Showing papers on "Cystic fibrosis published in 1985"
TL;DR: Evidence for tight linkage between the CF locus and a DNA sequence polymorphism at the met oncogene locus is obtained, which places theCF locus in the middle third of the long arm of chromosome 7, probably between bands q21 and q31.
Abstract: Cystic fibrosis is a recessive genetic disorder, characterized clinically by chronic obstructive lung disease, pancreatic insufficiency and elevated sweat electrolytes; affected individuals rarely live past their early twenties. Cystic fibrosis is also one of the most common genetic diseases in the northern European population. The frequency of carriers of mutant alleles in some populations is estimated to be as high as 1 in 20, carrying a concomitant burden of about one affected child in 1,500 births. Because little is known of the essential biochemical defect caused by the mutant gene, a genetic linkage approach based on arbitrary genetic markers and family studies is indicated to determine the chromosomal location of the cystic fibrosis (CF) gene. We have now obtained evidence for tight linkage between the CF locus and a DNA sequence polymorphism at the met oncogene locus. This evidence, combined with the physical localization data for the met locus presented in the accompanying paper1, places the CF locus in the middle third of the long arm of chromosome 7, probably between bands q21 and q31.
403 citations
TL;DR: It is concluded that tobramycin penetrates cystic fibrosis sputum and accumulates over time and 3 wk of intravenous therapy combined with an antipseudomonal beta-lactam antibiotic may be effective in eradication of P. aeruginosa fromSputum of certain CF patients.
Abstract: We studied sputum tobramycin concentrations after intravenous administration in 10 cystic fibrosis patients. Tobramycin concentrations were determined by a bioassay and a radioenzymatic assay (REA). The bacterial density of Pseudomonas aeruginosa in sputum was examined serially during therapy. Bioactivity of tobramycin in the sputum was low and increased little during treatment. In contrast, tobramycin content (as assayed by REA) showed a progressive accumulation of the drug to high concentrations: a mean of 82 micrograms/g sputum after 3 wk of therapy in 4 patients. Pseudomonas aeruginosa was eradicated from the sputum in 3 of 4 patients receiving antibiotic therapy for 3 wk. Eradication correlated with tobramycin sputum concentrations measured by REA, which were 20-fold greater than the apparent tobramycin inhibitory concentration. A bactericidal effect of aminoglycosides in the presence of sputum in vitro could only be reliably produced with concentrations 25-fold the MIC. We conclude that tobramycin penetrates cystic fibrosis (CF) sputum and accumulates over time. Although CF sputum antagonized the bioactivity of aminoglycosides, 3 wk of intravenous therapy combined with an antipseudomonal beta-lactam antibiotic may be effective in eradication of P. aeruginosa from sputum of certain CF patients.
239 citations
TL;DR: It is concluded that fluid secretion in patients with cystic fibrosis may be a rate-limiting factor in protein output and that a limited flow of hyperconcentrated protein secretions may predispose to protein precipitation and ductal obstruction in the pancreas.
Abstract: To study pancreatic protein and water secretion in 28 patients with cystic fibrosis and 21 controls matched for pancreatic acinar function as defined by trypsin secretion, we used a quantitative-marker perfusion technique and continuous intravenous secretin-pancreozymin stimulation. Regardless of the level of pancreatic acinar function, secretions from the patients contained significantly higher concentrations of protein than those from the controls. Total protein output and albumin:protein ratios were not increased in secretions from the patients, but their fluid secretion was significantly decreased at any level of pancreatic function. A significant linear correlation was found between protein and volume secretion in the patients (r = 0.86, P less than 0.001), most of whom had a fluid output of less than 4.2 ml per kilogram of body weight per hour. No such relation was found in the control subjects, whose flow was always above 4.2 ml per kilogram per hour. We conclude that fluid secretion in patients with cystic fibrosis may be a rate-limiting factor in protein output and that a limited flow of hyperconcentrated protein secretions may predispose to protein precipitation and ductal obstruction in the pancreas.
202 citations
TL;DR: Pseudomonas is the harbinger of death for any cystic fibrosis patient, and once it begins to march through the lungs, it multiplies with impunity and sweeps everything in its path.
Abstract: "... perhaps the worst thing about cystic fibrosis is that it attracts a bacteria known as pseudomonas. The excessive, filthy mucus overwhelms the defense mechanisms in the lungs, so the pseudomonas bacteria colonize there. Pseudomonas is most common with cystic fibrosis, but it is also a threat to patients why have been severely burned, and it is found in the bloodstreams of certain types of cancer patients. Still, for all the research that has been done, there is as yet no antibiotic to deal with pseudomonas, and once it begins to march through the lungs, it multiplies with impunity and sweeps everything in its path. For any cystic fibrosis patient, pseudomonas is the harbinger of death." [1]
197 citations
TL;DR: The data suggest that host-selective pressures, associated primarily with patients with cystic fibrosis that are in poor clinical condition, result in the loss of factors related to invasiveness such as motility and chemotaxis.
Abstract: Selected physiological parameters of 31 classic and rough Pseudomonas aeruginosa strains from respiratory tract cultures of patients with cystic fibrosis were examined. An association of a patient9s clinical condition (good or poor) with strain physiology was made. Rough strains from patients in poor clinical condition demonstrated severe alterations in motility when compared with M-2, a highly motile and chemotactic burn strain. Of the 10 rough strains from patients in poor clinical condition, 70% lacked flagella, as determined by electron microscopy. The remaining few flagellated strains from this group exhibited weak motility both in soft agar and by the capillary assay. Their chemotactic response to three amino acids, when compared with that of strain M-2, was reduced approximately 30 to 90%. Classic strains from patients in poor clinical condition were less chemotactic than those from patients in good clinical condition. A majority of classic and rough strains from patients in good clinical condition were comparable to M-2 in both chemotaxis and motility. Changes in other physiological characteristics indicated by reduced growth rates, or auxotrophy, were seldom observed in the cystic fibrosis strains studied. The data suggest that host-selective pressures, associated primarily with patients with cystic fibrosis that are in poor clinical condition, result in the loss of factors related to invasiveness such as motility and chemotaxis. We propose that these results may reflect that there is a more general alteration in the cell envelope of cystic fibrosis strains.
134 citations
TL;DR: In this article, the effects of neonatal diagnostic screening on cystic-fibrosis (CF)-related morbidity were evaluated by comparing hospital admissions for CF-related illness in the first 2 years of life in 40 patients detected by means of Neonatal screening and 56 patients born in the 3 years before screening began.
89 citations
TL;DR: The results suggest that soon after the onset of P. aeruginosa lung infection in cystic fibrosis patients, bacterial proteases, but not exotoxin A, become important virulence factors and do not directly contribute to lung damage after immune response to bacterial antigens has begun.
Abstract: We investigated the role of Pseudomonas aeruginosa exoenzymes in cystic fibrosis lung infection in the presence and absence of specific serum antibodies. In sputa of 21 cystic fibrosis patients, concentrations of P. aeruginosa proteases and exotoxin A were determined by sensitive radioimmunoassays. In all sputa, detection of exoenzymes was negative (less than or equal to 10 ng). Positive serum antibody titers to bacterial exoenzymes were found in the majority of patients. Purified immunoglobulin G (IgG) preparations from the sera of two patients revealing specific antibody titers to the bacterial proteases neutralized these enzymes at ratios of 1,000:1 to 5,600:1 (wt/wt). Above the neutralizing capacity of IgG, proteases caused cleavage of IgG; below that level, no enzymatic activity was observed. In vitro incubation of P. aeruginosa elastase, alkaline protease, or exotoxin A with elastase derived from polymorphonuclear leukocytes showed that polymorphonuclear leukocyte elastase: (i) was cleaved by bacterial elastase, (ii) was not inactivated by alkaline protease, and (iii) inactivated exotoxin A. The results suggest that soon after the onset of P. aeruginosa lung infection in cystic fibrosis patients, bacterial proteases, but not exotoxin A, become important virulence factors. The results also suggest that exoenzymes do not directly contribute to lung damage after immune response to bacterial antigens has begun.
87 citations
85 citations
TL;DR: Significant increases in mean corneal endothelial permeability and mean pump rate occurred in Group 1, indicating a defect in the endothelial barrier function early in type I diabetes mellitus, and in Group 3, suggesting a primary defectIn cystic fibrosis, aggravated by the hyperglycemic state.
81 citations
TL;DR: The innervation of acini and ducts of eccrine sweat glands by immunoreactive, vasoactive intestinal peptide-containing nerve fibers was sharply reduced in patients with cystic fibrosis compared to eight normal subjects, suggesting a basic mechanism for the decreased water content and relative impermeability of the epithelium to chloride and other ions.
Abstract: The innervation of acini and ducts of eccrine sweat glands by immunoreactive, vasoactive intestinal peptide-containing nerve fibers was sharply reduced in seven patients with cystic fibrosis compared to eight normal subjects. The decrease in innervation by this neuropeptide, which has been shown to promote blood flow and the movement of water and chloride across epithelial surfaces in other systems, may be a basic mechanism for the decreased water content and relative impermeability of the epithelium to chloride and other ions that characterize cystic fibrosis.
75 citations
01 Jan 1985
TL;DR: Dispersed isolated cells were obtained from human tracheal mucosa by digestion with collagenase and showed up to 95% viability, as judged by trypan blue exclusion, and electron microscopy revealed a polarized structure.
Abstract: Dispersed isolated cells were obtained from human tracheal mucosa by digestion with collagenase. Up to 1.5 X 10(8) cells were obtained per trachea and showed up to 95% viability, as judged by trypan blue exclusion. When grown in culture, the cells formed monolayers after approximately 4 days. Electron microscopy of the monolayers revealed a polarized structure. An apical membrane, containing microvilli and a pronounced glycocalyx, was separated from a relatively unspecialized basolateral membrane by typical tight junctions. Monolayers grown on nucleopore filters showed resistances of 44-1,800 omega. cm2 and transepithelial potential differences of 0.1-7.6 mV. Short-circuit current (Isc) was increased by isoproterenol, prostaglandins E2 and F2 alpha, and bradykinin. The loop diuretic, bumetanide, reduced Isc when added to the basolateral (serosal) side but had no effect from the apical (mucosal) side of the monolayers. Furosemide and MK-196 also inhibited Isc. Mucosal amiloride inhibited Isc. Serosal amiloride or mucosal ouabain had no effect on Isc. Serosal ouabain brought Isc to zero after approximately 15 min.
TL;DR: It is suggested that enhanced absorption in cystic fibrosis is most likely due to a decrease in intestinal diffusion barriers possibly due to abnormal mucus overlying the intestinal mucosa and an intrinsic defect in the mucosal glucose transport system.
TL;DR: Meconium ileus was the presenting feature of cystic fibrosis in 46 per cent of the couples which have been referred for prenatal diagnosis.
Abstract: Meconium ileus was the presenting feature of cystic fibrosis in 46 per cent of the couples which have been referred for prenatal diagnosis. In fetuses which have been aborted on the basis of alkaline phosphatase isoenzymes assays, meconium ileus represented the only pathological feature of cystic fibrosis, and was observed in three fourths of the cases. Real-time sonographic examination of fetuses at the time of amniocentesis was able to show an echogenic mass in the abdomen corresponding to the meconium ileus, and thus may afford a complementary means of diagnosis.
TL;DR: It is suggested that the Cl- permeability defect of CF respiratory epithelial cells is preserved in heterologous culture, and is intrinsic to cells rather than secondary to local or circulating mediators.
TL;DR: It is concluded that epithelial cells from CF patients grown in the absence of extracellular factors of the host express reduced cellular chloride permeability, a defect similar to that found in vivo and in freshly excised nasal epithelium.
Abstract: The chloride permeability of airway and sweat ductal epithelium of cystic fibrosis (CF) patients is decreased. This abnormality could represent an intrinsic characteristic of the epithelial cell or the response to a tonic extrinsic stimulus, in vivo. We cultured airway epithelial cells derived from CF and non-CF individuals under identical conditions that were free from donor-specific factors. Differences in the characteristics of cells that multiplied under these circumstances are unlikely to reflect the effects of extrinsic modulation present in the host. After 8-12 days in culture, the cells of CF and non-CF patients were similar in morphology and intracellular electrolyte content, but the CF cultures took up chloride at a reduced rate. The difference could not be attributed to a higher intracellular potential in CF cells or to the presence of a stilbene anion-sensitive chloride-chloride exchange in non-CF cells. We conclude that epithelial cells from CF patients grown in the absence of extracellular factors of the host express reduced cellular chloride permeability, a defect similar to that found in vivo and in freshly excised nasal epithelium.
TL;DR: A girl with cystic fibrosis who developed a neurological syndrome probably secondary to vitamin E deficiency at the age of 10 years is described.
Abstract: A girl with cystic fibrosis who developed a neurological syndrome probably secondary to vitamin E deficiency at the age of 10 years is described. The severity of the deficiency and the early development of neurological features probably result from reduced intraluminal bile salt concentrations in addition to the pancreatic insufficiency.
TL;DR: There was no significant interaction between allergic skin reactions and either age at onset of chronic PA infection or subsequent duration of survival in children with cystic fibrosis.
Abstract: • Allergy and chronic Pseudomonas aeruginosa (PA) infection are two factors that possibly affect the clinical severity of cystic fibrosis pulmonary disease, although the role of allergy is controversial. We have examined the effects of these factors on actuarial survival rates in 117 children with cystic fibrosis who were skin tested in 1974 and classified as allergic (A+) or nonallergic (A−) by their reactions to 12 prick tests with common environmental allergens. Patients were also classified according to whether or not they had chronic pulmonary infection with PA in 1974 ( PA -positive or PA -negative). Survival rates in A + patients were not significantly different from those in the A− group (percent survival to age 16 years, 67% vs 80%), whereas the PA + group had significantly worse survival rates than the PA− group (percent survival to age 16 years, 53% vs 84%). There was no significant interaction between allergic skin reactions and either age at onset of chronic PA Infection or subsequent duration of survival. ( AJDC 1985;139:669-671)
TL;DR: It is suggested that low levels of circulating selenium are associated with increased risk of carcinoma, particularly in the presence of reduced vitamin E levels, and older patients with CF may be at increased risk for the development of carcinomas.
TL;DR: It is shown here that an immunologically indistinguishable protein is present at high concentrations in granulocytes from normal and cystic fibrosis individuals as well as in myeloid leukaemia cells.
Abstract: The basic gene defect in the autosomal recessive disorder cystic fibrosis has not been identified, and no firm linkage of the disorder to any other marker has been reported. However, a serum protein abnormality present in unaffected heterozygotes as well as in affected homozygotes has been described1, and immunological quantitation of this protein, termed cystic fibrosis antigen, allows the three genotypes to be distinguished2,3. We show here that an immunologically indistinguishable protein is present at high concentrations in granulocytes from normal and cystic fibrosis individuals as well as in myeloid leukaemia cells. Somatic cell hybrids between the mouse myeloid stem-cell line WEHI-TG and myeloid leukaemia cells express cystic fibrosis antigen only when human chromosome 1 is present.
TL;DR: Retrospective analysis of sodium and chloride results from sweat tests carried out in Bristol and Sheffield has shown that misdiagnosis of cystic fibrosis (false negatives and false positives) is considerably less if Sodium and chloride are both measured.
Abstract: Retrospective analysis of sodium and chloride results from sweat tests carried out in Bristol and Sheffield has shown that misdiagnosis of cystic fibrosis (false negatives and false positives) is considerably less if sodium and chloride are both measured. In patients with cystic fibrosis the chloride concentration is usually higher than the sodium, whereas in normal subjects the reverse usually occurs. This observation is particularly useful when borderline results (50–70 mmol/L) are obtained.
TL;DR: Various combination and single-agent therapies with aminoglycosides, cephalosporins, and beta-lactam antibiotics are reviewed critically, and the importance of high activity against Pseudomonas strains is addressed, as is the potential value of antibiotic prophylaxis.
TL;DR: Examination of renal function in 10 healthy control subjects and eight patients with cystic fibrosis in stable condition found that increased clearance of drugs in these patients is unlikely to be the result of enhanced glomerular filtration or tubular secretion.
TL;DR: Ceftazidime can be recommended for the treatment of acute pulmonary exacerbations in patients with cystic fibrosis and the clinical response, when evaluated using an objective clinical efficacy scoring system, was considered favorable.
TL;DR: A 19-year-old woman with cystic fibrosis who developed muscle pain and weakness after 3 months on total parenteral nutrition which was not supplemented with Se is reported, and markedly elevated serum creatine kinase values were observed compared to baseline levels.
Abstract: The need for routine supplementation of total parenteral nutrition solutions with selenium (Se) has not been clearly defined. Although clinical selenium deficiency in patients on prolonged total parenteral nutrition has been reported, it is rarely observed in the United States. We report a 19-year-old woman with cystic fibrosis who developed muscle pain and weakness after 3 months on total parenteral nutrition which was not supplemented with Se. Coincident with her onset of symptoms, markedly elevated serum creatine kinase values were observed compared to baseline levels. Subsequent evaluations revealed undetectable (less than 0.02 microgram/ml) serum and urine Se levels in this patient. In addition, electromyographic evidence of myositis and nonspecific membrane irritability was documented. Therapy with oral Se rapidly reversed her symptoms and normalized with serum creatine kinase values over a 10-day period. Prolonged treatment with Se was required to achieve normal values of Se in the serum. Patients with severe pancreatic insufficiency, such as cystic fibrosis, may be at risk for clinical Se deficiency if on prolonged total parenteral nutrition without supplementation. Elevated creatine kinase levels should alert physicians to the possibility of Se deficiency in such patients.
TL;DR: Four patients with cystic fibrosis diagnosed in middle and later life with chronic bronchopulmonary infection with a high sweat sodium concentration and chest radiographic evidence of upper zone bronchiectasis are presented.
Abstract: Four patients with cystic fibrosis diagnosed in middle and later life are presented. All had chronic bronchopulmonary infection with a high sweat sodium concentration, and chest radiographic evidence of upper zone bronchiectasis. Two patients had pancreatic dysfunction. Sputum culture grew mucoid Pseudomonas aeruginosa in three patients and Haemophilus influenzae in one. Ages at diagnosis were 63, 42, 40, and 35 years. These patients confirm the possibility of occasional longevity in cystic fibrosis and emphasise the need to consider the diagnosis at all ages. They also provide encouragement for younger patients.
TL;DR: Nine adult patients with cystic fibrosis, nearly a quarter of the 38 patients with this disease who were treated with piperacillin during 1981-3 at the Brompton Hospital, developed a swinging pyrexia after a mean of 13.5 days' treatment with this antibiotic.
Abstract: Nine adult patients with cystic fibrosis, nearly a quarter of the 38 patients with this disease who were treated with piperacillin (59 courses in all) during 1981-3 at the Brompton Hospital, developed a swinging pyrexia after a mean of 13.5 days' treatment with this antibiotic. The fever resolved shortly after the piperacillin treatment was stopped, as did the widespread rashes in the two patients who developed them. Three of four patients who had probable reactions to azlocillin may have been sensitised by piperacillin. As piperacillin does not appear to be any more effective than other antipseudomonal penicillins in cystic fibrosis, it is no longer used at the hospital for treating bronchopulmonary exacerbations in such patients.