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Changes in rat and mouse salivary glands and pancreas after chronic treatment with diuretics: a potential animal model for cystic fibrosis.

Defective transepithelial chloride and water transport is thought to be the cellular basis of the disease cystic fibrosis (CF). Therefore, it was attempted to develop an animal model for this disease by chronically inhibiting transepithelial chloride transport in experimental animals by long term treatment with high doses of diuretics. In the present study, changes in the salivary glands and pancreas after such treatment were investigated by X-ray microanalysis and electron microscopy. Treatment of rats for one month with diuretics caused a significant decrease in chloride and an increase in calcium in the acinar cells of the submandibular gland. This increase was due to accumulation of mucus in the cells. The strongest effect was obtained after combined treatment with furosemide and acetazolamide. Only minor changes were noted in the parotid gland and the pancreas. Treatment of mice for three months with diuretics caused similar changes in the submandibular glands. In addition, marked changes in the pancreas were observed. The chloride content of the pancreatic acinar cells was decreased. In many acinar cells, only very few zymogen granules were present. The morphological and microanalytical results point to severe dysfunction of the exocrine pancreas. These changes parallel those found in patients with CF, and the chronically furosemide-treated mouse thus could serve as an animal model for this disease.

Acetazolamide↗

The effect of supplemental vitamin E on vitamin A serum levels in cystic fibrosis.

Effects of the ingestion of vitamin E with vitamin A on the serum levels of these vitamins and the urinary creatine to creatinine ratios of 18 children with cystic fibrosis disease of the pancreas (CF) was studied. After the daily ingestion for two months of a specially prepared capsule containing 5000 IU vitamin A palmitate and 100 mg d alpha-tocopherol acetate in aqueous dispersible form there was a significant increase in vitamin A as well as vitamin E levels of serum taken 3 1/2 hr postprandially. Creatine to creatinine ratios in single voiding of urine decreased.

Adolescent↗

COMPARISON OF SOME PROPERTIES OF PSEUDOMONAS AERUGINOSA ISOLATED FROM INFECTIONS IN PERSONS WITH AND WITHOUT CYSTIC FIBROSIS.

Doggett, Robert G. (Texas Institute for Rehabilitation and Research, Houston), Gunyon M. Garrison, and Everett S. Wallis. Comparison of some properties of Pseudomonas aeruginosa isolated from infections in persons with and without cystic fibrosis. J. Bacteriol. 87:427-431. 1964.-Pseudomonas aeruginosa, isolated from the respiratory tract of a group of patients diagnosed as having cystic fibrosis (CF) of the pancreas, attained the ability to produce in its capsule a material which was insoluble in certain organic solvents, such as ethanol. The capsule obtained from P. aeruginosa isolated from infected individuals who did not have CF was ethanol-soluble. This alcohol-insoluble mucoid from the CF P. aeruginosa could be demonstrated to persist after sequential subcultures of this organism. The relative viscosity and carbohydrate moiety of this insoluble mucoid fraction of P. aeruginosa from individuals with CF differed from that of the non-CF P. aeruginosa soluble mucoid fraction.

Chromatography↗

Isolation and culture of rhesus monkey pancreatic ductules and ductule-like epithelium.

The objective of this work was to devise methods for the isolation and culture of duct epithelium from rhesus monkey pancreas with the expectation that such methods would be applicable to the human pancreas. This objective is important because of the role duct epithelium appears to play in human diseases such as pancreatic cancer and cystic fibrosis. Pieces of freshly procured pancreas were minced and enzymatically dissociated, resulting in a digest that contained a few isolated ductules (intralobular ducts) as well as numerous small tissue fragments consisting of roughly equal proportions of ductular and acinar cells. These fragments were suspended in a rat tail collagen gel and cultured for up to 2 weeks in a medium supplemented with cholera toxin, epidermal growth factor, and other additives. A few cystic ductular fragments were initially observed among a large number of predominantly solid fragments. Later, most of the solid fragments also became cystic and eventually resembled the ductules except for being spherical. Autoradiographic analysis of DNA synthesis showed that the cysts possessed a proliferative potential. The cysts consisted almost entirely of ductule-like epithelium with no recognizable acinar cells, and exhibited greatly reduced concentrations of the acinar marker enzymes amylase, chymotrypsin, and gamma-glutamyl transferase. In contrast, the specific activity of the duct marker enzyme carbonic anhydrase was elevated in freshly isolated digests compared with the whole pancreas and this elevated activity was maintained for 4-5 days of culture, after which it declined. Other evidence for the ductular nature of the cysts was their low density relative to freshly isolated acinar tissue, their ability to distend (suggestive of fluid/electrolyte secretion), and the accumulation of mucins at the apical borders of the cells. The results show that fragments of rhesus monkey pancreas that are enriched in ductular epithelium assume some of the properties of ductular cells when cultured in a collagen gel. These epithelial preparations should facilitate biochemical and physiological studies of this important pancreatic cell type.

Amylases↗

[Glucose homeostasis in mucoviscidosis].

In patients with cystic fibrosis (CF) of the pancreas an endocrine imbalance especially of insulin secretion due to progressive structural abnormalities of the pancreas must be expected. 30-75 percent of CF-patient exhibit impaired oral glucose tolerance tests (oGTT). Deterioration of the glucose homeostasis leads to a secondary diabetes mellitus that mimics a type II diabetes in the early stage, in the later course of disease it resembles a type I diabetes with absolute insulinopenia. In this study glucose homeostasis was investigated after an oral glucose load with 1.75 g glucose/kg bodyweight. Glucose, C-peptide and insulin were measured during 180 minutes. 32 nondiabetic CF-patients were studied. 16 patients revealed an impaired oral glucose tolerance according to the criteria of the National Diabetes Data Group. 6 patients showed a normal glucose tolerance and 10 patients with normal fasting and 120 minute glucose concentrations were hyperglycemic at midtest determinations. Impaired oGTTs were observed in malnourished CF-patients in a higher rate than in normal weight patients. A delayed and exceeded C-peptide and insulin response to the oral glucose load was determined with deteriorating glucose tolerance. Glucose values did not drop to fasting values at the 180 minute determination in cases of impaired oral glucose tolerance.

Adolescent↗

Cystic fibrosis.

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Cystic Fibrosis↗

Absolute bioavailability and intracellular pharmacokinetics of azithromycin in patients with cystic fibrosis.

Chronic pulmonary infections with Pseudomonas aeruginosa are the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). The macrolide antibiotics exhibit immunomodulatory and antivirulence activity. Clinical trials with azithromycin in CF have demonstrated significant improvements in pulmonary function and decreased hospitalizations. The purpose of this study was to compare the pharmacokinetics (PK) of azithromycin in patients with CF and controls. The study was conducted as an open-label, parallel, two-period crossover study involving 12 healthy volunteers and 12 patients with CF. Period 1 examined the serum PK following a single oral and intravenous dose, while period 2 examined the intracellular PK following multiple-dose oral administration. CF subjects differed significantly from controls based on weight (53.1 versus 71.0 kg; P < 0.01) and body mass index (19.7 versus 23.2; P < 0.01), respectively. Ninety-two percent of CF patients were pancreatic insufficient and were receiving pancreatic enzymes. The rate (time to reach maximum serum drug concentration, 3.0 versus 3.0 h; P = 0.78) and extent of absorption (absolute bioavailability, 34.2 versus 42.8%; P = 0.37) were similar in patients with CF and controls, respectively. Distribution to the tissues (rate of drug transfer from the central to the peripheral compartment, 1.22 versus 0.759 h(-1); P = 0.03) and elimination (rate of elimination from the central compartment, 0.693 versus 0.492 h(-1); P < 0.01) were more rapid in the healthy volunteers than in the CF subjects, respectively. Mononuclear cell concentrations (15.2 +/- 6.0 mg/liter) far exceeded the maximum serum drug concentration ( approximately 50-fold), demonstrating significant intracellular accumulation. These results indicate no alteration in dosage of azithromycin is necessary in patients with CF taking pancreatic enzymes.

Adult↗