Mannan-binding lectin in young children with asthma differs by level of severity.
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Adrenal Cortex Hormones↗
Biomedical subjects
Michael Silverman
Publications and source records attributed to Michael Silverman.
A randomized, double-blind, placebo-controlled trial of combined nevirapine and zidovudine compared with nevirapine alone in the prevention of perinatal transmission of HIV in Zimbabwe.
BACKGROUND: A single dose of nevirapine (sdNVP) administered to both mother and infant can decrease mother-to-child transmission of human immunodeficiency virus (HIV) by 47%, compared with ultra-short course zidovudine therapy (usZDV). There is limited data about the benefit of usZDV added to sdNVP to prevent mother-to-child transmission. METHODS: We performed a double-blind, randomized, placebo-controlled trial to determine whether usZDV combined with sdNVP improved neonatal outcome, compared with sdNVP alone. Mothers were randomized to 1 of 2 treatment groups. Mothers in the usZDV/sdNVP group received a loading dose of zidovudine (600 mg administered orally) and continued to receive 300-mg doses of zidovudine orally every 3 h while in labor, and their infants received zidovudine at a dosage of 2 mg per kg of body weight 4 times per day orally for 72 h. Mothers and infants in the sdNVP group received zidovudine placebo dosed in the same manner. All mothers also received nevirapine at a dosage of 200 mg orally while in labor, and all infants received nevirapine 2 mg per kg of body weight orally within 72 h of delivery. RESULTS: The study was stopped on the basis of futility, because interim data showed that, at present trends, superiority would not be demonstrated. Results at 6 weeks of age were available for 609 infants. The primary end point of HIV RNA positivity or death occurred in 21.8% of infants in the usZDV/sdNVP arm and 23.6% of the infants in the sdNVP arm. CONCLUSION: usZDV, when added to a standard 2-dose regimen of sdNVP, did not demonstrate a clinically important decrease in the combined end point of mother-to-child transmission or infant death. High rates of adverse maternal and infant outcome in both study arms suggest that improved approaches are necessary.
Adult↗
Quantitative linkage genome scan for atopy in a large collection of Caucasian families.
Quantitative phenotypes correlated with a complex disorder offer increased power to detect linkage in comparison to affected-unaffected classifications. Asthma is a complex disorder characterized by periods of bronchial obstruction and increased bronchial hyper reactivity. In childhood and early adulthood, asthma is frequently associated also with quantitative measures of atopy. Genome wide quantitative multipoint linkage analysis was conducted for serum IgE levels and percentage of positive skin prick test (SPT(per)) using three large groups of families originally ascertained for asthma. In this report, 438 and 429 asthma families were informative for linkage using IgE and SPT(per) which represents 690 independent families. Suggestive linkage (LOD > or = 2) was found on chromosomes 1, 3, and 8q with maximum LODs of 2.34 (IgE), 2.03 (SPT(per)), and 2.25 (IgE) near markers D1S1653, D3S2322-D3S1764, and D8S2324, respectively. The results from chromosomes 1 and 3 replicate previous reports of linkage. We also replicate linkage to 5q with peak LODs of 1.96 (SPT(per)) and 1.77 (IgE) at or near marker D5S1480. Our results provide further evidence implicating chromosomes 1, 3, and 5q. The current report represents one of the biggest genome scans so far reported for asthma related phenotypes. This study also demonstrates the utility of increased sample sizes and quantitative phenotypes in linkage analysis of complex disorders.
Adolescent↗
Food intolerance and wheezing in young South Asian and white children: prevalence and clinical significance.
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Asian People↗
Association between reported exposure to road traffic and respiratory symptoms in children: evidence of bias.
BACKGROUND: Many studies showing effects of traffic-related air pollution on health rely on self-reported exposure, which may be inaccurate. We estimated the association between self-reported exposure to road traffic and respiratory symptoms in preschool children, and investigated whether the effect could have been caused by reporting bias. METHODS: In a random sample of 8700 preschool children in Leicestershire, UK, exposure to road traffic and respiratory symptoms were assessed by a postal questionnaire (response rate 80%). The association between traffic exposure and respiratory outcomes was assessed using unconditional logistic regression and conditional regression models (matching by postcode). RESULTS: Prevalence odds ratios (95% confidence intervals) for self-reported road traffic exposure, comparing the categories 'moderate' and 'dense', respectively, with 'little or no' were for current wheezing: 1.26 (1.13-1.42) and 1.30 (1.09-1.55); chronic rhinitis: 1.18 (1.05-1.31) and 1.31 (1.11-1.56); night cough: 1.17 (1.04-1.32) and 1.36 (1.14-1.62); and bronchodilator use: 1.20 (1.04-1.38) and 1.18 (0.95-1.46). Matched analysis only comparing symptomatic and asymptomatic children living at the same postcode (thus exposed to similar road traffic) showed similar ORs, suggesting that parents of children with respiratory symptoms reported more road traffic than parents of asymptomatic children. CONCLUSIONS: Our study suggests that reporting bias could explain some or even all the association between reported exposure to road traffic and disease. Over-reporting of exposure by only 10% of parents of symptomatic children would be sufficient to produce the effect sizes shown in this study. Future research should be based only on objective measurements of traffic exposure.
Air Pollutants↗
Airway function measurements and the long-term follow-up of survivors of preterm birth with and without chronic lung disease.
This seventh paper in a review series on different aspects of chronic lung disease following preterm birth focuses on the current knowledge of respiratory symptoms, airway function, airway hyperresponsiveness, and exercise capacity from childhood to adulthood. This paper further considers the long-term implications of these studies for both future research and clinical practice.
Adolescent↗
A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p.
Asthma is a complex disease and the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Families with at least two siblings with asthma were collected from Europe, Australia and the US. A genome scan using a set of 364 families with a panel of 396 microsatellite markers was conducted. Nonparametric linkage analyses were conducted for asthma and three asthma-related phenotypes: bronchial hyper-reactivity (BHR), strict definition of asthma and atopic asthma. Nine chromosomal regions with LOD scores greater than 1.5 were identified (chromosomes 1q, 2p, 3q, 4p, 4q, 6q, 12q, 20p and 21). Linkage refinement analysis was performed for three BHR loci by genotyping single nucleotide polymorphisms at an average marker density of 1 cM. The LOD scores increased to 3.07 at chromosome 4p and 4.58 at chromosome 2p, while the chromosome 6p locus did not refine. The LOD score at the chromosome 2p locus is highly significant on a genome-wide basis. The refined locus covers a region with a physical size of 12.2 Mb. Taken together, these results provide evidence for a major asthma susceptibility locus on chromosome 2p.
Adolescent↗
Safety and tolerability of inhaled budesonide in children in the Steroid Treatment As Regular Therapy in early asthma (START) trial.
The safety and tolerability of asthma medications are still a concern to many asthma patients receiving long-term treatment. Therefore, more safety data from long-term, controlled trials are needed. The aim of this study was to evaluate the safety and tolerability of long-term treatment with once-daily budesonide in children aged 5-10 yrs with mild persistent asthma of recent onset in the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study. Children aged 5-10 yrs with early asthma were randomized to double-blind treatment with budesonide 200 microg or placebo once daily via Turbuhaler in addition to usual asthma therapy, for 3 yrs. Adverse events were recorded from both spontaneous reports and responses to standard questions, and asthma-related events and asthma control were recorded between visits and subsequently graded by the blinded investigators. Of the study population of 1981 children (1004 budesonide and 977 usual care), 81% (812 of 1004) in the budesonide group and 82% (797 of 977) in the usual care group experienced a total of 6414 events listed by preferred term (3209 budesonide plus usual care and 3205 placebo plus usual care). The most commonly reported events included respiratory infection, pharyngitis, rhinitis, viral infection and bronchitis, and there were no clinically relevant differences in incidence between treatments. There were no reports of tuberculosis or aspergillosis, and no evidence of increased risk of systemic or ocular adverse events with budesonide relative to placebo. There were 106 serious adverse events in the budesonide group and 128 with usual care. The most frequent, aggravated asthma, was more common with usual care than with budesonide. There were no deaths among children participating in START. In conclusion, the addition of once-daily inhaled budesonide 200 microg via Turbuhaler to usual care is safe and well tolerated in children with recent-onset mild persistent asthma.
Administration, Inhalation↗
Balancing efficacy and safety in the use of oral sedation in dental outpatients.
BACKGROUND: Concerns about the safety of pediatric oral sedation and the incremental use of triazolam in adults prompted a workshop cosponsored by several professional organizations. OVERVIEW: There is a strong need and demand for adult and pediatric sedation services. Using oral medication to achieve anxiolysis in adults appears to have a wide margin of safety. Mortality and serious morbidity, however, have been reported with oral conscious sedation, especially in young children. Most serious adverse events are related to potentially avoidable respiratory complications. CONCLUSIONS: Clinical trials are needed to evaluate oral sedative drugs and combinations, as well as to develop discharge criteria with objective quantifiable measures of home readiness. Courses devoted to airway management should be developed for dentists who provide conscious sedation services. State regulation of enteral administration of sedatives to achieve conscious sedation is needed to ensure safety. PRACTICE IMPLICATIONS: Safety in outpatient sedation is of paramount concern, with enteral administration of benzodiazepines appearing safe but poorly documented in the office setting. Conscious sedation by the enteral route, including incremental triazolam, necessitates careful patient evaluation, monitoring, documentation, facilities, equipment and personnel as described in American Dental Association and American Academy of Pediatric Dentistry guidelines.
Adult↗
Risk of severe asthma episodes predicted from fluctuation analysis of airway function.
Asthma is an increasing health problem worldwide, but the long-term temporal pattern of clinical symptoms is not understood and predicting asthma episodes is not generally possible. We analyse the time series of peak expiratory flows, a standard measurement of airway function that has been assessed twice daily in a large asthmatic population during a long-term crossover clinical trial. Here we introduce an approach to predict the risk of worsening airflow obstruction by calculating the conditional probability that, given the current airway condition, a severe obstruction will occur within 30 days. We find that, compared with a placebo, a regular long-acting bronchodilator (salmeterol) that is widely used to improve asthma control decreases the risk of airway obstruction. Unexpectedly, however, a regular short-acting beta2-agonist bronchodilator (albuterol) increases this risk. Furthermore, we find that the time series of peak expiratory flows show long-range correlations that change significantly with disease severity, approaching a random process with increased variability in the most severe cases. Using a nonlinear stochastic model, we show that both the increased variability and the loss of correlations augment the risk of unstable airway function. The characterization of fluctuations in airway function provides a quantitative basis for objective risk prediction of asthma episodes and for evaluating the effectiveness of therapy.
Adult↗
Spontaneous contraction of pseudoglandular-stage human airspaces is associated with the presence of smooth muscle-alpha-actin and smooth muscle-specific myosin heavy chain in recently differentiated fetal human airway smooth muscle.
BACKGROUND: Recent investigations demonstrating that pseudoglandular-stage airspaces contract spontaneously suggest that the production of contractile proteins by airway wall smooth muscle (ASM) is an important factor in the functional and structural differentiation of ASM. AIMS: Ouraim was to determine if smooth muscle (SM)-myosin heavy chain (MHC) myofilaments, the 'motor' underlying SM contraction, and SM-alpha-actin myofilaments were distributed simultaneously in pseudoglandular-stage human lungs and to further define the nature of fetal airway contractions. METHODS: Immunohistochemically stained sections of fetal lung (14 fetuses, 10.1-17 weeks gestation) were analysed by computer-assisted morphometry to determine airspace dimensions and detect SM-MHC- and SM-alpha-actin-ASM. Lung tissue from the same fetuses was also placed in explant culture to observe airway contractions using videomicroscopy. We found that the smallest airspaces were just as likely to be invested by a layer of SM-MHC-positive ASM as by a layer of SM-alpha-actin-positive ASM. In addition, larger airways or airways from more mature fetal lungs were more likely to be invested by either SM-MHC- or SM-alpha-actin-positive ASM. Spontaneous airspace contractions were peristalsis-like and variable in amplitude. The time interval between contractions was temperature dependent (mean+/-SEM, 44+/-7.5 s at 37 degrees C), shortened by carbachol and increased by nitric oxide (NO)-donating drugs. CONCLUSIONS: These observations suggest that ASM differentiation is characterised by the simultaneous production of SM-alpha-actin and SM-MHC myofilaments and that the presence of these proteins is likely to be responsible for cholinergic- and NO-sensitive spontaneous contractions of fetal human airspaces.
Actins↗
Rates of hospitalisation for influenza, respiratory syncytial virus and human metapneumovirus among infants and young children.
To inform the development of a national influenza immunisation programme and the potential role of antiviral drugs in young children, we studied 613 children aged 71 months or younger who attended Leicester Childrens' Hospital during winter 2001-2002. During periods of respiratory syncytial virus (RSV), influenza, and human metapneumovirus activity, an estimated 12.2% (95% CI: 11.4-13.1), 7.1% (6.3-7.9), and 2.5% (2.1-2.9), respectively, of all medical cases assessed in the hospital were associated with these infections. The respective rates of hospital assessments for RSV, influenza, and human metapneumovirus (HMPV) were 1042 (95% CI: 967-1021), 394 (348-443), and 223 (189-262) per 100,000 children, and for admissions were 517 (465-574), 144 (117-175), and 126 (101-156) per 100,000. Few children with influenza had a prior risk factor. Children with influenza were admitted a median of 4 days after onset of illness and none was coded at discharge as influenza. We conclude that antivirals have little role in the hospital management of children with influenza. Our data provide health economists with information to evaluate the place of universal immunisation of young children against influenza. Hospitalisation rates decreased markedly with referral age, so vaccine would need to be given in early infancy for maximum benefit.
Age Factors↗
Intramuscular triamcinolone for difficult asthma.
We treated a selected group of children attending a difficult asthma clinic with intramuscular triamcinolone acetonide. This study retrospectively reviews markers of asthma severity in those who received one or more monthly doses for three periods: 1) 3 months preceding the first injection (pretreatment), 2) from the first injection to 1 month after the last injection (treatment period), and 3) 3 months after the treatment period (follow-up period). Severity markers during the treatment and follow-up periods were compared with the pretreatment period by paired t-test. Five children (5-13 years old) received a single dose, and 8 children (12-15 years old) received multiple doses. Multiple doses of triamcinolone (n = 3-5) were associated with a fall in the number of asthma exacerbations (P < 0.01) and hospital admissions (P < 0.01) in both the treatment and follow-up periods. A single dose reduced exacerbations (P < 0.05, treatment vs. pretreatment) but not hospital admissions. We conclude that intramuscular triamcinolone is a useful short-term therapy in difficult asthma. Whether its efficacy is due to improved compliance, or an improved anti-inflammatory profile compared with oral steroids, remains unclear.
Adolescent↗
Outcome of pregnancy in a randomized controlled study of patients with asthma exposed to budesonide.
BACKGROUND: Budesonide is the only inhaled corticosteroid to be given a category B pregnancy rating by the US Food and Drug Administration, based on observational data from the Swedish Medical Birth Registry. However, data from large randomized controlled trials are lacking. OBJECTIVE: To compare pregnancy outcomes among patients with recent-onset mild-to-moderate persistent asthma receiving low-dose budesonide vs placebo. METHODS: In a randomized, double-blind, placebo-controlled trial, 7241 patients aged 5 to 66 years with mild-to-moderate persistent asthma for less than 2 years and no previous regular corticosteroid therapy received once-daily budesonide or placebo via dry powder inhaler in addition to their usual asthma medication for 3 years. This trial was followed by a 2-year open-label treatment period. The daily dose of budesonide was 400 microg for adults. The study included 2473 females aged 15 to 50 years at randomization. Pregnancy was not an exclusion criterion (except for U.S. patients). RESULTS: Of 319 pregnancies reported, 313 were analyzed. Healthy children were delivered in 81% and 77% of all pregnancies in the budesonide and placebo groups, respectively. Of the 196 pregnancies reported by participants taking budesonide, 38 (19%) had adverse outcomes: 23 (12%) had miscarriages, 3 (2%) had congenital malformations, and 12 (6%) had other outcomes. Of the 117 pregnancies reported in the placebo group, 27 (23%) had adverse outcomes: 11 (9%) had miscarriages, 4 (3%) had congenital malformations, and 12 (10%) had other outcomes. CONCLUSIONS: Treatment with low-dose inhaled budesonide in females with mild-to-moderate persistent asthma does not seem to affect the outcome of pregnancy.
Abortion, Spontaneous↗
Medical and physical readiness of the U.S. Army Reserve for Noble Eagle/Enduring Freedom/Iraqi Freedom: recommendations for future mobilizations.
The U.S. Army Reserve plays an important role in the war-fighting capabilities of the U.S. military. There have been concerns, however, regarding the health and physical readiness of this force. Recently Army Reservists were mobilized for Operation Noble Eagle/Iraqi Freedom. We report on both the medical waivers requested and issues related to soldiers found medically nonavailable for deployment on data collected and analyzed from several mobilization sites. Four hundred thirty-one medical waivers were requested. Of 60,000 mobilized, approximately 2.7% were found to be medically nonavailable for deployment, predominately enlisted and male. The most common problems identified were orthopedic, psychiatric, diabetes, asthma, obstetrical-gynecological, and cardiac. The overall prevalence of medically nonavailable for deployment of Army Reservists was low. Most of the conditions leading to nondeployable troops were attributable to chronic disease. Interventions to decrease the level of medically nonavailable for deployment and to lessen mobilization site operations are being implemented.
Adolescent↗
The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity.
Although previous studies have investigated the role of IL-27/WSX-1 interactions in the regulation of Th1 responses, little is known about their role in regulating Th2-type responses. Studies presented in this work identify a direct role for IL-27/WSX-1 interactions in the negative regulation of type 2 responses independent of effects on type 1 cytokines. WSX-1-/- mice infected with the gastrointestinal helminth Trichuris muris displayed accelerated expulsion of parasites and the development of exaggerated goblet cell hyperplasia and mastocytosis in the gut due to increased production of Th2 cytokines. Enhanced mast cell activity in the absence of WSX-1 was consistent with the ability of wild-type mast cells to express this receptor. In addition, IL-27 directly suppressed CD4+ T cell proliferation and Th2 cytokine production. Together, these studies identify a novel role for IL-27/WSX-1 in limiting innate and adaptive components of type 2 immunity at mucosal sites.
Animals↗
Interrupter resistance and wheezing at 4 years.
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Airway Resistance↗