a commercial osmotic laxative, Colyte, provided continuously in the drinking water, to increase the survival of cftr(-/-) mice. Genotype analysis of 623 offspring surviving at 10 days of age yielded 28.1% cftr(+/+), 59.6% cftr(+/-), and 12.4% cftr(-/-) mice (25% predicted), suggesting that cftr(-/-) mice have a significant perinatal mortality rate. However, of the 77 cftr(-/-) mice alive at 10 days of age, >98% survived weaning and were maintained in apparent health to a minimum of 56 days of age (arbitrary age for experimentation). In intestinal bioelectric studies Colyte-treated drinking water, compared with tap water, had no significant effect on basal short-circuit current, cyclic AMP-stimulated Cl- secretion, Na+-coupled glucose absorption, or electrogenic Na+ absorption across intestinal sections from cftr(+/+ or +/-) mice. Other than a mild dilatation of the distal portion of the colon in the Colyte-treated animals, examination of jejunal and colonic sections revealed no histologic differences between the two treatments. These findings indicate that the chronic use of Colyte osmotic laxative in drinking water is an economical means of greatly increasing the survival of CFTR knockout mice without altering the major electrolyte transport processes or histomorphologic integrity of the intestine.
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PMID:Increased survival of CFTR knockout mice with an oral osmotic laxative. 900 Nov 72

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.
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PMID:[Characteristics and specificities of cystic fibrosis in adults: evolutive disease of childhood or recently diagnosed disease?]. 1107 85

Cystic fibrosis is the most common life-limiting recessive genetic disorder in Caucasian. It is caused by mutations of CFTR gene (cystic fibrosis transmembrane conductance regulator); at present over 500 mutations are known. Cystic fibrosis as a cause of respiratory distress in the neonate is quite rare. In neonatal period the most important clinical manifestations are meconium ileum and much rarely cholestatic jaundice. We present two cases of cystic fibrosis in newborns. In the first one, we point out the strict association between meconium ileum and cystic fibrosis. The patient underwent a surgical treatment for meconium ileum and the diagnosis was rapidly confirmed by genetic analysis and sweat test. The second one had intestinal obstruction from birth caused by meconium ileum associated with ileal atresia; besides, he developed cholestatic jaundice, severe and rapidly progressive respiratory disease. He died at 102 degrees day of age for cardiac failure. The diagnosis of cystic fibrosis, supported by typical clinical features and high level of serum trypsin, unfortunately wasn't confirmed by genetic analysis (lambda F508/neg), in addition, the sweat test wasn't reliable because an inadequate quantity of sweat was collected.
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PMID:[Neonatal cystic fibrosis: report of 2 cases]. 1142 48

While most cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-knockout animals die due to intestinal obstruction before or at the time of weaning, a subpopulation of these animals are long living and exhibit a milder phenotype. The decreased severity of intestinal disease in these mildly affected CF mice is related to the expression of non-CFTR genetic modifiers. The identity of these genetic modifiers is not known, but we hypothesize that they may complement CFTR function as a chloride channel in this tissue. To assess the contribution of non-CFTR chloride channels to chloride secretion across the small intestine of CF mice with mild disease, we measured the basal transepithelial potential difference across this tissue as well as the secretory response to agonists of the cAMP and the calcium-mediated signaling pathways. Chloride secretion across the small intestine of mildly affected CF mice was not stimulated by forskolin or by carbachol. The absence of CFTR is thus not compensated by the activity of a distinct, cAMP- or calcium-activated chloride channel at the apical surface of the intestinal epithelium. On the other hand, a basal chloride secretion across the intestinal epithelium was present in these animals, and we hypothesize that this activity may be linked to improved survival of these animals.
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PMID:Non-CFTR chloride channels likely contribute to secretion in the murine small intestine. 1184 13

Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16-20% of CF newborns, providing linkage and association results from large family and case-control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case-control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy-Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up.
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PMID:Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results. 1966 35

In Cftr-/- mice that mostly die because of intestinal obstruction, intestinal expression of Clca3 is decreased, whereas upregulation of Clca3 results in amelioration of intestinal disease. The aim of the study was to investigate whether the p.S357N variant in CLCA1, the human orthologue of Clca3, acts as a modifier gene in a cohort of 682 European patients with cystic fibrosis (CF)-99 patients with meconium ileus. The 357SS genotype was significantly overrepresented in both patients with meconium ileus and also with a severe CFTR genotype (P = 0.009) and in p.F508del homozygotes (P = 0.002). This suggests that CLCA1 has similar important functions in CF-related intestinal obstruction in humans as in Cftr-/- mice.
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PMID:Association of the CLCA1 p.S357N variant with meconium ileus in European patients with cystic fibrosis. 2017 44


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