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PubMed1984

Appendiceal abscess in cystic fibrosis. A diagnostic challenge.

A patient with cystic fibrosis who developed appendicitis, rupture, and a periappendiceal abscess is presented. A retrospective chart review revealed 5 other cases that demonstrate a spectrum of clinical presentation of periappendiceal abscess in patients with cystic fibrosis. Three patients were symptomatic for less than 5 days, but the remaining 3 patients were symptomatic for 8, 12, and 30 days before diagnosis. There were two deaths due to respiratory failure. Other complications included a perirectal fistula and 2 cases of recurrent abscess. This demonstrates the difficulty with which this diagnosis is reached in this patient population and the relatively high incidence of abscess formation compared with normal populations. A retrospective autopsy review of 51 cystic fibrosis patients showed that in 49 of 51 instances, the mucosa of the appendix was hyperplastic, and the mucosal glands were distended with eosinophilic secretions. In 12 cases (24%), the appendix itself was grossly firm, dilated, and distended, although the mucosal wall was free of inflammation. This lends credence to the suggestion that these inspissated secretions may be protective against the occurrence of appendicitis, the incidence of which may be as low as 1%-2% among cystic fibrosis patients.

Abscess↗

PubMed2005

[Cystic fibrosis presenting as acute recurrent pancreatitis].

Cystic fibrosis is a multiorgan autosomal recessive disease resulting from mutations in a gene located on the long arm of chromosome 7. The disease is usually diagnosed in the first few years of life when it typically presents with severe pulmonary manifestations and pancreatic insufficiency; however, a small percentage of patients with less dramatic symptoms is not diagnosed until adolescence or even adulthood. The genotype of each patient seems to influence the various forms of clinical presentation. Although uncommon, acute recurrent pancreatitis can be one of the forms of delayed presentation of cystic fibrosis. We report the case of an 17-year-old man who was diagnosed with cystic fibrosis after presenting 2 episodes of acute pancreatitis without associated pancreatic insufficiency. Subsequent study also revealed nasal polyps.

Acute Disease↗

PubMed1986

Kinetic analysis of chloride efflux from normal and cystic fibrosis fibroblasts.

Chloride permeability in 9 cystic fibrosis- and 11 normal-skin fibroblast lines has been investigated. Chloride efflux, under steady-state conditions, involves two intracellular compartments characterized by slow- and fast-rate constants of efflux. We show here that the fast rate constant in cystic fibrosis cells is reduced by 25% in comparison with controls. The data presented support recent studies indicating that isolated sweat glands and respiratory epithelia of patients suffering from cystic fibrosis have an unusual low permeability to chloride ions compared to control epithelia. It is concluded that variation in chloride transport can successfully be studied in cultured fibroblasts, which are not directly involved in the pathology of the disease.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2006

New insights into cystic fibrosis: molecular switches that regulate CFTR.

Cystic fibrosis transmembrane conductance regulator (CFTR), a Cl(-)-selective ion channel, is a prototypic member of the ATP-binding cassette transporter superfamily that is expressed in several organs. In these organs, CFTR assembles into large, dynamic macromolecular complexes that contain signalling molecules, kinases, transport proteins, PDZ-domain-containing proteins, myosin motors, Rab GTPases, and SNAREs. Understanding how these complexes regulate the intracellular trafficking and activity of CFTR provides a unique insight into the aetiology of cystic fibrosis and other diseases.

Cystic Fibrosis↗

PubMed1986

Alteration of the N-formyl-methionyl-leucyl-phenylalanine-induced response in cystic fibrosis neutrophils.

In order to determine whether cystic fibrosis neutrophils are affected in their secretory functions, lysosomal enzyme release and chemiluminescence (light emission from cells) were assayed in patients' cells and compared with those in normal control cells. We observed a decreased response of cystic fibrosis neutrophils in beta-glucuronidase release and chemiluminescence after stimulation by N-formyl-methionyl-leucyl-phenylalanine. There was no significant correlation of these results with the clinical score nor with the medical treatment. On the other hand, responses to the calcium ionophore A23187 and to opsonized zymosan showed no significant difference between normal and cystic fibrosis subjects in lysosomal enzyme release. N-formyl-methionyl-leucyl-phenylalanine receptor alterations did not seem involved in the observed effect as demonstrated by Scatchard plot analysis of N-formyl-methionyl-leucyl-phenylalanine binding to these receptors. These results clearly demonstrate a difference between normal and cystic fibrosis neutrophils in release and chemiluminescence responses to N-formyl-methionyl-leucyl-phenylalanine stimulation, a difference that might be located in the plasma membrane as both responses are membrane dependent.

Adolescent↗

PubMed1995

Effect of double-blind cross-over selenium supplementation on lipid peroxidation markers in cystic fibrosis patients.

Lipid peroxidation was assessed in 27 cystic fibrosis children during a double-blind selenium supplementation study (2.8 micrograms of sodium selenite per kg per day) with a placebo control and inversion of treatment periods. Simultaneously, 17 healthy children living in the same area were also investigated as control subjects. Before any treatment whatsoever and despite a selenium status close to those of control subjects, cystic fibrosis patients showed significant increase in plasma lipid peroxidation markers. Thiobarbituric acid reactants (TBARs) were normalized after the first treatment period of 5 months in both cystic fibrosis groups receiving either selenium supplementation or placebo. In this latter group, TBARs were reduced despite a significant decrease in plasma selenium concentrations as compared with the control group. Organic hydroperoxide concentrations were also simultaneously normalized in both cystic fibrosis groups at the end of the second treatment period. These results showed that improvement of lipid peroxidation markers was not related to the selenium supplementation. Nevertheless, oxidative stress sustained by cystic fibrosis children must be taken into account so that it does not aggravate the prognosis of the disease.

Adolescent↗

PubMed2006

Cough-induced hemiplegic migraine with impaired consciousness in cystic fibrosis.

The coughing paroxysms of patients with cystic fibrosis may occasion neurological symptoms. Although cough syncope is well-known, and is associated with headache and paralysis, a migrainous mechanism has not been reported. We reviewed the medical records, autonomic testing results, and responses to treatment in two cystic fibrosis patients with similar presentations of cough-induced impairment of consciousness followed by headache and paralysis. A 24-year-old woman and an unrelated 38-year-old man, both with cystic fibrosis, developed post-tussive neurologic deficits. Both patients reported infrequent dramatic spells, always preceded by major hemoptysis, and associated with left-sided paralysis, transient blindness, nausea, and severe pulsating headaches. Autonomic testing demonstrated only postural tachycardia and a near-vasodepressor episode in the woman, and mild, generalized sympathetic dysfunction in the man. Treatment for presumptive migraine with aura with verapamil nearly eradicated symptoms in both patients. Discontinuation of verapamil in the woman was associated with symptom recurrence and a stroke, with significant persistent residual left hemiparesis. In conclusion, cough-induced neurologic deficits were previously reported with cystic fibrosis, without clear understanding of the mechanism of impairment of consciousness. Based on the hemiparesis, nausea, and throbbing headache, which repeatedly followed the events in both patients, and based on the response to verapamil, we hypothesize a migrainous mechanism in both of our patients. The pathophysiology that links the hemoptysis to the spells deserves further investigation.

Adult↗

PubMed2001

A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease.

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in North America, leading to significant morbidity and early mortality. The defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) function can be corrected in vitro by gene replacement with a wild-type gene. A Phase I, single administration, dose escalation trial was designed and executed to assess safety and delivery of tgAAVCF, an adeno-associated virus (AAV) vector encoding the human CFTR cDNA, by nebulization to the lungs of CF subjects. Four cohorts of three subjects each were administered increasing doses of the study agent, beginning with 10(10) DNase-resistant particles (DRP) and escalating in log increments up to 10(13) DRP. Sequential bronchoscopies were performed to gather analytical samples throughout the study. All 12 subjects completed the study. There were a total of 242 adverse events (AEs), six of which were defined as serious and three of which were defined as possibly being related to the study drug. A clear dose-response relationship was observed in vector gene transfer. A maximum of 0.6 and 0.1 vector copies per brushed cell were observed 14 days and 30 days, respectively, following nebulization of 10(13) DRP tgAAVCF, and this declined to nearly undetectable levels by day 90. Vector gene transfer was evenly distributed throughout the fourth airway generation following single-dose administration. RNA-specific PCR did not detect vector-derived mRNA. This Phase I trial shows that aerosolized tgAAVCF is safe and widely delivered to the proximal airways of CF subjects by nebulization.

Adult↗

PubMed1992

Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease.

Only about 30% of the cystic fibrosis chromosomes in the Israeli cystic fibrosis patient populations carry the major CF mutation (delta F508). Since different Jewish ethnic groups tended to live as closed isolates until recent times, high frequencies of specific mutations are expected among the remainder cystic fibrosis chromosomes of these ethnic groups. Genetic factors appear to influence the severity of the disease. It is therefore expected that different mutations will be associated with either severe or mild phenotype. Direct genomic sequencing of exons included in the two nucleotide-binding folds of the putative CFTR protein was performed on 119 Israeli cystic fibrosis patients from 97 families. One sequence alteration which is expected to create a termination at residue 1282 (W1282X) was found in 63 chromosomes. Of 95 chromosomes, 57 (60%) are of Ashkenazi origin. Together with the delta F508 (23% in this group), G542X, N1303K, and 1717-1G----A mutations, the identification of 92% of cystic fibrosis chromosomes of Ashkenazi origin becomes possible. Patients homozygous for the W1282X mutation (n = 16) and patients heterozygous for the delta F508 and W1282X mutations (n = 22) had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. In conclusion, the W1282X mutation is the most common cystic fibrosis mutation in the Ashkenazi Jewish patient population in Israel. This nonsense mutation is associated with presentation of severe disease.

Cystic Fibrosis↗

PubMed1994

Cystic fibrosis gene therapy.

A variety of cystic fibrosis gene therapy approaches based on viral (adenovirus, retrovirus, and adeno-associated virus) and non-viral (liposomes and receptor-mediated endocytosis) routes are currently being assessed for safety and efficacy. Of these, the trials involving liposomal and adenoviral vectors are the most advanced, as both have been shown to correct the cystic fibrosis Cl- conductance defect in vivo.

Adenoviruses, Human↗

PubMed1990

[Increased survival rates of children with cystic fibrosis].

Seventy-two patients with cystic fibrosis were under care between January 1st 1972 and December 31st 1988, and 75 until now (July 1989). Fifty are alive, 24 died and 1 was lost to follow-up. The number of alive patients under control at the end of every year rose from 5 in 1972 up to 47 in 1988 and 50 at present. In order to assess the progress of survival rates, we compared two periods: 1972-1980 and 1981-1988. Twenty-eight were under control during the first period and 16 (57%) died, these figures for the second period being 55 and 8 (14%) (p 0.001) respectively. A remarkable increase in cumulative survival rates during the second period was observed at ages 1 (96% vs 68%), 5 (94% vs 55%) and 10 (86% vs 28%). Greater experience and closer follow-up, together with more aggressive treatment are likely to account for the increase in survival. It is vital that reference cystic fibrosis centers should be set-up in our country for the management of so complex a disease as 'cystic fibrosis.

Adolescent↗

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)↗

PubMed1995

Nocturnal oxygen desaturation and spirometric parameters in adults with cystic fibrosis.

BACKGROUND: Correction of nocturnal hypoxaemia in patients with cystic fibrosis may delay the development of pulmonary hypertension. Descriptive statistics used for nocturnal arterial oxygen saturation (SpO2) lack uniformity. The relationship between SpO2 and spirometric parameters has not previously been explored in a large number of exacerbations in adult patients with cystic fibrosis. METHODS: Over a 21 month period overnight SpO2, forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) were recorded on admission and discharge in 120 treatments of pulmonary exacerbations in 47 patients with cystic fibrosis who did not receive supplemental oxygen during recording. Nocturnal SpO2 was related to spirometric parameters for the whole group and individually in 11 patients, each of whom had at least five treatments. RESULTS: There was a close linear relationship between the percentage of the recording spent with SpO2 < 90% and mean overnight SpO2. Mean SpO2 correlated moderately with percentage predicted FEV1(%FEV1), r = 0.6, and poorly with percentage predicted FVC (%FVC), r = 0.34. The relationship between mean SpO2 and % FEV1 was non-linear at mean SpO2 < 89%, but approximated to linearity above this value. After exclusion of treatments with mean SpO2 < 89% the regression relationship between mean SpO2 and %FEV1 was the same on admission and discharge. Individual correlation coefficients of mean SpO2 versus % FEV1 in the 11 patients with repeated treatments ranged from 0.57 to 0.77. The slopes of the regression lines did not differ, with a pooled slope of 0.116, but the intercepts varied widely. CONCLUSIONS: In patients with cystic fibrosis mean overnight SpO2 can be substituted for percentage of recording < 90%. The relationship between mean SpO2 and percentage predicted FEV1 is non-linear at low values of SpO2 and is not influenced by treatment of pulmonary exacerbations. Patients with cystic fibrosis desaturate at a uniform rate compared with percentage predicted FEV1, but the value of FEV1 at which desaturation first occurs varies between patients. The spirometric values do not accurately predict nocturnal desaturation in a cystic fibrosis population, but FEV1 is a useful guide in individual patients with moderate desaturation.

Adult↗

PubMed1993

Clinical features of individuals with cystic fibrosis in New Zealand.

AIMS: To determine the status of cystic fibrosis patients, their mode of diagnosis and source of medical care in New Zealand. METHODS: A database was established in 1988 to record clinical information on individuals with cystic fibrosis in New Zealand. Three hundred and two cystic fibrosis patients were identified and clinical information on 248 obtained. RESULTS: Thirty five per cent of patients at diagnosis had gastrointestinal and pulmonary and 33% had gastrointestinal symptoms alone. Ninety three infants were diagnosed after a positive screening test and confirmatory sweat test. The mean age at diagnosis overall was 1.8 years, while 61% of children were diagnosed before one year of age. 74.2% of patients were said to be pancreatic insufficient, 4% pancreatic sufficient and in 22% the results were unavailable or unknown. Medical care was provided by 28 sources comprising paediatricians, physicians or combined clinics. One cystic fibrosis clinic cared for more than 40 patients. Sixty-one per cent of cystic fibrosis subjects were colonised with Staphylococcus aureus at some time, and 44% were reported to be colonised with Pseudomonas aeruginosa. CONCLUSIONS: Common clinical features of cystic fibrosis have been characterised for New Zealand patients. It is unknown to what extent the clinical features of the disease and source of medical care in New Zealand are responsible for previously reported survival for the condition but it is planned to examine serial measurements of growth, nutrition, pulmonary function and survival and it is hoped that these measurements will be the subject of a further report.

Adolescent↗

PubMed1980

Fertility problems associated with cystic fibrosis.

A case of a cystic fibrosis patient with two pregnancies that ended in deliveries at 30 and 29 weeks' gestation, respectively, is presented. The author suggests that the increased life expectancy of cystic fibrosis patients because of therapeutic advances will increase the need to examine the association and effects of fertility in individuals with this genetic disease.

Adult↗

PubMed2002

Airway mucus in cystic fibrosis.

Defective expression and function of the cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) airway epithelial cells are associated with airway mucus hypersecretion, inflammation and infection that begin early in life and lead, at an advanced stage of the disease, to severe airway obstruction with hyperviscous and adhesive airway mucus. Whether the abnormalities of airway mucus are already present at birth before infection is debatable. In CF, the impaired Cl(-) and HCO(3)(-) secretion associated with increased epithelial Na(+) absorption results in dehydration of airway mucus, decreased antimicrobial functions and impaired mucociliary clearance. Alterations in antibacterial peptide function, as well as the increased mucin expression and secretion (MUC 5AC and MUC 5B), are important biochemical factors responsible for the propensity for infection in CF airways. Alterations in mucin and lipid composition induce an increased viscosity and adhesiveness to the airways that can affect the mucociliary and cough transport. The increased content of pro-inflammation cytokines such as interleukin-8 (IL-8) suggest that, before infection, airway inflammation occurs very early in CF. The development of non-invasive techniques and humanised animal models (xenografts) represents a major opportunity to identify early abnormalities in CF airway mucus.

Cystic Fibrosis↗

PubMed1988

Home intravenous antibiotic treatment in cystic fibrosis.

The prognosis for patients with cystic fibrosis who are colonised with Pseudomonas aeruginosa has improved as a result of the regular use of intravenous antibiotics; however, this necessitates long periods of hospitalisation. Home intravenous antibiotic treatment has potential advantages over hospital treatment. We describe our experience during the first 20 months of using a system of home intravenous antibiotic treatment in which a cystic fibrosis liaison sister has an essential role. Thirteen patients have received 40 courses of treatment. There were highly significant improvements in weight, respiratory function, and white cell count during home treatment. There was no significant difference in weight and forced expiratory volume in one second between the end of home treatment and the end of hospital treatment while forced vital capacity was better after home treatment. All patients preferred home treatment. The advantages of home visits by the cystic fibrosis liaison sister during treatment are emphasised.

Adolescent↗

PubMed2002

Update: epidemiology of cystic fibrosis.

The natural history of cystic fibrosis (CF) is an evolving phenomenon. As such, it is continually being redefined as epidemiologic data is collected and processed and as advances in treatment for patients with CF improve the quality and quantity of life. The past year was no exception and has produced exciting new insights regarding outcomes in CF. We review the recent literature and focus our discussion on two specific areas with regard to their impact on the natural history of the disease: (1) low socioeconomic status and (2) wasting and cystic fibrosis related diabetes.

Cystic Fibrosis↗