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PubMed1992

Expression and chromosome localization of the murine cystic fibrosis transmembrane conductance regulator.

A 13.5-kb genomic fragment of the mouse cystic fibrosis transmembrane conductance regulator (CFTR) gene was isolated from a C57BL/6J liver DNA library, using a human CFTR exon 10 probe. This region of the human gene includes the most common cystic fibrosis mutation (deletion of the Phe508 residue) in the first nucleotide binding domain of CFTR. Sequence analysis demonstrated 87% identity between the predicted mouse and the normal human CFTR exon 10 sequences, including conservation of the Phe508 residue. Northern analysis revealed that the mouse gene is expressed in intestine, lung, stomach, kidney, and salivary gland. In contrast to human CFTR, murine CFTR transcripts were not detectable by Northern analysis in the liver or pancreas. More sensitive PCR analysis, however, revealed that the mouse CFTR gene is weakly expressed in other tissues, including liver and pancreas. During development, mouse CFTR transcripts were observed as early as Embryonic Day 13. Southern analysis of mouse x Chinese hamster somatic cell hybrid DNAs mapped the mouse CFTR locus (Cftr) to Chromosome 6 (Chr 6). Subsequent typing of the progeny of an interspecies backcross revealed that Cftr is closely linked to the proto-oncogene c-met locus (Met) in the centromeric region of mouse Chr 6, consistent with the observation that there is a conserved chromosomal segment on human chromosome 7 and mouse Chr 6.

Amino Acid Sequence↗
PubMed1983

Neuro-hormonal control of pancreatic function in man and its failure.

Regulation of pancreatic exocrine secretion is comprised of a complex interplay between hormonal and nervous mechanisms. Stimulatory gut hormones which act via the circulation include secretin, CCK, gastrin and bombesin, while VIP operates through peptidergic nervous release. Pancreatic polypeptide and glucagon are two examples of circulating inhibitory hormones while inhibition by somatostatin is through a paracrine release mechanism. Although the effects of vagal cholinergic nerves have been previously thought to be indirect through hormone release evidence is now accumulating for a direct role. Altered hormone release has been noted in chronic pancreatic insufficiency, cystic fibrosis and coeliac disease and may contribute in an important way to the pathophysiology of these malabsorptive disorders.

Autonomic Nervous System↗
PubMed1992

The Pitt-UNOS Liver Transplant Registry.

Since the establishment of the scientific LTR, the frequency of OLTX has been increasing. Between 1988 and 1991, the number of procedures performed on pediatric patients increased by 28.2%, and among adult patients OLTX increased 84.8%. During this same period, the number of transplant centers performing OLTX rose 62.5% for children, and 54.7% for adult recipients. In 1991 there was a larger proportion of recipients under 1 year of age than in previous years. The effect was to lower the median age at transplantation from over 2 to between 1 and 2. In pediatric recipients of initial transplantation in 1991, compared with earlier recipients, the functional status at time of liver transplantation was improved. Fewer children were in the ICU while awaiting transplantation, and more were able to wait at home. Multiorgan transplantations in pediatric patients remained relatively rare, but a larger portion of these procedures in 1991 than was seen previously included the small intestine. Biliary atresia remained the most common indication for liver transplantation among children, accounting for over 55% of all OLTX procedures in 1991. There was a significant change in the racial distribution among adult recipients. Compared with previous years, there were greater proportions of Hispanic and Asian recipients in 1991. Adult recipients were older in 1991 than previously, and the median age increased from 46 to 49. As with pediatric recipients, adult recipients had better functional status in 1991 than earlier recipients. The increase in positive CMV serology was likely to be a function of older age. Among multiorgan recipients, the combination of liver and pancreas only was much less common in 1991 than previously. As was found previously (1), alcoholic cirrhosis continued to be the most common reason for OLTX, with the proportion of patients diagnosed with this condition increasing in 1991. Twice as many patients with cystic fibrosis were recipients in 1991 as in the prior 3 years. There were decreases in the proportion of patients receiving OLTX due to fulminant liver failure, metabolic disease, and malignant neoplasms. The cumulative probability of surviving (without retransplantation) 4 years after initial transplantation was 0.74 (0.61) for pediatric recipients. Univariate (unadjusted) analyses detected significant differences in survival for age (the youngest recipients had the worst survival), UNOS description (poorer functional status just prior to transplantation led to poorer survival), and primary liver disease (survival was worst for recipients transplanted due to fulminant liver failure, and best for patients with alpha-1 antitrypsin deficiency).(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1984

The noninvasive biochemical diagnosis of gastrointestinal disease, with special reference to children.

Invasive tests to diagnose patients with gastrointestinal disease are rapidly being replaced by procedures which enable organ function to be assessed by monitoring the product of a metabolic reaction in readily available materials such as breath, blood, and urine. Examples of these approaches that will be assessed in this review include the hydrogen breath test for lactase deficiency, radioactive carbon dioxide breath measurements to test for fat digestion and absorption, and tests of pancreatic function based upon synthetic substrates from which fluorescein or para-aminobenzoic acid can be liberated by pancreas-specific enzymes. Significant advances have been made in improving the organ sensitivity of enzyme determinations. The determination of amylase isoenzymes has been less useful than the measurement of immunoreactive trypsin; this latter enzyme is greatly elevated in the blood of neonates with cystic fibrosis, whereas serum levels are greatly depressed in cystic fibrosis patients with pancreatic insufficiency as well as in most patients with steatorrhea due to chronic pancreatitis. Many of these tests are now becoming standard procedures in the investigation of infants with gastrointestinal disease.

Amylases↗
PubMed1987

Immunocytochemistry of band 3 protein in kidney and other tissues of control and cystic fibrosis patients.

Current evidence indicates that the underlying genetic defect in cystic fibrosis (CF) results in defective chloride transport, and more specifically, chloride impermeability. However, recent consideration has been given to a possible defect in band 3 protein at CF-affected sites. In an effort to determine a possible role for band 3, an anion exchange channel protein, a series of immunocytochemical localizations was performed. Immunocytochemical staining for the anion channel band 3, 43K, in normal and CF human kidney was confined to erythrocytes, glomerular podocytes, the basal region of half of the cells of the initial connecting segment of cortical collecting ducts, and a minority of cells in medullary ray-collecting ducts. Erythrocytes alone evidenced immunoreactivity for band 3 protein in human pancreas, submandibular gland, trachea, and lung. In all cases, specimens from patients with CF stained like those from control subjects for band 3. Abnormal Cl- transport in CF tissues is not reflected in altered band 3, 43K, localizations.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1995

New pancreas cancers cell lines that represent distinct stages of ductal differentiation.

BACKGROUND: Most available pancreas cancer cell lines have been in culture for long periods of time, have not been extensively characterized from the cell biology standpoint, or lack differentiated properties. EXPERIMENTAL DESIGN: We have established four new cell lines from ductal pancreatic cancers (IMIM-PC-1, IMIM-PC-2, SK-PC-1, and SK-PC-3). The phenotype and functional properties of the cell lines were analyzed using ultrastructural methods, antibodies detecting cytokeratin polypeptides and mucin epitopes, and cDNA probes of epithelial differentiation markers. RESULTS: IMIM-PC-2 and SK-PC-1 cells grow as a polarized monolayer, form domes, and express all CK polypeptides typical of simple epithelia and the MUC1 mucin. IMIM-PC-1 and SK-PC-3 are morphologically less differentiated and express low or undetectable levels of CK7 and MUC1. By Northern blotting, we found that SK-PC-1 and SK-PC-3 cells express carbonic anhydrase II and that the cystic fibrosis transmembrane regulator was undetectable in the four lines. Secretin induces a marked stimulation of cAMP levels in all cell lines except for SK-PC-3. Cytogenetic analysis demonstrates their human origin. CONCLUSIONS: Levels of CK7 and MUC1 are associated with less differentiated cultures. The new cell lines should be useful tools to study the cell biology of exocrine pancreas cancer.

Antigens↗
PubMed2002

Histologic and fine-needle aspiration cytologic features of polycystic disease of the parotid glands: case report and review of the literature.

Polycystic disease of the parotid glands is a rare disorder, with only eight examples to our knowledge being reported in the literature. The disease presents as a painless enlargement of one or both parotid glands and does not appear to be associated with other disease processes within the head and neck, or with polycystic disease of the kidney, pancreas, or congenital fibrosis of the liver. The histology has been well described. The overall glandular architecture is preserved but the lobules are markedly distended by cysts whose lining appears to be intercalated duct in differentiation. Characteristic eosinophilic laminated spheroliths lie in many of the cystic spaces. Aspirate smears are characterized by a relatively clean background in which are distributed histiocytes, red blood cells, and small clusters of ductal epithelial cells. Polycystic disease of the parotid glands must be differentiated cytologically from mucous retention reaction, mucoceles, benign lymphoepithelial cysts, and cystic neoplasms, including Warthin's tumor, low-grade mucoepidermoid carcinoma, cystadenoma, and papillary cystadenocarcinoma.

Adult↗
PubMed1999

Overview of the clinical experience with Neoral in transplantation.

The microemulsion preparation of cyclosporine, Neoral, was introduced to improve the limited and sometimes unpredictable absorption of cyclosporine from the gut. Preclinical studies proved a superior bioavailability measured by the AUC and a definitively better predictability of the pharmacokinetic properties. Large-scale randomized and open-labeled studies have been carried out to prove and establish the safety, tolerability, and equal or superior efficacy of NEO if compared with SIM. There is broad evidence that NEO is safe and well tolerated in de novo and stable renal allografts. There are some arguments that NEO has favorable properties in poor absorbers, in patients in need for high dosage per kg body weight. Benefits for some populations such as children, African Americans, and diabetics have been detected. In combined kidney-pancreas transplantation a significant improvement of absorption has been proven. NEO has also been investigated in nonrenal transplants such as heart, lung, and liver transplantation. There are proven dose reduction in heart transplants; significant better absorption in lung transplants, in particular in patients with cystic fibrosis; and no further or even a diminished need for intravenously given CsA in liver transplantation. Studies are now reported for the use of NEO in differing indications of autoimmune disease. No characteristic profile of adverse events has been recognized, nor has an increase of nephrotoxicity if carefully monitoring in the first weeks after conversion was provided.

Autoimmune Diseases↗
PubMed1996

Colonic strictures in patients with cystic fibrosis: results of a survey of 114 cystic fibrosis care centers in the United States.

We describe 15 cases of stricture of the colon requiring surgery in cystic fibrosis patients identified from a survey of 114 cystic fibrosis care centers in the United States. Patient ages ranged from 2 to 8 years, seven of the 15 patients were female. A history of meconium ileus was reported in nine of the 15 cases. Fibrosis of the submucosa was described in 14 surgical pathology reports. Pancreatic enzyme use history was available from 14 reports. All had taken delayed-release products for 6-96 months at average doses ranging from 6,700 to 29,100 units lipase/kg/meal, but only eight of them used products containing >20,000 units lipase per capsule prior to surgery.

Administration, Oral↗
PubMed1965

LATE INTESTINAL OBSTRUCTION IN PATIENTS SURVIVING NEONATAL MECONIUM ILEUS.

Two of 15 children who survived neonatal meconium ileus had "meconium ileus equivalent." They were treated with hydration, pancreatic enzyme therapy and antibiotics. One of these children died from pulmonary disease at the time of the bowel obstruction. The survival rate of infants with meconium ileus is steadily improving because of prompt operative intervention, better preoperative and postoperative care and long-term treatment with enzyme supplements and antibiotics. Late intestinal obstruction due to adhesive bands, volvulus, intussusception or "meconium ileus equivalent" may occur in children previously treated for meconium ileus of infancy. The omission of pancreatic enzyme supplementation and the occurrence of respiratory infections are frequently associated with "meconium ileus equivalent."In this series of patients four of the infants treated surgically for neonatal meconium ileus died in the early postoperative period.

Anti-Bacterial Agents↗
PubMed1992

Liver disease in cystic fibrosis.

Liver disease associated with cystic fibrosis (CF) is considered a secondary effect of the basic defect of the disease, leading to obstruction of bile ductules by abnormal mucoid secretions; additional factors have been involved in the pathogenesis, such as abnormalities in bile acid metabolism, nutritional deficiencies, drug hepatotoxicity, stenosis of the common bile duct by the fibrotic pancreas. Clinical presentation of liver disease in CF is rare during the first few years of life, although neonatal cholestasis can be occasionally the first manifestation of the disease. Isolated massive steatosis has been reported in less than 5% of cases as a consequence of malnutrition. Focal biliary cirrhosis is the pathognomonic hepatic lesion and is present in 25-30% of CF patients, most of whom are asymptomatic. The focally distributed lesions can extend leading to multi-lobular biliary cirrhosis with occurrence of signs and symptoms of cirrhosis and portal hypertension. Early diagnosis of CF-associated liver disease is difficult since liver function tests may be normal even in cases of overt cirrhosis: no test has proved to be sufficiently sensitive and specific and even liver biopsy is of questionable relevance due to the focal distribution of hepatic lesions. Clinical examination is of major importance, since the presence of hepatomegaly seems to correlate well with the histologic finding of fibrosis. The rationale for the use of the choleretic non-toxic bile acid ursodeoxycholic acid in CF-associated liver disease is to reduce the viscosity of bile and to replace toxic bile acids which accumulate in the hepatocyte.(ABSTRACT TRUNCATED AT 250 WORDS)

Cystic Fibrosis↗
PubMed2003

Identification of patients with genetic risk factors of pancreatitis: impact on treatment and cancer prevention.

Recent data suggest that genetic alterations are relevant risk factors for chronic pancreatitis. The highest risk is associated with autosomal-dominant mutations (N29I, R122H) of the cationic trypsinogen (PRSS1). Further mutations were identified in the genes of the pancreatic trypsin inhibitor (SPINK1) and in the cystic fibrosis transmembrane conductance regulator (CFTR). A remarkable finding was that both molecules were also mutated in patients suffering from alcoholic chronic pancreatitis. According to recent estimations, genetic alterations may be regarded as more severe risk factors than chronic alcohol consumption. To identify patients with mutations, a positive family history could be of help, but mutations were also found in a significant number of those with a negative family history. On the other hand, in approximately 40% of the patients with a positive family history no mutations were found up to now. The age at onset is lower in patients with genetic risk factors; however, no clear limit can be denominated above which a screening is not appropriate. Therefore, in our department genetic screening is offered to all patients with chronic pancreatitis of unclear origin. There is no specific treatment in patients with a genetically based disease. The patients with familial pancreatitis-increased rates of pancreas cancer were described but there is no agreement concerning the prophylactic strategy. Prevention of cancer by routine pancreatectomy, though performed recently, is not justified at the moment. Clinical criteria may be more appropriate to decide the timing and the extent of the operation.

Chronic Disease↗
PubMed1998

Faecal immunoreactive lipase: a simple diagnostic test for cystic fibrosis.

UNLABELLED: The study evaluates faecal immunoreactive lipase (IRL) measurement in spot stool samples as an index of exocrine pancreatic function in patients with cystic fibrosis (CF). Stool samples (211) from 183 healthy volunteers (age range: 2 days-14.2 years) showed a normal log distribution of IRL values with a median concentration of 71.4 micrograms/g (range: 0.53-4160 micrograms/g). In 156 stool samples from 58 patients with proven CF, the median IRL concentration of 0.4 microgram/g (range: 0.003-107 micrograms/g) was significantly lower (P < 0.001) than that of normal controls. In healthy controls, IRL levels were age related with significantly higher levels (P < 0.001) shortly after birth compared to older children. Stimulation of the exocrine pancreas by oral milk feeding resulted in a significant (P < 0.001) increase in a faecal IRL concentration. Faecal IRL concentrations in meconium were very low and of the same magnitude as in patients with CF. CONCLUSION: Faecal IRL determination had a high diagnostic sensitivity (87%) and excellent diagnostic specificity (97%) in patients with CF. A negative test result (PVneg. 99%) virtually excluded CF under screening conditions.

Adolescent↗
PubMed2001

Targeting transgene expression for cystic fibrosis gene therapy.

We have developed an expression cassette for cystic fibrosis (CF) gene therapy using control elements from the human cytokeratin 18 gene (KRT18, also known as K18). KRT18 is naturally expressed in a spatial pattern similar to that of CFTR, the gene mutated in CF. We delivered a KRT18-driven lacZ plasmid complexed with cationic liposomes intravenously to mice and examined expression in various tissues. We found expression in nasal and bronchial epithelium, airway submucosal glands, gall bladder, and kidneys. Expression was low in pancreas and gut, and absent from liver and alveolar lung. This is consistent with the expression pattern reported for a K18lacZ transgenic mouse. Following delivery of a cytomegalovirus (CMV) major immediate-early promoter/enhancer-driven lacZ plasmid, we found expression in bronchi, submucosal glands, alveolar cells, liver, and kidney. We did not detect expression in nose, pancreas, gall bladder, or gut. Using fluorescently labeled plasmid delivered by means of liposomes, we identified the liver, alveolar lung, and kidneys as the major plasmid deposition sites. Our data demonstrate that a KRT18-driven expression vector delivered systemically can target gene expression to CF-affected tissues, despite an uneven distribution of plasmid DNA. A KRT18-based vector may be a useful alternative to viral promoter-based vectors in clinical gene therapy trials to treat CF.

Animals↗
PubMed2004

Chronic pancreatitis: controversies in etiology, diagnosis and treatment.

The pathogenesis of idiopathic chronic pancreatitis remains poorly understood despite the high expectations for ascribing the pancreatic damage in affected patients to genetic defects. Mutations in the cationic trypsinogen gene, pancreatic secretory trypsin inhibitor, and the cystic fibrosis conductance regulator gene do not account for the chronic pancreatitis noted in most patients with idiopathic chronic pancreatitis. Small duct chronic pancreatitis can be best diagnosed with a hormone stimulation test. Endoscopic ultrasonography can detect abnormalities in both the parenchyma and ducts of the pancreas. The true value of endoscopic ultrasonography in diagnosing small duct chronic pancreatitis remains to be fully defined and is under active investigation. It is not clear whether endoscopic ultrasonography is more sensitive for early structural changes in patients with small duct disease or is over diagnosing chronic pancreatitis. Pancreatic enzyme supplementation with non-enteric formulation along with acid suppression (H2 blockers or proton pump inhibitors) is an effective therapy for pain in patients with small duct chronic pancreatitis. The role of endoscopic ultrasonography-guided celiac plexus block should be limited to treating those patients with chronic pancreatitis whose pain has not responded to other modalities. Total pancreatectomy followed by autologous islet cell autotransplantation appears to be potential therapeutic approach but for now should be considered experimental.

Chronic Disease↗
PubMed1995

Pancreatic insufficiency and pulmonary disease in German and Slavic cystic fibrosis patients with the R347P mutation.

Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) that codes for a cAMP-regulated chloride channel. The R347P is a missense mutation located within the first membrane spanning domain (MSD1) of the CFTR protein. This mutation occurs with an overall worldwide frequency of about 0.2%. The patients, originally described with this mutation were compound heterozygotes with the delta F508 mutation and had a very mild course of CF, suggesting that R347P, similar to other missense mutations affecting the MSD1 domain, causes a mild phenotype. We report here a group of 19 CF patients with the R347P mutation of German, Bulgarian, Czech, and Slovak origin, including two homozygotes. Most patients presented with early disease onset, pancreas insufficiency (PI), and early pulmonary involvement, suggesting that this mutation can lead to a severe course of CF. Most R347P alleles in the group studied share a common polymorphic haplotype. In addition, these analyses gave evidence for recurrence of the mutation in two CF patients of German and Czech origin.

Cystic Fibrosis↗