Exhaled nitric oxide in the diagnosis of asthma in adults: a systematic review.

OBJECTIVES: To identify and synthesize evidence on the diagnostic accuracy of FE NO for asthma in adults. MATERIALS AND METHODS: Systematic searches (nine key biomedical databases and trial registers) were carried out on November 2014. Records were included if they recruited patients with the symptoms of asthma; used a single set of inclusion criteria; measured FE NO50 in accordance with American Thoracic Society guidelines, 2005 (off-line excluded); reported/allowed calculation of true-positive, true-negative, false-positive and false-negative patients as classified against any reference standard. Study quality was assessed using QUADAS II. Meta-analysis was planned where clinical study heterogeneity allowed. Rule-in and rule-out uses of FE NO were considered. RESULTS: A total of 4861 records were identified originally and 1312 in an update. Twenty-seven studies were included. Heterogeneity precluded meta-analysis. Results varied even within subgroups of studies. Cut-off values for the best sum of sensitivity and specificity varied from 12 to 55 p.p.b., but did not produce high accuracy. 100% sensitivity or 100% specificity was reported by some studies indicating potential use as a rule-in or rule-out strategy. CONCLUSIONS AND CLINICAL RELEVANCE: FE NO50 had variable diagnostic accuracy even within subgroups of studies with similar characteristics. Diagnostic accuracy, optimal cut-off values and best position for FE NO50 within a pathway remain poorly evidenced.

Current options in aerosolised drug therapy for children receiving respiratory support.

Inhalation of aerosolised medications are the mainstay of treatment for a number of chronic lung diseases and have several advantages over systemically-administered medications. These include more rapid onset of action for drugs such as ß-adrenergic agonists when compared with oral medication, high luminal doses for inhaled antibiotics when used to treat endobronchial infection, and an improved therapeutic index compared with systemic delivery for these and other classes of drugs such as corticosteroids. The use of aerosolised drugs to treat patients whose tracheas are intubated is less well established, in part because systemic delivery via the intravenous route can be a simpler alternative for many drugs. Consequently, research in this area is largely limited to a number of in vitro studies and very few clinical trials. Unfortunately, a lack of focus in this area has resulted in a number of practices which at best are ineffective, and at worst dangerous for the patient. Although there have been some attempts to re-invigorate research in order to improve delivery systems, current devices are, to a great extent, based on long-standing technology developed more than 50 years ago. In this review, we explore current knowledge and provide guidance as to when and how the inhaled route may be of value when treating patients whose tracheas are intubated, and we set out the challenges facing those attempting to advance the topic. We conclude by reviewing current areas of interest that may lead to more effective and widespread use of aerosols in the treatment of intubated patients.

International consensus on (ICON) pediatric asthma.

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved.

What the pulmonary specialist should know about the new inhalation therapies.

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patient's inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.

Diagnosing and preventing chronic suppurative lung disease (CSLD) and bronchiectasis.

Current diagnostic labelling of childhood bronchiectasis by radiology has substantial limitations. These include the requirement for two high resolution computerised tomography [HRCT] scans (with associated adversity of radiation) if criteria is adhered to, adoption of radiological criteria for children from adult data, relatively high occurrence of false negative, and to a smaller extent false positive, in conventional HRCT scans when compared to multi-detector CT scans, determination of irreversible airway dilatation, and absence of normative data on broncho-arterial ratio in children. A paradigm presenting a spectrum related to airway bacteria, with associated degradation and inflammation products causing airway damage if untreated, entails protracted bacterial bronchitis (at the mild end) to irreversible airway dilatation with cystic formation as determined by HRCT (at the severe end of the spectrum). Increasing evidence suggests that progression of airway damage can be limited by intensive treatment, even in those predestined to have bronchiectasis (eg immune deficiency). Treatment is aimed at achieving a cure in those at the milder end of the spectrum to limiting further deterioration in those with severe 'irreversible' radiological bronchiectasis.

A feasibility study of sequential doublet chemotherapy comprising carboplatin-doxorubicin and carboplatin-paclitaxel for advanced endometrial adenocarcinoma and carcinosarcoma.

BACKGROUND: Platinum compounds, taxanes and anthracyclines provide the major effective drug classes in the treatment of advanced and recurrent endometrial cancer and carcinosarcoma. PATIENTS AND METHODS: A total of 52 women with advanced or recurrent endometrial cancer and carcinosarcoma were treated with four cycles of carboplatin area under the curve (AUC) 5 and doxorubicin (50 mg/m(2)) for four cycles before or after four cycles of carboplatin AUC5 and paclitaxel (175 mg/m(2)) with each cycle administered at 21-day intervals. RESULTS: Thirty-seven patients (71.2%) completed all planned treatment. Excluding six patients who did not complete treatment for non-drug-related causes, 80.4% completed all planned treatment. Three hundred and seventy-one treatment cycles were administered and 303 (81.7%) occurred on time. Common Toxicity Criteria grade 3/4 haematological toxic effects, particularly neutropenia and thrombocytopenia, were the predominant cause of treatment delays and dose reductions. A low incidence of grade 3 neurotoxicity and no cardiac toxicity were observed. The overall response rates for patients with evaluable disease were 82.1% and 66.7% for endometrial and carcinosarcoma, respectively. At a median follow-up of 21 months, the median progression-free survival for the endometrial adenocarcinoma and carcinosarcoma cohorts were 15.3 and 12.0 months, respectively. CONCLUSION: This regimen is generally well tolerated with encouraging efficacy.

Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach.

There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

Persistent of respiratory syncytial virus in human dendritic cells and influence of nitric oxide.

The annual epidemics of respiratory syncytial virus (RSV) infection are probably explained by poor herd immunity and the existence of a dormant reservoir of virus that is activated by an unknown trigger. The virus causes particular problems in infants, the elderly and patients with chronic obstructive airways disease (COPD). During two consecutive winters, human monocyte-derived dendritic cells (DCs) were exposed on a single occasion to one of two forms of RSV labelled with a fluorescent expresser genes (rgRSV or rrRSV) during the epidemic season. The cultures were maintained for many months, with fresh DCs being added at monthly intervals. The cultures were variously exposed to 600 parts per billion (ppb) nitric oxide for 15 min, nitric oxide (NO) donors and NO inhibitors outside the RSV epidemic season. The pattern of productive infection of DCs in vitro appeared to parallel the natural epidemics, in that DCs exhibited evidence of viral replication and productive infection only as manifested by intracellular fluorescence and infection of HeLa cells during the RSV epidemic season. When the long-term cultures were exposed to the above agents outside the RSV epidemic season there was again evidence of vigorous replication and productive infection, as shown by the reappearance of fluorescence and productive infection of HeLa cells. The results indicate that RSV may remain dormant in dendritic cells for prolonged periods and that replication appears to be activated by suppression of endogenous NO production. These observations may be key to our understanding of the mechanisms contributing to the annual epidemics of RSV infection.

Omega-3 fatty acids (from fish oils) for cystic fibrosis.

BACKGROUND: Epidemiological and other studies suggest that a diet rich in omega-3 essential fatty acids (derived from fish oil) may have beneficial anti-inflammatory effects for chronic conditions such as cystic fibrosis (CF). OBJECTIVES: To determine whether there is evidence that omega-3 polyunsaturated fatty acid supplementation reduces morbidity and mortality. To identify any adverse events associated with omega-3 polyunsaturated fatty acid supplementation. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Authors and persons interested in the subject of the review were contacted. Most recent search: April 2007 SELECTION CRITERIA: Randomised controlled trials in people with CF comparing omega-3 fatty acid supplements with placebo. DATA COLLECTION AND ANALYSIS: Two authors independently selected the studies for inclusion in the review, independently extracted data and assessed the methodological quality of the studies. MAIN RESULTS: Searches identified seven studies; three of which, involving 48 participants, were eligible for inclusion in the review. Two studies compared omega-3 fatty acids to olive oil controls for a six-week treatment period. One study compared omega-3 fatty acids in the form of a liquid dietary supplement containing polyunsaturated fatty acids to a liquid dietary supplement control for six months. One short-term study (19 participants) comparing omega-3 to placebo reported a significant improvement in forced expiratory volume in one second, forced vital capacity and Shwachman score and a reduction in sputum volume in the omega-3 group. The longer-term study (17 participants) demonstrated a significant increase in essential fatty acid content in neutrophil membranes in study participants taking omega-3 supplements compared to placebo, weighted mean difference 0.90 (95% confidence interval 0.46 to 1.34). AUTHORS' CONCLUSIONS: This review found that regular omega-3 supplements may provide some benefits for people with CF with relatively few adverse effects, although the evidence is insufficient to draw firm conclusions or to recommend routine use of supplements of omega-3 fatty acids in people with CF. This review has highlighted the lack of data for many of the outcomes likely to be meaningful to people with or making treatment decisions about CF. A large, long-term, multicentre, randomised controlled study is needed in order to determine if there is a significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes.

Pulmonary infection in mild variant cystic fibrosis: implications for care.

BACKGROUND: Disease phenotype in cystic fibrosis (CF) shows considerable heterogeneity. Atypical or mild mutations in the CFTR gene have been linked to late-onset pulmonary disease; however, few reports document the condition of the airway in infants and young children with apparent "mild" disease. Prognosis is uncertain in this group of patients and this, in turn, has led to inconsistency in management. Our initial experience of pulmonary infection in children with mild variant CF prompted a more detailed review of clinical outcome. METHODS: A retrospective cohort study was carried out comparing frequency of bacterial isolates and clinical outcomes in eleven compound heterozygotes for DeltaF508 and a second mild mutation, mainly R117H, with a matched group of DeltaF508 homozygotes. RESULTS: Staphylococcus aureus was isolated in 8 of the 11 patients with mild variant disease and Pseudomonas aeruginosa found in 7 (64%), although the frequency of positive cultures was significantly less (2.8/year) than the DeltaF508 homozygotes (6.1/year, p<0.05). Shwachman scores (median+range) were significantly higher in patients with mild mutations - 94, 74-92 vs. 88, 77-91; p<0.005); there was also a small but significant difference in chest radiograph (Chrispin-Norman) scores (median+range) (mild 5.1, 4-9, vs. severe 5.8, 3-10; p 0.04). There was little difference in lung function in terms of FEV1 (median+range) between the two groups (% predicted, mild 86.5, 68-87 vs. severe 76.0, 65-88; p 0.5). CONCLUSIONS: Most patients with mild variant CF will have bacterial isolates from airway cultures requiring antibiotic therapy three to four times a year. Infection with both S. aureus and P. aeruginosa is common. Anti-staphylococcal prophylaxis for the first two years should be considered.

Indoor air modification interventions for prolonged non-specific cough in children.

BACKGROUND: Non-specific cough has been defined as non-productive cough in the absence of identifiable respiratory disease or known aetiology and is common in childhood. These children are treated with a variety of therapies, including non-pharmacological treatments. There is a wide variety and a growing market for these non-pharmacological treatments that include air-modification modalities. OBJECTIVES: To determine the efficacy of air-modification modalities, (ionisers, vaporisers, humidifiers, air filters, regular vacuuming), in treating children with non-specific cough. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, OLDMEDLINE and EMBASE databases were searched by the Cochrane Airways Group. The latest searches were performed in November 2005. SELECTION CRITERIA: All randomised controlled trials comparing air-modification modalities with a placebo treatment, for any duration. DATA COLLECTION AND ANALYSIS: Results of searches were reviewed against pre-determined criteria for inclusion. Five papers were considered for inclusion but no eligible trials were identified and thus no data was available for analysis. MAIN RESULTS: No randomised controlled trials that examined the efficacy of air-modification modalities in the management of prolonged, non-specific cough in children were found. AUTHORS' CONCLUSIONS: Based on the evidence currently available, a recommendation can not be given for air-modification interventions in the treatment of prolonged, non-specific cough in children.

Autocrine function for insulin-like growth factor I in human small cell lung cancer cell lines and fresh tumor cells.

We showed previously that insulin-like growth factor I (IGF-I) is detectable in small cell lung cancer (SCLC) tumor biopsies and cell lines and that recombinant human IGF-I stimulates DNA synthesis in SCLC cells. Here we report further studies on the role of IGF-I in 2 SCLC cell lines: HC12, classic; and ICR-SC17, variant. Immunoreactive IGF-I was detected in medium conditioned by HC12 but not ICR-SC17. Both HC12 and ICR-SC17 bound IGF-I with 100-fold greater affinity than insulin. Scatchard analysis revealed two classes of IGF-I binding site of high (Kd 0.1 nM, n = 2,300) and lower (Kd 3 nM, n = 28,000) affinity. In both cell lines [3H]thymidine incorporation was enhanced by recombinant human IGF-I, 100-1000 ng/ml. ICR-SC17 also showed growth enhancement as measured by increase in cell numbers. There was no response in HC12, probably due to endogenous IGF-I production. 125I-IGF-I binding and basal and IGF-I-stimulated mitogenesis were inhibited by monoclonal antibodies to IGF-I (SM1.20B, SM1.25) or the type I IGF receptor alpha IR3 but not an isotypic control monoclonal antibody. Antiproliferative effects were manifest in [3H]thymidine incorporation assays in serum-free conditions and growth of serum-supplemented liquid cultures. We also tested fresh or newly cultured tumor cells obtained by fine needle aspiration of metastases in three previously untreated and four relapsed patients with SCLC. IGF-I binding sites were demonstrable on fresh SCLC cells, and specific binding was inhibited by SM1.20B. All seven samples showed stimulation of [3H]thymidine incorporation in the presence of recombinant human IGF-I, 100-500 ng/ml. As in cultured cells, basal and IGF-I-stimulated DNA synthesis was inhibited by monoclonal antibodies SM1.20B, SM1.25, and alpha IR3 but not the isotypic control. These results confirm the findings of previous studies and suggest that IGF-I can function as an autocrine growth factor in SCLC in vitro and possibly also in vivo.

A pilot study of oral L-arginine in cystic fibrosis.

Exhaled nitric oxide has previously been found to be low in cystic fibrosis. The aim of this study was to determine whether exhaled nitric oxide levels would increase in response to oral L-arginine supplementation administered daily for 4 weeks. Exhaled and nasal nitric oxide was measured weekly. Plasma L-arginine levels increased in response to supplementation but this was not reflected in an increase in eNO levels.

Anticholinergic drugs for wheeze in children under the age of two years.

BACKGROUND: Wheeze in infancy and early childhood is common and appears to be increasing though the magnitude of any increase is unclear. Most wheezing episodes in infancy are precipitated by respiratory viral infections. Treatment of very young children with wheeze remains controversial. Anti-cholinergics are often prescribed but practice varies widely and the efficacy of this form of therapy remains the subject for debate. OBJECTIVES: Wheeze in infancy and early childhood is common and appears to be increasing. Most wheezing episodes in infancy are a result of viral infection. Bronchodilator medications such as beta2-agonists and anti-cholinergic agents are often used to relieve symptoms, but patterns of use vary. The objective of this review was to assess the effects of anti-cholinergic therapy in the treatment of wheezing infants. This is a second update of this review. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials and the reference lists of articles. We contacted researchers in the field and industry sources. Searches were current as of June 2004. SELECTION CRITERIA: Randomised trials that compared anti-cholinergic therapy with placebo or beta2-agonists in wheezing children under two years of age. Children with acute bronchiolitis and chronic lung disease were excluded. DATA COLLECTION AND ANALYSIS: Eligibility for inclusion and quality of trials were assessed independently by two reviewers. MAIN RESULTS: Six trials involving 321 infants in three different settings were included. Compared with beta2-agonist alone, the combination of ipratropium bromide and beta2-agonist was associated with a reduced need for additional treatment, but no difference was seen in treatment response, respiratory rate or oxygen saturation improvement in the emergency department. There was no significant difference in length of hospital stay between ipratropium bromide and placebo; or between ipratropium bromide and beta2-agonist combined compared with beta2-agonist alone. However, combined ipratropium bromide and beta2-agonist compared to placebo showed significantly improved clinical scores at 24 hours. Parents preferred ipratropium bromide over nebulised water or placebo for relief of their children's symptoms at home. A further updated search conducted in June 2004 did not yield any new studies. AUTHORS' CONCLUSIONS: There is not enough evidence to support the uncritical use of anti-cholinergic therapy for wheezing infants, although parents using it at home were able to identify benefits.

Gene therapy with autologous, interleukin 2-secreting tumor cells in patients with malignant melanoma.

We vaccinated metastatic melanoma patients with irradiated, autologous melanoma cells genetically engineered to secrete interleukin 2 (IL-2) to investigate whether an anti-tumor immune response would be induced. Melanoma cell cultures were established from surgical specimens and were engineered to secrete IL-2 by infection with recombinant retrovirus. Twelve patients were vaccinated subcutaneously one, two, or three times with approximately 10(7) irradiated, autologous, IL-2-secreting tumor cells. Treatment was well tolerated, with local reactions at 11 of 24 injection sites and minor systemic symptoms of fever and headache after 6 injections. One patient developed anti-tumor DTH after the first vaccination and showed an increased response after the second vaccination. Anti-autologous tumor CTLs could be detected prevaccination in the peripheral blood of seven patients and their activity increased after vaccination in four patients. No UICC-defined clinical responses were seen, but three patients had stable disease for 7-15 months, one of whom has not yet progressed (15+ months). Thus, patient vaccination with autologous, genetically engineered tumor cells is feasible and safe. Anti-tumor DTH and CTLs can be induced in some patients with such a vaccine.

[D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P inhibits the growth of human small cell lung cancer xenografts in vivo.

We report the effect of substance P analogue, [D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P (D-Phe5SP), on the growth of human small cell lung cancer (SCLC) xenografts HC12 and ICR-SC112. Daily intraperitoneal (ip) administration (500 micrograms/day for 3 weeks) had no effect on HC12 growth rate. When administered by continuous 14-day subcutaneous (sc) infusion by osmotic minipump implanted adjacent to the tumour, D-Phe5SP 2.1 micrograms/day, caused significant inhibition (P < 0.05) of the growth of HC12 and ICR-SC112 on day 7 and day 14 compared with phosphate buffered saline (PBS)-treated controls. HC12 and ICR-SC112 tumour volume remained at 53-67% of control for 14-21 days postinfusion. D-Phe5SP 1 mg/day did not inhibit tumour growth, but dense fibrous capsules developed at the minipump outlet. Animals treated by sc infusion (but not ip) of PBS or D-Phe5SP failed to gain weight, and some groups lost weight. D-Phe5SP-treated animals had lower white blood counts than controls (not significant). These data suggest a potential clinical role for D-Phe5SP in the treatment of SCLC.

Bronchiolitis. Origins and optimal management.

There is currently no prospect of an end to the annual epidemics of acute bronchiolitis, which cause considerable morbidity in previously healthy infants and are a major threat to the well-being of infants with underlying cardiac, respiratory or immunological disease. The respiratory syncytial virus remains the major cause of this condition, and prospects of developing a vaccine remain bleak while our understanding of the viral-host interaction remain incomplete. Treatment of patients with this condition has remained essentially unchanged for more than 30 years. Correction of hypoxia with oxygen, minimal handling to reduce the risk of exhaustion and careful noninvasive monitoring for complications such as apnoea and respiratory failure are the mainstays of management. Mortality in at-risk groups has fallen substantially during the past 10 years. This appears to be due to improved supportive and intensive care. The role of the antiviral agent ribavirin in the improved outcome, if any, is unclear. Other novel therapies have been tried, but none have been shown to significantly alter the natural history of the condition. The only effective preventive intervention currently available is strict adherence to measures designed to prevent nosocomial infection. This condition is likely to remain a continuing challenge to paediatricians for the foreseeable future.

Treatment of childhood asthma. Options and rationale for inhaled therapy.

Epidemiological studies suggest the prevalence of asthma is increasing, though some remain sceptical as to the magnitude or indeed the presence of an increase. However, despite improved diagnosis and the availability of the potent drugs now available there remains considerable respiratory morbidity associated with asthma. It is clear from a number of studies that failure to deliver drugs to the lungs when using inhaler devices is a factor contributing to this high level of morbidity. Failure of drug delivery may result from the prescribing of inappropriate devices, failure to use devices appropriately or failure to comply with a treatment regimen. For most of the currently available forms of asthma therapy there are significant advantages to be gained from administering them in aerosol form. The benefits to be derived from administering these drugs as an aerosol include a rapid onset of action for drugs such as beta-agonists and a low incidence of systemic effects from drugs such as beta-agonists and corticosteroids. Over the past 25 years our understanding of the nature of asthma has changed. Though this has been reflected in the emphasis on inhaled corticosteroid therapy in recent guidelines, it has not been reflected in the range of inhaler devices available. Manufacturers continue to place drugs such as corticosteroids in the same devices as short acting beta-agonists even though the requirements for these different drug classes are very different. It is likely that this contributes to suboptimal therapeutic responses with inhaled corticosteroids. However, the variability associated with current delivery systems is relatively small compared with the variability introduced by poor compliance. There is no work currently available to indicate how the use of cheap disposable devises which do not incorporate any form of positive feedback influence compliance with inhaled steroids. Optimising aerosolised drug delivery in childhood involves consideration of the class of drugs, the particular drug within a class but more importantly, the age and abilities of the child. Devices must be selected to suit a particular child's needs and abilities. Devices utilising tidal breathing are generally used such as spacing chambers or, less commonly these days, nebulisers. A screaming or struggling child, or failure to use a closely fitting mask, reduces drug delivery to the lungs enormously. Failure to respond to inhaled therapy in early childhood may be attributable to failure of drug delivery. Drug delivery in early childhood using current devices remains more an art than a science.

A sensitive method to detect initiation of growth in Streptococcus gordonii using ribosomal RNA operon-reporter gene fusions.

A system for studying the early growth response of Streptococcus gordonii to environmental stimuli has been developed. A reporter gene, encoding alpha-amylase, has been integrated into an rRNA operon to monitor changes in cellular physiology associated with the initiation of growth. Two such strains with single integrants have been characterized during the transition from lag phase to exponential growth. Synthesis of the reporter is correlated to growth initiation in both strains, and the reporter enzyme is detectable with sufficient sensitivity. Comparison of the expression profiles of the two rrn operons containing the reporter gene suggests that they are differentially expressed over the course of growth.

Budesonide/formoterol in a single inhaler versus inhaled corticosteroids alone in the treatment of asthma.

The aim of this study was to evaluate the efficacy (expressed as effect on lung function) and tolerability of Symbicort (budesonide/formoterol in a single inhaler) in children with asthma. This was a double-blind, double-dummy, randomized, parallel-group, multicenter trial. After a 2-4-week run-in period, 286 asthmatic children (177 boys, 109 girls; mean age, 11 years; mean forced expiratory volume in 1 sec (FEV(1)), 75% predicted normal), previously treated with inhaled corticosteroids (average dose 548 microg/day), were randomized to 12 weeks' treatment with either budesonide/formoterol 80/4.5 microg, two inhalations twice daily (n = 148), or an equivalent dose of budesonide 100 microg, two inhalations twice daily (n = 138). Efficacy variables included morning and evening peak expiratory flow (PEF), spirometery, asthma symptoms, and use of rescue medication (beta(2)-agonists). Serial FEV(1) assessments were carried out on a subgroup of children (budesonide/formoterol, n = 41; budesonide, n = 40) at randomization and at week 12. Relative to baseline, morning PEF (primary variable) increased to a significantly greater extent with budesonide/formoterol than with budesonide alone (7.22% predicted normal vs 3.45% predicted normal; P < 0.001). Evening PEF also increased significantly with budesonide/formoterol (6.13% predicted normal vs. 2.73% predicted normal; P < 0.001), as did mean FEV(1) and serial FEV(1) measured over 12 hr (both P < 0.05). Similar improvements in asthma symptoms and rescue medication use were observed in both groups. The two treatment groups were similar in terms of their adverse-event profile and rates of discontinuation. Budesonide/formoterol in a single inhaler provided rapid improvements in PEF and FEV(1) compared to inhaled budesonide alone. These improvements were sustained throughout the study period. Budesonide/formoterol was well-tolerated in children with moderate persistent asthma.