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Biomedical subjects

Andrew Bush

Publications and source records attributed to Andrew Bush.

At least 37 records · Page 2Linked to original sources
PubMed2006

Quantification of siderophages in bronchoalveolar fluid in transfusional and primary pulmonary hemosiderosis.

Transfusional iron overload may occur in the lungs. We hypothesized that quantitating siderophages in the bronchoalveolar fluid (BALF) of heavily transfused patients may prove to be a useful tool in determining lung iron overload in transfusion-dependent patients. The study included six patients (7-20 years) with thalassemia major (TM) who had received multiple blood transfusions, one with hereditary spherocytosis (four blood transfusions) and one with sickle cell disease (never transfused); they were compared to three children with idiopathic pulmonary hemosiderosis (IPH) (2.5-7.0 years) as positive controls. Fiberoptic bronchoscopy with bronchoalveolar lavage was performed in seven patients under general anesthesia for elective surgery and the rest were bronchoscoped electively under sedation. Spirometry was also performed in eight patients. There was no significant difference between children with TM and IPH in siderophages as percentage of total count (95% CI -31.0 to 1.5, P = 0.068). There were positive relationships between both mean serum ferritin values during the preceding year and the total number of units of transfused blood, and percent siderophage count among multiply transfused patients (P = 0.010, P = 0.052, respectively); similar findings were noted for the Golde score (P = 0.001, P = 0.031, respectively). None of the patients showed lung function impairment. In conclusion, in this small study, we found that the BALF of multiply transfused patients with benign hematological disorders contain similar numbers of siderophages to that of patients with IPH; this is strongly suggestive of secondary pulmonary hemosiderosis. The correlation between the patients' serum ferritin, and the BALF siderophages suggests that the later may serve as a marker of pulmonary iron overload in patients requiring blood transfusion and appear to be more sensitive than standard pulmonary function tests.

Adolescent↗
PubMed2006

Noninvasive monitoring of airway inflammation and steroid reduction in children with asthma.

PURPOSE OF REVIEW: Management of pediatric asthma is currently based on symptoms (often a second-hand report from parents) and lung function. Inhaled steroids are the mainstay of asthma management targeted at controlling airway inflammation. They should be used in the lowest possible doses. A number of noninvasive methods to assess inflammation have been developed in an effort to optimize anti-inflammatory treatment. RECENT FINDINGS: The first longitudinal studies have been published demonstrating an improvement in asthma control in children by adding noninvasive monitoring of inflammation into the clinical management. New methods include exhaled nitric oxide measurements, induced sputum and markers in exhaled breath condensate. SUMMARY: Further studies will show the practicability of including these measurement methods into everyday clinical practice. Their addition to the conventional assessment of asthma control appears promising. Using these methods to evaluate the current inflammatory state seems obligatory in research into new asthma therapeutics and management strategies. Managing asthma in children in specialist practice relying only on symptoms and lung function is no longer state of the art.

Administration, Inhalation↗
PubMed2006

Public perception of realtime information services for environmental monitoring and management of asthma.

A questionnaire was distributed to asthma patients and relatives of paediatric patients in the Royal Brompton Hospital outpatient clinic in London during March 2003. The aim was to determine how well informed those affected by asthma and allergic diseases were, to find out the best medium for distributing relevant information (e.g. Internet, mobile phones) and to discover the type of information they wished to receive. A total of 298 questionnaires were distributed and all were completed (100% response rate). The level of education of the respondents was high and the majority lived outside the London area. The questionnaire showed that the respondents would like to be informed about a wide range of information related to monitoring and self-management of asthma. Avoidance measurements and prevention was the first choice, followed closely by information on substances, and the environment and allergies. The Internet was the preferred means of communication with an information service provider. The telephone was also popular, and more popular than the mobile phone. The majority of participants were not willing to pay for an information service.

Adolescent↗
PubMed2006

Mucus properties in children with primary ciliary dyskinesia: comparison with cystic fibrosis.

OBJECTIVE: It has been assumed that cystic fibrosis (CF) lung disease is due in part to abnormal airway mucus. Primary ciliary dyskinesia (PCD) is a form of bronchiectasis that is similar to CF in many ways but is caused by congenital defects in mucociliary clearance. Our objective was to compare the biophysical and transport properties of CF and PCD sputa in subjects matched for age and degree of lung function impairment. DESIGN, SETTING, PARTICIPANTS: PCD patients (n = 19; mean age, 9.5 +/- 3.0 years [+/- SD]; FEV1, 65.0 +/- 7.8 L) were recruited from the clinic at the Royal Brompton Hospital. Patients with CF (n = 30, mean age, 10.8 +/- 2.6 years; FEV1, 61.8 +/- 22.8 L) were identified from the Wake Forest University School of Medicine CF Center. Pulmonary function testing and sputum collection were performed as part of routine, scheduled clinic visits. MEASUREMENTS: Pulmonary function was measured by spirometry, and sputum was collected during the pulmonary function test maneuver. Some patients were longitudinally assessed at visits during the course of 3 years. Sputum properties measured were dynamic viscoelasticity, wettability, cohesivity, interfacial (surface) tension, solids composition, DNA and interleukin (IL)-8 concentration, in vitro mucociliary transportability, and cough transportability. RESULTS: Inflammation as measured by IL-8 concentration was three times greater in the PCD sputa (p < 0.0001). There were no significant differences in the sputum biophysical or transport properties comparing CF with PCD sputum. CONCLUSIONS: It is unlikely that established CF lung disease is principally due to abnormal sputum properties, and it is more likely that the biophysical and transport properties reflect disease severity regardless of whether bronchiectasis is due to CF or PCD.

Biomarkers↗
PubMed2006

Clinical trials research in pediatrics: strategies for effective collaboration between investigator sites and the pharmaceutical industry.

There is a paucity of clinical trials work in children, which leads to the frequent use of off-label and unlicensed medications in this very vulnerable group. Clinical trials work in children may be more difficult than in adults, and there are certainly ethical constraints. However, the differences between adults and children, and at different stages of childhood development, mandate strategies to improve this situation rather than continually relying on extrapolation from adult studies. Therefore, new strategies have to be established between the pharmaceutical industry and pediatric centers to facilitate effective trials work. These must be based on a clear and mutual understanding of the differences between working with children and adults. Disease phenotypes may be completely different in children; for example, wheeze in infants is not miniature adult asthma. Clinical trial design must be practical, and a trial is more likely to succeed if a simple design is utilized, with minimal interference with school work and the work of carers. The new UK initiative, 'Medicines for Children', should go a long way towards addressing the problem, and increase the evidence base for the utilization of medications in pediatric practice.

Biomedical Research↗
PubMed2005

Cystic fibrosis in neonates and infants.

Cystic fibrosis (CF) is a common autosomal recessive disorder, characterized by chronic bronchopulmonary infection, pancreatic insufficiency, and subsequently, other multisystem complications. Most children are diagnosed before school age. Here we review the pathophysiology of the condition, the age-related presentations of CF up until school age, and the appropriate use of diagnostic tests. A specialist centre should supervise treatment. There are exciting new advances in monitoring techniques in the preschool years, including CT scanning, bronchoscopy and gas mixing indices. Recent advances in the knowledge of the molecular biology of CF hold out the hope of specific therapies which can reverse the underlying defect causing death from CF lung disease.

Child, Preschool↗
PubMed2005

Voriconazole therapy in children with cystic fibrosis.

BACKGROUND: There is increasing evidence for the efficacy of the antifungal voriconazole, particularly in immunosuppression. We describe our experience of using voriconazole in children with CF. METHODS: We performed a retrospective case note review of children with CF treated with voriconazole in a single centre over an 18 month period. RESULTS: A total of 21 children aged 5 to 16 years (median 11.3) received voriconazole for between 1 and 50 (22) weeks. Voriconazole was used as monotherapy in 2 children with recurrent allergic bronchopulmonary aspergillosis (ABPA); significant and sustained improvements in clinical and serological parameters for up to 13 months were observed, without recourse to oral steroids. Voriconazole was used in combination with an immunomodulatory agent in a further 11 children with ABPA, with significant improvement in pulmonary function and serology. 8 children without ABPA but who had recurrent Aspergillus fumigatus isolates and increased symptoms also received voriconazole; this group did not improve with treatment. Adverse effects occurred in 7 children (33%: photosensitivity reaction 3, nausea 2, rise in hepatic enzymes 1, hair loss 1). CONCLUSIONS: Voriconazole may be a useful adjunctive therapy for ABPA in CF. Voriconazole monotherapy appears to be an alternative treatment strategy when oral corticosteroids may not be suitable.

Adolescent↗
PubMed2005

Exploring the mechanisms of macrolides in cystic fibrosis.

Several studies have reported clinical improvements in cystic fibrosis (CF) patients on macrolide antibiotics although the mechanism of action remains unclear. We conducted an open-label study of azithromycin (500 mg daily for 2 weeks) in 9 adult CF patients to explore 3 possible mechanisms: up-regulation of the multi-drug resistance (MDR) or cystic fibrosis transmembrane regulator (CFTR) proteins, correction of epithelial ion transport and reduced bacterial adherence. End-points included nasal potential difference (PD) measurements, nasal epithelial MDR and CFTR mRNA levels and Pseudomonas aeruginosa adherence to nasal epithelium. Forced expiratory volume in the 1st second (FEV(1)) increased significantly after 2 weeks of azithromycin (pre- 41.1 [5.0]%; post- 44.6 [5.8]%; P<0.05), although improvements in forced vital capacity (FVC) did not reach significance (pre- 61.3 [4.0]%; post- 67.1 [5.4]%, NS). Before treatment all subjects had nasal PD measurements characteristic of CF. Treatment led to no significant group differences in any measures of either sodium absorption or chloride secretion. Neither CFTR nor MDR mRNA levels had altered significantly and the adherence of P. aeruginosa did not decrease. We conclude that these are unlikely to be significant contributing mechanisms accounting for the consistent beneficial results observed in clinical trials of macrolides in CF.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Exhaled 8-isoprostane in childhood asthma.

BACKGROUND: Exhaled breath condensate (EBC) is a non-invasive method to assess airway inflammation and oxidative stress and may be useful in the assessment of childhood asthma. METHODS: Exhaled 8-isoprostane, a stable marker of oxidative stress, was measured in EBC, in children (5-17 years) with asthma (13 steroid-naïve and 12 inhaled steroid-treated) and 11 healthy control. RESULTS: Mean exhaled 8-isoprostane concentration was significantly elevated in steroid-naïve asthmatic children compared to healthy children 9.3 (SEM 1.7) vs. 3.8 (0.6) pg/ml, p < 0.01. Children on inhaled steroids also had significantly higher 8-isoprostane levels than those of normal subjects 6.7 (0.7) vs. 3.8 (0.6) pg/ml, p < 0.01. Steroid-naïve asthmatics had higher exhaled nitric oxide (eNO) than those of controls 28.5 (4.7) vs. 12.6 (1.5) ppb, p < 0.01. eNO in steroid-treated asthmatics was similar to control subjects 27.5(8.8) vs. 12.6(1.5) ppb. Exhaled 8-isoprostane did not correlate with duration of asthma, dose of inhaled steroids or eNO. CONCLUSION: We conclude that 8-isoprostane is elevated in asthmatic children, indicating increased oxidative stress, and that this does not appear to be normalized by inhaled steroid therapy. This suggests that 8-isoprostane is a useful non-invasive measurement of oxidative stress in children and that antioxidant therapy may be useful in the future.

Adolescent↗
PubMed2005

Safety and efficacy of Sildenafil therapy in children with pulmonary hypertension.

OBJECTIVE: Sildenafil is a selective Phosphodiesterase-5 inhibitor that has been reported to be a potent pulmonary vasodilator. We evaluated the safety, efficacy and pharmacokinetics of oral Sildenafil in a case series of children with pulmonary hypertension. METHODS: Three children, 1 with primary pulmonary hypertension (patient 1) and 2 with pulmonary hypertension associated with congenital heart disease (patients 2 and 3) were enrolled. Sildenafil was started at 0.5 mg/kg 4-hourly and the dose increased to 1.0 and then to 2.0 mg/kg/dose. Patients were assessed at baseline and then monthly for a total of 6 visits. RESULTS: All patients reported increased exercise capacity with improvement in New York Heart Association functional class. The distance walked during the 6-min test increased by 74% (patient 1), 75% (patient 2) and 25% (patient 3) and oxyhaemoglobin saturations increased from 79%, 97% and 80% to 93%, 100% and 93%, respectively. There were no side effects and no fall in systemic blood pressure. Sildenafil plasma levels 1 h after a 0.5, 1.0 and 2 mg/kg dose of Sildenafil were 109+/-87, 150+/-62 and 368+/-200 ng/ml, respectively. They fell to 211+/-106 ng/ml 3 h after the 2.0 mg/kg dose. CONCLUSIONS: Medium term Sildenafil therapy improves oxyhaemoglobin saturations and exercise tolerance in children with pulmonary hypertension without any side effects. Mean plasma levels 1 h after doses of 0.5-2.0 mg/kg are similar to the maximum plasma concentrations reported in adults receiving doses within the therapeutic range. Sildenafil use in children appears to be safe and may be beneficial in the management of pulmonary arterial hypertension.

Administration, Oral↗
PubMed2005

Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children.

The use of noninvasive methods of monitoring airway inflammation, such as exhaled nitric oxide (eNO) and induced sputum, has been shown to improve asthma monitoring and optimize treatment in adult patients with asthma. There is a lack of comparable data in children. Forty children with stable asthma eligible for inhaled steroid reduction were reviewed every 8 weeks, and their inhaled steroid dose halved if clinically indicated. eNO, sputum induction combined with bronchial hyperreactivity testing, and exhaled breath condensate collection were performed at each visit to predict success or failure of reduction of inhaled steroids. Thirty of 40 (75%) children tolerated at least one dose reduction, 12 of 40 (30%) were successfully weaned off, and in total, 15 of 40 (38%) children experienced loss of asthma control. Treatment reduction was successful in all children who had no eosinophils in induced sputum before the attempted reduction. Using multiple logistic regression, increased eNO (odds ratio, 6.3; confidence interval, 3.75-10.58) and percentage of sputum eosinophils (odds ratio, 1.38; confidence interval, 1.06-1.81) were significant predictors of failed reduction. These findings suggest that monitoring airway inflammation may be useful in optimizing treatment in children with asthma.

Administration, Inhalation↗
PubMed2005

Airway remodeling and inflammation in symptomatic infants with reversible airflow obstruction.

RATIONALE: We hypothesized that the epithelial reticular basement membrane (RBM) thickening and eosinophilic inflammation characteristic of asthma would be present in symptomatic infants with reversible airflow obstruction. METHODS: RBM thickness and numbers of inflammatory cells were determined in ultrathin sections of endobronchial biopsies obtained from 53 infants during clinical bronchoscopy for severe wheeze and/or cough. Group A: 16 infants with a median age of 12 months (range 3.4-26 months), with decreased specific airway conductance (sGaw) and bronchodilator reversibility; Group B: 22 infants with a median age of 12.4 months (5.1-25.9 months), with decreased sGaw but without bronchodilator reversibility; and Group C: 15 infants with a median age of 11.5 months (3.4-24.3 months) with normal sGaw. Additional comparisons were made with the following groups. Group D: 17 children, median age 10.3 years (6-16 years), with difficult asthma; Group E: 10 pediatric control subjects without asthma, median age 10 years (6-16 years); and Group F: nine adult normal, healthy control subjects, median age 27 years (21-42 years). MAIN RESULTS: There were no significant differences in RBM thickness or inflammatory cell number between the infant groups. RBM thickness was similar in the infants and Groups E and F. However, the RBM in all infant groups (Group A: median 4.3 microm [range 2.8-9.2 microm]; Group B: median 4.15 microm [range 2.7-5.8 microm]; Group C: median 3.8 microm [range 2.7-5.5 microm]) was significantly less thick than that in the older children with asthma (Group D: median 8.3 microm [range 5.3-12.7 microm]; p < 0.001). CONCLUSION: RBM thickening and the eosinophilic inflammation characteristic of asthma in older children and adults are not present in symptomatic infants with reversible airflow obstruction, even in the presence of atopy.

Adolescent↗
PubMed2005

Potential difference measurements in the lower airway of children with and without cystic fibrosis.

Nasal potential difference measurements are valuable endpoint assays in clinical studies of novel treatments for cystic fibrosis (CF). Similar measurements made on the lower airway via the bronchoscope have been successful in adults, but have not been reported in children, the group most likely to benefit from such therapies. Here we report the design and validation of a small, single-lumen catheter technique allowing baseline potential difference and chloride secretion to be assessed in the distal airways of children as young as 1 year of age. Tracheal baseline values were significantly higher in children with CF than those without, although this was not the case more distally. In airways between the third and seventh generation, perfusion with a zero chloride solution containing isoprenaline led to a significant change in potential difference in children without CF, whereas no change was seen in those with CF. This measure provided a reliable distinguishing test between the two disease groups. We confirm that invasive bronchoscopic techniques can be performed safely and reliably in small children. Potential difference measurements could form a useful functional endpoint assay for future studies of either the CFTR gene or protein-based therapies in future trials in the pediatric age group.

Bronchi↗
PubMed2005

Beyond chloride transport: CFTR in the 21st century-introductory remarks to a new state of the art series.

This new series of articles on cystic fibrosis provides an overview of the confusing plethora of problems that arise from the loss of function in a low abundance protein, the cystic fibrosis membrane conductance regulator CFTR. The references are designed to take the clinical reader into areas and journals that they might not normally read. In particular we have concentrated on recent advances that suggest CFTR has functions that do not relate to chloride transport alone. In forthcoming issues of the journal the topics covered range from prospects and difficulties in the translation of new therapies into clinical practice, the regulation of the defective gene (promoters, enhancers, silencers, etc.), regulation and interaction of the CFTR protein product with other proteins in the cell, to functional approaches using developmental and secretory paradigms. These themes have been chosen to bring controversies at the cutting edge of cystic fibrosis research to the practicing pulmonologist in order to stimulate lateral thinking, which we hope will ultimately benefit our patients.

Cystic Fibrosis↗