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At least 145 records · Page 8Linked to original sources
PubMed2003

Rescue of defective pancreatic secretion in cystic-fibrosis cells by suppression of a novel isoform of phospholipase C.

BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding an ion-transport protein, the cystic-fibrosis transmembrane conductance regulator (CFTR). Defective secretion of anions is the primary cause of many of the clinical manifestations of cystic fibrosis, including pancreatic insufficiency. We aimed to identify a molecular mechanism from which a new method to circumvent defective pancreatic secretion could be derived. METHODS: Multiple-human-tissue RT-PCR and semiquantitative RT-PCR analyses were used to examine gene expression. An antisense technique was used in conjunction with radioimmunoassay, Fura-2 spectrofluorometry, immunohistochemistry, and the short-circuit current technique (Ussing chamber) for elucidation of gene function and its application in rescuing defective pancreatic secretion. FINDINGS: We cloned a newly identified gene, NYD-SP27, which has structural similarity to an isoform of phospholipase C. NYD-SP27 was expressed endogenously in human pancreatic-duct cells and upregulated in cystic fibrosis. Suppression of NYD-SP27, by transfection of its antisense into human cystic-fibrosis pancreatic-duct cells, resulted in augmentation of phospholipase-C-coupled calcium-ion release and protein kinase C activity, improvement in the amount of mutated CFTR reaching the plasma membrane, and restoration of cAMP-activated pancreatic anion secretion. INTERPRETATION: NYD-SP27 exerts an inhibitory effect on phospholipase-C-coupled processes that depend on calcium ions and protein kinase C, including CFTR trafficking and function. Its upregulation in pancreatic-duct cells may reveal a previously unsuspected defect in cystic fibrosis contributing to pancreatic insufficiency, and thus represents a new target for pharmacological intervention in cystic fibrosis.

Antisense Elements (Genetics)↗
PubMed1992

Chromatographic characterization of CA 19-9 molecules from cystic fibrosis and pancreatic carcinoma.

We have compared the size, the binding to Concanavalin A (Con A), and the affinity for monoclonal antibody 1116NS-199 (Mab 19-9) among CA 19-9 molecules from sera of cystic fibrosis (CF) and pancreatic carcinoma patients and from sputum extracts. CA 19-9 molecules of two different sizes were found in all types of specimens by Sepharose 4B chromatography. While the smaller CA 19-9 molecule was predominant in CF patient sera, the larger molecule was associated with most of the sera from patients with pancreatic carcinoma. The majority of the sputum extracts contained the larger CA 19-9 molecule. All CA 19-9 molecules studied by Con A chromatography did not appear to bind to Con A, and almost 100% were found in the nonreactive fraction. The CA 19-9 molecules from sera of either CF or pancreatic carcinoma patients exhibited variable affinities for Mab 19-9, some approaching that of the standard curve but many also having lower affinities. The lowest affinity was displayed by CA 19-9 molecules from the sputum extract. It appears that development of more specific assays for CF and for carcinoma is possible if the correct CA 19-9 molecule is selected for antibody preparation and for use as standards.

Antibodies, Monoclonal↗
PubMed2000

Detection and follow up of exocrine pancreatic insufficiency in cystic fibrosis: a review.

UNLABELLED: Pancreatic function testing is particularly difficult when the degree of remaining function has to be quantified. Detection of pancreatic insufficiency can suggest the diagnosis of cystic fibrosis (CF). It is, however, also important to follow the degree of pancreatic insufficiency in CF since its function can decline with age. Adaptation of pancreatic enzyme replacement therapy on residual function is necessary. Different tests with their advantages and disadvantages are critically reviewed in this article with respect to specificity, sensitivity, performance and cost-effectiveness. CONCLUSION: Elastase-1 detection in faeces is probably the easiest test for the detection of pancreatic insufficiency in cystic fibrosis. For clinical follow-up tests, measuring the fat assimilation such as steatocrit and breath tests are more suited.

Aftercare↗
PubMed2003

Chronic pancreatitis and cystic fibrosis.

Recent discoveries of trypsinogen and trypsin inhibitor mutations in patients with chronic pancreatitis (CP) support the hypothesis that an inappropriate activation of pancreatic zymogens to active enzymes within the pancreatic parenchyma starts the inflammatory process. Current data suggest that CP may be inherited dominant, recessive, or complex as a result of mutations in the above mentioned or yet unidentified genes. Evaluation of patients with CP should include genetic testing. Cystic fibrosis (CF) is an autosomal recessive inherited disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene and is characterised by pancreatic insufficiency and chronic bronchopulmonary infection. The progression and severity of pulmonary disease differs considerably between people with identical CFTR mutations and does not seem to correlate with the type or class of the CFTR mutation. The identification of further disease modifying genetic factors will increase the pathophysiological understanding and may help to identify new therapeutic targets.

Chronic Disease↗
PubMed1998

Paediatric and hereditary aspects of chronic pancreatitis.

Cystic fibrosis is by far the commonest cause of chronic pancreatitis in children, but pancreatitis itself is only rarely its presenting feature. In this paper an hypothesis for the development of the pancreatic lesions is presented. Impaired activation of pancreatic proteases in the small intestine is perceived as the pivotal problem that leads to continual feedback release of cholecystokinin, thus, in effect, causing a chronic hyperstimulation pancreatitis with intra-acinar activation of zymogens and, when bicarbonate secretion falls, precipitation of 'Reg' and other proteins in the duct system. This position contrasts with that in hereditary pancreatitis in which a mutation in the cationic trypsinogen gene leads to a form of trypsin that resists degradation by mesotrypsin and enzyme Y. A survey of the literature suggests that oxidant stress is a plausible contributor to pancreatic injury in both these diseases and in several other conditions linked with childhood pancreatitis.

Acute Disease↗
PubMed1993

Serum immunoglobulin G directed against porcine trypsin in the serum of cystic fibrosis children receiving porcine pancreatic enzyme supplements.

Cystic fibrosis (CF) patients require pancreatic enzyme replacement therapy to correct pancreatic insufficiency. These enzymes are derived from porcine pancreas and are known to be antigenic. To determine the possible clinical consequences, a specific ELISA was developed to detect IgG antibody directed against porcine trypsin (PTAb) in the sera of CF patients. The assay was used to evaluate the occurrence of PTAb in a cross sectional study of 103 CF patients in relation to the introduction of porcine enzyme therapy, clinical status and genotype. Antibodies against porcine trypsin were detected in the sera of 63% of patients unrelated to the age of commencement or the duration of enzyme therapy. No differences were observed in the clinical status of CF patients who had developed PTAb (n = 65) and those who had no detectable PTAb (n = 38) as determined from: the current prescribed dose of porcine pancreatic enzyme capsules; Z scores for height and weight; and respiratory function tests. It is suggested that the PTAb commonly found in the sera of CF patients are of doubtful clinical significance but the prospect of PTAb contributing to immune complex disease should be examined further.

Adolescent↗
PubMed2005

Update on the evaluation of pancreatic exocrine status in cystic fibrosis.

PURPOSE OF REVIEW: Pancreatic functional status has a very strong effect on outcome in cystic fibrosis and pancreatic insufficiency requires lifelong treatment with pancreatic enzymes. Traditionally, clinical signs and symptoms have been used to decide who should be treated with pancreatic enzyme supplements; however, recent studies show that patients with cystic fibrosis are both undertreated and over-treated using this approach. This paper reviews recent progress in the development of noninvasive, indirect tests of pancreatic function for use as diagnostic tools for patients with cystic fibrosis. RECENT FINDINGS: Breath testing using C-labeled fat and measurement of several pancreatic enzymes in stool, such as chymotrypsin, lipase, and elastase have been explored as ways to define pancreatic functional status. Fecal elastase has good sensitivity, specificity, and positive and negative predictive value for defining severe pancreatic insufficiency in patients with cystic fibrosis and appears to be more useful than measurement of other fecal enzymes. Its role in milder pancreatic insufficiency and in disease states other than cystic fibrosis, such as chronic pancreatitis, is less clear. SUMMARY: Several new noninvasive, indirect tests of pancreatic function have been developed to aid in the definition of pancreatic functional status in patients with cystic fibrosis. An objective measure of pancreatic functional status should be obtained in all patients with cystic fibrosis, and the recent development of new screening tools such as fecal elastase makes this feasible.

Breath Tests↗
PubMed2004

Serum lipase after secretin stimulation detects mild pancreatic involvement in cystic fibrosis.

BACKGROUND: The assessment of severe pancreatic insufficiency in cystic fibrosis (CF) is not a diagnostic problem. However, identification of mild cases remains a challenge. The aim of this study was to assess the ability of serum lipase after secretin stimulation to identify mild pancreatic insufficiency in patients with CF. MATERIAL AND METHODS: Thirty patients with CF and pancreatic insufficiency (CF-PI) and 30 patients with CF and pancreatic sufficiency (CF-PS) were studied. Thirty healthy subjects with no known gastrointestinal disease served as controls. In all subjects, fecal fat excretion, fecal elastase-1 (E1) concentration and basal and secretin-stimulated serum lipase concentration were measured. RESULTS: All patients with CF-PI and 3 with CF-PS had abnormally low fecal E1 concentrations. The remaining 27 CF-PS patients and all controls had normal values. Basal and post-stimulation lipase levels were extremely low in patients with CF-PI. Mean basal and poststimulation serum lipase concentrations were significantly higher in CF-PS who had normal fecal E1 concentrations but were still below those of controls (P < 0.001). Among the 27 CF-PS patients with normal fecal elastase, high basal and poststimulation lipase values were found in 6 and 17 patients respectively. CONCLUSION: In patients with CF-PS who have normal fecal elastase-1 concentration, the measurement of basal or secretin-stimulated lipase levels might be helpful in identifying the progression of the destructive process in the pancreas.

Adolescent↗
PubMed1986

Pancreatic cystosis in cystic fibrosis.

Two patients with cystic fibrosis and pancreatic cystosis are described who had complete replacement of the pancreas by multiple macroscopic cysts. The possible causes and clinical significance of this condition are discussed.

Adolescent↗
PubMed1998

Desensitization to pancreatic enzyme intolerance in a child with cystic fibrosis.

OBJECTIVE: Pancreatic enzyme is essential in the treatment of cystic fibrosis (CF), but intolerance to it occasionally occurs. We encountered a child who was intolerant to multiple commercially available preparations of pancreatic enzymes and, hence, desensitization was attempted, with success. CASE PRESENTATION: A 33-month-old girl was diagnosed with CF at 6 months of age. Initially, she was started on Pancrease MT 16, which was subsequently discontinued because fecal fat studies were normal and she seemed to do well on Nutramigen and vitamin supplements. At 29 months of age, she developed diarrhea with bulky stools and weight loss. A fecal fat 72-hour study revealed a coefficient of absorption of 50%. She was treated with Pancrease MT 16, but had consistent vomiting 1 to 2 hours after administration of enzymes. The vomiting occurred on switching to different pancreatic enzymes preparations, ie, Creon 10, Viokase, and Pancrease MT 16. Vomiting occurred even with small doses of enzymes disguised in food. She had no history suggestive of gastroesophageal reflux, peptic ulcer, or pork allergy, and no vomiting on days when enzymes were not given. This was suggestive of type I hypersensitivity reaction. Pancreatic enzymes were discontinued, and she was given a low-fat, high-carbohydrate diet with satisfactory weight gain. METHODS: Double-blind, placebo-controlled titrated oral challenges with pancreatic enzymes resulted in definite vomiting within 1 to 1.5 hours after challenges with Viokase and Pancrease MT 16, but not with placebo. Rush oral desensitization with Viokase solution was attempted, starting with 5 mg, and the dose was doubled every 20 minutes, aiming to reach a cumulative dose of 700 mg. However, the child vomited when a cumulative dose of 315 mg was reached. Another trial of slower desensitization was done using Pancrease MT 16 (1 capsule: 16 000 U of lipase, 48 000 U of amylase, and 48 000 U of protease), starting with 1/4 capsule per day, with increments of 1/4 capsule every 3 days, until an entire capsule was reached by day 10, then increased by approximately 1/2 capsule every 4 days until reaching the therapeutic dose of 1 capsule with each meal by day 25. RESULTS: The patient tolerated this fairly well and has been on this treatment and regular diet for >1 year, without any adverse reaction. This illustrates a rare case of gastrointestinal adverse reaction to pancreatic enzymes that was treated successfully with desensitization. CONCLUSION: Pancreatic enzyme intolerance, although rare, would be a major problem in the management of patients with CF. Hence, desensitization would be essential and may be accomplished successfully using the protocol described in this report.

Child, Preschool↗
PubMedDate not supplied

Multifocal myocardial necrosis: a distinctive cardiac lesion in cystic fibrosis, lipomatous pancreatic atrophy, and Keshan disease.

Multifocal myocardial necrosis (MMN) is an unusual cardiomyopathy of childhood, characterized by multiple patchy areas of myocardial fiber necrosis/fibrosis involving mainly the middle part of the left ventricle, but also, to a lesser extent, the right ventricle and the atria. These necrotic lesions are isolated and are not accompanied by an inflammatory reaction or vascular alterations. They are responsible for acute cardiac failure. MMN lesions are observed in various pathologic conditions including cystic fibrosis of the pancreas, pancreatic lipomatous hypoplasia/atrophy, malnutrition due to extensive intestinal resection with subsequent total parenteral feeding, and in Keshan disease. MMN is the main and the most characteristic feature of Keshan disease, an endemic and idiopathic condition affecting Chinese rural children. The causes and mechanisms of MMN presently are unknown. However, the presence of similar cardiac lesions in such different pathological conditions suggests the role of a selective deficiency of a hypothetical extrinsic factor (selenium, molybdenum iodide, other), probably crucial for the metabolism of the myocardial fiber.

Atrophy↗
PubMed1999

Synergistic effects of cAMP- and calcium-mediated amylase secretion in isolated pancreatic acini from cystic fibrosis mice.

We evaluated pancreatic enzyme secretory response to secretagogues (cAMP- and Ca2+-mediating) involved in exocytosis and in chloride channel activation in an exon 10 knockout cystic fibrosis (CF) mouse model. Experiments were performed in isolated pancreatic acini from liquid-fed Cftr-/- mice (5-6 wk of age) and age-matched Cftr+/+ controls fed a solid or liquid diet. BrcAMP and forskolin alone induced higher amylase secretion (% initial amylase content) in the Cftr+/+ acini than carbachol (p < 0.05). Carbachol and BrcAMP or BrcAMP and forskolin, given in combination, produced additive effects on enzyme secretion in the Cftr+/+ acini. Ca2+- and cAMP-mediated amylase secretion in isolated pancreatic acini from the Cftr-/- mice was no different to that observed in the age- and diet-matched Cftr+/+ animals. However, Cftr-/- pancreatic acini showed a significantly greater amylase response to the combination of BrcAMP and carbachol than the sum of the individual responses in separate experiments (p < 0.05). The amylase response was not different in acini from solid-fed or liquid-fed Cftr+/+ controls. In summary, this study suggests that cystic fibrosis transmembrane conductance regulator is not essential for enzyme secretion as evidenced by no reduction in cAMP-mediated amylase secretion in Cftr-/- mice. The results in Cftr+/+ acini suggest pancreatic enzyme secretion is mediated via multiple intracellular pathways acting in parallel and probably converge at a distal step in the secretory process. However, Cftr-/- pancreatic acini exhibited a synergistic secretory response following stimulation by BrcAMP plus carbachol. The enhanced secretory response may partially contribute to the development of pancreatic dysfunction in CF patients by facilitating occlusion of digestive enzymes in the secretory canaliculus of the pancreatic acini.

8-Bromo Cyclic Adenosine Monophosphate↗