Pulmonary disease severity in men with deltaF508 cystic fibrosis and residual chloride secretion.
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Adenosine Triphosphate↗
Biomedical subjects
M E Hodson
Publications and source records attributed to M E Hodson.
Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial.
BACKGROUND: We and others have previously reported significant changes in chloride transport after cationic-lipid-mediated transfer of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to the nasal epithelium of patients with cystic fibrosis. We studied the safety and efficacy of this gene transfer to the lungs and nose of patients with cystic fibrosis in a double-blind placebo-controlled trial. METHODS: Eight patients with cystic fibrosis were randomly assigned DNA-lipid complex (active) by nebulisation into the lungs followed 1 week later by administration to the nose. Eight control patients followed the same protocol but with the lipid alone (placebo). Safety was assessed clinically, by radiography, by pulmonary function, by induced sputum, and by histological analysis. Efficacy was assessed by analysis of vector-specific CFTR DNA and mRNA, in-vivo potential difference, epifluorescence assay of chloride efflux, and bacterial adherence. FINDINGS: Seven of the eight patients receiving the active complex reported mild influenza-like symptoms that resolved within 36 h. Six of eight patients in both the active and placebo groups reported mild airway symptoms over a period of 12 h following pulmonary administration. No specific treatment was required for either event. Pulmonary administration resulted in a significant (p<0.05) degree of correction of the chloride abnormality in the patients receiving active treatment but not in those on placebo when assessed by in-vivo potential difference and chloride efflux. Bacterial adherence was also reduced. We detected no alterations in the sodium transport abnormality. A similar pattern occurred following nasal administration. INTERPRETATION: Cationic-lipid-mediated CFTR gene transfer can significantly influence the underlying chloride defect in the lungs of patients with cystic fibrosis.
Adult↗
Considerations of uncertainty in setting critical loads of acidity of soils: the role of weathering rate determination.
The concept of critical loads has been generally accepted throughout Europe, and increasingly in Asian countries and the rest of the world, as providing the data which forms the basis for international negotiations on abatement strategies for emissions of acidifying pollutants. Central to the determination of quantitative critical loads of acidity for forests (and other ecosystems) is the rate at which the minerals in the soil weather or dissolve. Seven methods for determining these rates on a regional basis for the production of critical load maps have been suggested by the official bodies which are responsible for co-ordinating the European critical load mapping efforts. These methods are largely correlations which require a knowledge of the soil parent material and/or the soil mineralogy. The purpose of this paper is to review these weathering rate calculation methods and to assess whether it is currently possible to calculate numerically accurate critical loads for the production of regional critical load maps. A consideration of the data used to generate these methods and comparisons of the weathering rates calculated using various methods leads to the conclusion that at present it is not. Further work is needed to develop and maintain the initial credibility of critical loads both scientifically and as an aid to policy decisions.
Journal Article↗
Percutaneous endoscopic gastrostomy feeding in patients with cystic fibrosis.
BACKGROUND: Malnutrition is a common management problem in patients with cystic fibrosis (CF). Various approaches to supplemental nutrition by both parenteral and enteral routes have been used. AIM: To analyse the efficacy and acceptability of supplemental overnight feeding using a percutaneous endoscopic gastrostomy (PEG) in patients with CF. PATIENTS: 53 patients with CF (43 adults; age >17 years) with severe pulmonary disease. METHODS: The technical success and complications of PEG insertion were documented together with changes in nutritional and pulmonary status of the cohort. RESULTS: PEG tubes were successfully inserted in all patients, with immediate complications (respiratory depression) in two (4%) and late complications in 13 (25%). Feeding was well tolerated by 50/51 (98%) of the cohort during a mean (SEM) follow up of 14.5 (2.1) months. The adult cohort had a significant increase in weight and body mass index at six months which was maintained at 12 months. Serum albumin concentration remained stable at six months but had fallen by 12 months, although the differences were not statistically significant. These results were reflected in the paediatric cohort. Pulmonary function in those followed up for one year had apparently stabilised, but the number of admissions to hospital over the year before and the year after PEG did not change. Half of the cohort were accepted for heart-lung/lung transplantation, the improvement in nutritional status being a prerequisite for this. CONCLUSION: Supplemental PEG tube feeding is well tolerated and results in a significant improvement in nutritional status and an apparent stabilisation of pulmonary function in severely malnourished CF patients with advanced pulmonary disease
Adolescent↗
Diagnosis of cystic fibrosis related diabetes: a selective approach in performing the oral glucose tolerance test based on a combination of clinical and biochemical criteria.
BACKGROUND: Cystic fibrosis related diabetes (CFRD) has become increasingly common with the increasing longevity of patients with cystic fibrosis. The diagnosis of CFRD is important as its development may lead to a clinical deterioration which may be reversed with treatment. The oral glucose tolerance test (OGTT) is the method of choice in the diagnosis of CFRD, but performing OGTTs on all patients is inconvenient for patients and labour intensive for staff. The aim of this study was to identify a more selective approach in performing OGTTs in the diagnosis of CFRD based on the use of a combination of clinical and biochemical criteria. METHODS: Clinically stable adult patients with cystic fibrosis not known to be diabetic attending the Royal Brompton Hospital Cystic Fibrosis Clinic for their annual review were invited to return within a month to have an OGTT. The result of the OGTT was compared with the results of tests performed during the annual review. The sensitivities and specificities of various methods used in the screening or diagnosis of CFRD were determined using OGTT as the "gold standard" diagnostic method. The combination of clinical and biochemical criteria which resulted in the highest sensitivity and specificity in the diagnosis of CFRD was determined. RESULTS: Between August 1996 and May 1997 122 patients became eligible for the study, 91 of whom agreed to take part. The number of patients with normal, impaired, and diabetic glucose tolerance was 58 (64%), 21 (23%), and 12 (13%), respectively. When used alone, abnormal glycosylated haemoglobin (HbA1c) was found to have the highest sensitivity (83%; 95% CI 62 to 100) in the diagnosis of CFRD. The combination of an abnormal random blood glucose and/or abnormal HbA1c and/or symptoms of hyperglycaemia or weight loss was found to have the highest sensitivity (92%; 95% CI 76 to 100) in the diagnosis of CFRD. The specificity of this combination in the diagnosis of CFRD was 79% (95% CI 70 to 88). By selectively performing OGTTs in patients with one or more of the criteria cited above, 11 of the 12 patients with OGTT defined diabetes would have been identified. CONCLUSIONS: Patients with cystic fibrosis already have to undergo a large number of routine investigations. The selective approach in performing OGTTs described here has the potential to identify the majority of patients with CFRD without the need to perform this investigation on all patients. This approach is likely to be welcomed by patients and will lead to significant savings in terms of time and resources for patients and staff. Further larger studies are warranted to validate this selective approach in the diagnosis of CFRD.
Adolescent↗
Increased carbon monoxide in exhaled air of patients with cystic fibrosis.
BACKGROUND: Inflammation, oxidative stress, and recurrent pulmonary infections are major aggravating factors in cystic fibrosis. Nitric oxide (NO), a marker of inflammation, is not increased, however, probably because it is metabolised to peroxynitrite. Exhaled carbon monoxide (CO), a product of heme degradation by heme oxygenase 1 (HO-1) which is induced by inflammatory cytokines and oxidants, was therefore tested as a non-invasive marker of airway inflammation and oxidative stress. METHODS: Exhaled CO and NO concentrations were measured in 29 patients (15 men) with cystic fibrosis of mean (SD) age 25 (1) years, forced expiratory volume in one second (FEV(1)) 43 (6)%, 14 of whom were receiving steroid treatment. RESULTS: The concentration of exhaled CO was higher in patients with cystic fibrosis (6.7 (0.6) ppm) than in 15 healthy subjects (eight men) aged 31 (3) years (2.4 (0.4) ppm, mean difference 4.3 (95% CI 2.3 to 6.1), p<0.001). Patients not receiving steroid treatment had higher CO levels (8.4 (1.0) ppm) than treated patients (5.1 (0.5) ppm, mean difference 3.3 (95% CI -5.7 to -0.9), p<0.01). Normal subjects had higher NO levels (6.8 (0.4) ppb) than patients with cystic fibrosis (3.2 (0.2) ppb, mean difference 3.8 (95% CI 2.6 to 4.9), p<0.05) and were not influenced by steroid treatment (3.8 (0.4) ppb and 2.7 (0. 3) ppb for treated and untreated patients, respectively, mean difference 0.8 (95% CI -0.6 to 2.3), p>0.05). Patients homozygous for the DeltaF508 CFTR mutation had higher CO and NO concentrations than heterozygous patients (CO: 7.7 (1.8) ppm and 4.0 (0.6) ppm, respectively, mean difference 3.7 (95% CI -7.1 to -0.3), p<0.05; NO: 4.1 (0.5) ppb and 1.9 (0.7) ppb, respectively, mean difference 2.2 (95% CI -3.7 to -0.6), p<0.05). CONCLUSIONS: High exhaled CO concentrations in patients with cystic fibrosis may reflect induction of HO-1. Measurement of exhaled CO concentrations may be clinically useful in the management and monitoring of oxidation and inflammatory mediated lung injury.
Adrenal Cortex Hormones↗
Diabetes in cystic fibrosis.
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Cystic Fibrosis↗
Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis.
Cystic fibrosis (CF) is an inherited disorder associated with severe inflammation and repeated bacterial infection and colonization in the lung. Airway epithelium is involved in defence against bacteria, but this system may be defective in CF. Pro-inflammatory cytokines can stimulate the expression of inducible nitric oxide synthase (iNOS), an enzyme generating nitric oxide, which functions as an important mediator in host defence mechanisms. To understand better the poor resistance to infections in the CF lung, the expression of the iNOS gene was investigated in explanted lungs from patients with cystic fibrosis (n = 13), bronchiectasis (n = 3), emphysema (n = 14), and in normal lungs (n = 8). In addition, bronchial epithelial cell lines were examined to study iNOS gene expression in vitro. Strong immunoreactivity for iNOS was seen in inflammatory cells and bronchial epithelium in all the diseased lungs, except for bronchial epithelium in CF. Quantitative analysis showed a significant reduction in the area of epithelium immunostained in CF [CF 6.8 +/- 1.6 (% +/- SEM); emphysema 18.2 +/- 2.8; normal 9.6 +/- 0.8, P < 0.01], regardless of steroid treatment. These results were supported by in situ hybridization of iNOS mRNA, which showed a pattern of gene expression in CF, emphysema, and normal lung which paralleled that of protein immunoreactivity. Stimulation with cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) increased the expression of iNOS mRNA detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in cultures of normal (16HBE14o-), but not CF (CFBE41o-, with delta F508 CFTR mutation) epithelial cells. Expression of iNOS in inflammatory cells suggests that the gene is normal in CF. Absence of iNOS from bronchial epithelium may be due to low expression of the gene resulting from abnormalities in the signalling system that normally causes induction, such as cytokine receptors, second messengers or transcription factors. The resulting deficiency of the nitric oxide defence system may be relevant to the susceptibility of CF patients to pulmonary bacterial colonization.
Adult↗
Methicillin-resistant Staphylococcus aureus: impact at a national cystic fibrosis centre.
In many patient populations there has been a progressive increase in the prevalence of methicillin-resistant Staphylococcus aureus (MRSA). We examined the prevalence and consequences of acquiring MRSA in the adult cystic fibrosis (CF) population at Royal Brompton. Patients who became colonized by MRSA between 1965 and 1997 were identified from an existing database and case-notes were reviewed. Clinical and microbiological data were recorded. Twenty-six patients became colonized with MRSA during this period. Median age at acquisition was 23.4 years (range 11.8-43.3 years) and median FEV1 (percent predicted) was 28.9% (range 12-81%). Twenty patients (77%) had an FEV1 of < or = 40% predicted MRSA was probably acquired by four patients at Royal Brompton. In 17 patients isolates wer first identified whilst under the care of a total of 11 other institutions. Since the first case of MRSA infection in 1982, there has been an increase in prevalence to a current rate of nine cases in the first seven months of 1997. The commonest site of colonization was the lower airway (96%); the nose (23%) and skin sites (15%) were more rarely affected. Duration of colonization was frequently brief with nine cases (35%) lasting less than one month. The identification of MRSA appeared to be of little clinical significance, and did not generally affect outcomes. Only three patients were MRSA positive at the time of death, and in only one of these was MRSA considered a possible contributing factor.
Adolescent↗
Do Nottingham Health Profile scores change over time in cystic fibrosis?
We have previously shown that the Nottingham Health Profile (NHP) shows good correlation with physiological scores in an adult cystic fibrosis (CF) population when assessing health status (HS). The aim of this study was to determine whether the NHP can detect change in HS over time. Patients attending an adult CF clinic were studied at the time of their 'annual review' appointment. HS was assessed by the NHP and an 'in house' CF-specific score was used. FEV1% predicted, FVC% predicted, FEV1/FVC ratio, and body mass index (BMI) were calculated. The patients were then studied at subsequent annual review appointments. Change over time was calculated for each parameter and the relationship between change in HS and change in physiological parameters was examined using Spearman's rank correlation. Initial (t1), NHP scores were obtained from 204 patients, median age 26 years (range 16-56 years). Follow-up scores were obtained from 152 patients (t2). The mean rate of change in FEV1 was -8.6 (261) ml yr-1 or -0.2 (6.9)% predicted yr-1. The only dimension of the NHP which showed a significant change over time was emotion, which showed a small improvement in score (score at t1 = 11.3, score at t2 = 8.1, P = 0.02). There was a significant deterioration in the CF-specific total score (t1 = 4.4, t2 = 4.7, P = 0.008). There were no significant correlations between change in physiology and change in NHP scores. There was no overall difference in change in NHP scores between the patients whose FEV1 declined at > 4% predicted yr-1 and those who did not. In conclusion, although the NHP correlates well with one-off physiological parameters, there is poor correlation between change in NHP scores and change in physiological parameters over time.
Adolescent↗
Diabetic retinopathy in adult patients with cystic fibrosis-related diabetes.
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Adult↗
Management of respiratory failure in cystic fibrosis.
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Combined Modality Therapy↗
International practice patterns by age and severity of lung disease in cystic fibrosis: data from the Epidemiologic Registry of Cystic Fibrosis (ERCF).
The Epidemiologic Registry of Cystic Fibrosis provides clinical profiles for more than 6,800 patients and descriptions of practice patterns across eight European countries. Preliminary cross-sectional analysis has been performed by age and pulmonary function as an assessment of disease severity. In general, pulmonary treatments including inhaled bronchodilators and rhDNase increased as lung disease became more severe. Use of a number of treatments, including mucolytic agents and inhaled corticosteroids, varied markedly from country to country. Several widely used therapies are not yet supported by controlled clinical trials, particularly in patients under 6 years of age. Nutritional intervention was more common in patients with advanced lung disease regardless of age. Patients with nasal polyps had less severe lung disease at each age than patients without polyps. It is clear that studies of early interventions are needed to determine the optimal types of treatments and the ages at which to begin treatment.
Adolescent↗
Psychosocial aspects for the management of adults with cystic fibrosis.
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Adaptation, Psychological↗
Defective antigen presentation by lavage cells from terminal patients with cystic fibrosis.
Macrophages separated from lavage samples obtained from lungs removed at transplantation from patients with cystic fibrosis (CF) and other lung diseases, have been compared with circulating monocytes from the same patients for their ability to stimulate allogeneic normal circulating lymphocytes and to present antigen to autologous hilar lymph node cells. In general, macrophages separated from lavage samples from CF patients were unable to stimulate allogeneic lymphocytes and to present antigen, although monocytes from the same patients were functional in both assays. In contrast, lavage cells from non-CF patients were generally effective in both allogeneic stimulation and antigen presentation. These data suggest that immune cells within the lungs of CF patients are functionally compromised, a deficiency which may contribute to the recurrent infections characteristic of the disease.
Antigen Presentation↗
The overuse or underuse of dornase alfa.
The poor clearance of airway secretions in patients with cystic fibrosis perpetuates the chronic bronchopulmonary sepsis that is predominant. In recent years, novel drugs have been developed to alter the rheologic properties of the secretions in an attempt to improve airway clearance. Dornase alfa reduces the viscoelasticity of sputum from patients with cystic fibrosis and may enhance the clearance of secretions. Current clinical knowledge suggests that it is a safe treatment that improves pulmonary function and reduces respiratory exacerbations. The response, however, is heterogeneous and unpredictable. Scientific studies support the therapeutic rationale for the use of dornase alfa in that treatment reduces the viscoelasticity of airway secretions. Its effect on bacterial persistence and airway inflammation, however, is marginal. The key piece of information that would influence the long-term use of dornase alfa is how it affects disease progression, and at present this is unknown.
Bacterial Infections↗
A prognostic model for the prediction of survival in cystic fibrosis.
BACKGROUND: The treatment for endstage cystic fibrosis is, where appropriate, double-lung, heart-lung or, occasionally, heart-lung-liver transplantation. Optimising the timing of transplantation depends upon an accurate prediction of survival, but while current criteria give some guidance to this, they are not based upon statistically derived prognostic models. METHODS: Data collected prospectively on 403 patients with cystic fibrosis, recruited between 1969 and 1987 (cohort A), were analysed by log rank and univariate Cox regression analysis to determine variables that accurately predict survival. The significant variables were then subject to time dependent multivariate Cox regression analysis to generate a prognostic model. The model was validated, within the study population, using split sample testing, and was subsequently validated in a further cohort of patients recruited since October 1988 (cohort B). RESULTS: One hundred and eighty eight (50.4%) of the study cohort died within the study period. Percentage predicted forced expiratory volume in one second (FEV1), percentage predicted forced vital capacity (FVC), short stature, high white cell count (WBC), and chronic liver disease (as evidenced by the presence of hepatomegaly) were negatively correlated with survival. These variables, when combined into a prognostic index, accurately predicted one year survival in the study population and in the cohort recruited since 1988. CONCLUSION: This prognostic index may prove valuable in predicting prognosis in other cohorts with cystic fibrosis and thereby improve the timing of transplantation.
Adolescent↗
An evaluation of two aerosol delivery systems for rhDNase.
Increasingly, proteins are delivered to the respiratory tract as an aerosol, and clinical efficacy is dependent on optimal delivery of the protein in an intact form. The object of this study was to compare the in vivo and in vitro results of two aerosol delivery systems for the aerosolization of recombinant human deoxyribonuclease I (rhDNase) in patients with cystic fibrosis (CF). Patients with CF who were to be initiated on rhDNase were randomized either to the Hudson nebulizer and Pulmo-Aide compressor or to the Sidestream nebulizer driven by the CR50 air compressor. An in vitro study was performed in six sets of the two aerosol delivery systems. One hundred and seventy three patients were randomized in this open study, where rhDNase was administered for 7 days. Improvements in pulmonary function were observed in both groups following 1 week of therapy with rhDNase. Changes in the Sidestream/CR50 and Hudson/Pulmo-Aide groups, respectively, were: 16 and 11% for forced expiratory volume in one second (p=0.14); 12 and 10% for forced vital capacity (p=0.70); and 14 and 7% for forced expiratory flow at 25-75% of expiration (FEF(25-75)) (p=0.18). A greater proportion of patients in the Sidestream/CR50 group (58%) had a >10% response in FEF(25-75) compared to the Hudson/Pulmo-Aide group (42%; p=0.03). The Sidestream nebulizer had a faster nebulization rate (p<0.05), lower mass median diameter for the aerosol mass produced (p<0.001), higher percentage of particles in the respirable range (p<0.001) and greater respirable output (p<0.005), compared to the Hudson nebulizer. The Sidestream/CR50 combination is a quicker, more efficient system in vitro than the Hudson/Pulmo-Aide combination, whereas the in vivo study only suggested a difference. Clinically, the two systems have similar efficacy.
Adult↗