Showing papers by "National Jewish Health published in 2006"
TL;DR: In preschool children at high risk for asthma, two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year, and these findings do not provide support for a subsequent disease-modifying effect of inhaling corticosteroids after the treatment is discontinued.
Abstract: Background It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma. Methods We randomly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate (at a dose of 88 μg twice daily) or masked placebo for two years, followed by a one-year period without study medication. The primary outcome was the proportion of episode-free days during the observation year. Results During the observation year, no significant differences were seen between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function. During the treatment period, as compared with placebo use, use of the inhaled corticosteroid was associated with a greater proportion of episode-free days (P = 0.006) and a lower rate of exacerbations (P<0.001) and of supplementary use of controller medication (P<0.001). In the inhaled-corticosteroid group, as compared with the placebo group, the mean increase in height was 1.1 cm less at 24 months (P<0.001), but by the end of the trial, the height increase was 0.7 cm less (P = 0.008). During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively. Conclusions In preschool children at high risk for asthma, two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year. These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued. (ClinicalTrials.gov number, NCT00272441.)
962 citations
TL;DR: These practice parameters provide recommendations regarding behavioral and psychological treatment approaches, which are often effective in primary and secondary insomnia, which replace or modify those published in the 1999 practice parameter paper produced by the American Sleep Disorders Association.
Abstract: Insomnia is highly prevalent, has associated daytime consequences which impair job performance and quality of life, and is associated with increased risk of comorbidities including depression. These practice parameters provide recommendations regarding behavioral and psychological treatment approaches, which are often effective in primary and secondary insomnia. These recommendations replace or modify those published in the 1999 practice parameter paper produced by the American Sleep Disorders Association. A Task Force of content experts was appointed by the American Academy of Sleep Medicine to perform a comprehensive review of the scientific literature since 1999 and to grade the evidence regarding non-pharmacological treatments of insomnia. Recommendations were developed based on this review using evidence-based methods. These recommendations were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine. Psychological and behavioral interventions are effective in the treatment of both chronic primary insomnia (Standard) and secondary insomnia (Guideline). Stimulus control therapy, relaxation training, and cognitive behavior therapy are individually effective therapies in the treatment of chronic insomnia (Standard) and sleep restriction therapy, multicomponent therapy (without cognitive therapy), biofeedback and paradoxical intention are individually effective therapies in the treatment of chronic insomnia (Guideline). There was insufficient evidence to recommend sleep hygiene education, imagery training and cognitive therapy as single therapies or when added to other specific approaches. Psychological and behavioral interventions are effective in the treatment of insomnia in older adults and in the treatment of insomnia among chronic hypnotic users (Standard).
713 citations
TL;DR: Delaying initial exposure to cereal grains until after 6 months may increase the risk of developing wheat allergy, but results do not support delaying introduction of cereal grains for the protection of food allergy.
Abstract: OBJECTIVE.Early exposure to solid foods in infancy has been associated with the development of allergy. The aim of this study was to examine the association between cereal-grain exposures (wheat, barley, rye, oats) in the infant diet and development of wheat allergy. METHODS.A total of 1612 children were enrolled at birth and followed to the mean age of 4.7 years. Questionnaire data and dietary exposures were obtained at 3, 6, 9, 15, and 24 months and annually thereafter. The main outcome measure was parent report of wheat allergy. Children with celiac disease autoimmunity detected by tissue transglutaminase autoantibodies were excluded. Wheat-specific immunoglobulin E levels on children reported to have wheat allergy were obtained. RESULTS.Sixteen children (1%) reported wheat allergy. Children who were first exposed to cereals after 6 months of age had an increased risk of wheat allergy compared with children first exposed to cereals before 6 months of age (after controlling for confounders including a family history of allergic disorders and history of food allergy before 6 months of age). All 4 children with detectable wheat-specific immunoglobulin E were first exposed to cereal grains after 6 months. A first-degree relative with asthma, eczema, or hives was also independently associated with an increased risk of wheat-allergy development. CONCLUSIONS.Delaying initial exposure to cereal grains until after 6 months may increase the risk of developing wheat allergy. These results do not support delaying
290 citations
TL;DR: Evidence is provided of the benefit of telithromycin in patients with acute exacerbations of asthma; the mechanisms of benefit remain unclear.
Abstract: Background We conducted a double-blind, randomized, placebo-controlled study to evaluate the efficacy of telithromycin in patients with acute exacerbations of asthma. Methods A total of 278 adults with diagnosed asthma were enrolled within 24 hours after an acute exacerbation of asthma requiring short-term medical care. The patients were randomly assigned to receive 10 days of oral treatment with telithromycin (at a dose of 800 mg daily) or placebo in addition to usual care. Primary efficacy end points were a change from baseline over the treatment period in symptoms (as recorded by patients in a diary card) and in the peak expiratory flow in the morning at home. The presence of Chlamydophila pneumoniae or Mycoplasma pneumoniae was ascertained by serologic analysis, polymerase chain reaction, and culture. Results Of the two prespecified primary outcomes, only asthma symptoms showed a significantly greater reduction among patients receiving telithromycin than among those receiving placebo. Mean (±SD) scores on a test of asthma symptoms (on a 7-point scale, with 0 denoting no symptoms and 6 denoting severe symptoms) were 3.0±1.4 at baseline and 1.7±1.1 at the end of treatment for the telithromycin group and 2.8±1.3 at baseline and 2.0±1.0 at the end of treatment for the placebo group. The mean decrease in symptom scores during the treatment period was 1.3 for telithromycin and 1.0 for placebo (mean difference, −0.3; 95 percent confidence interval, −0.5 to −0.1; P = 0.004). There was no significant treatment effect on the other primary outcome measure, a change in morning peak expiratory flow. Nausea was more common among patients in the telithromycin group than in the placebo group (P = 0.01). Although 61 percent of patients had evidence of infection with C. pneumoniae, M. pneumoniae, or both, there was no relationship between bacteriologic status and the response to asthma treatment. Conclusions This study provides evidence of the benefit of telithromycin in patients with acute exacerbations of asthma; the mechanisms of benefit remain unclear. (ClinicalTrials. gov number, NCT00273520.)
283 citations
TL;DR: No practice parameters could be developed for a number of possible therapeutic modalities that had little or no evidence-based data on which to form a conclusion, and the role of an organized, targeted weight-loss program either as a single therapy or as a supplement to PAP needs to be clarified.
Abstract: Therapies for obstructive sleep apnea other than positive airway pressure, oral appliances, and surgical modifications of the upper airway are reviewed in this practice parameter. Several of these therapies such as weight loss and positional therapy hold some promise. Others, such as serotonergic agents, may gain credibility in the future but lack well-designed clinical trials. No practice parameters could be developed for a number of possible therapeutic modalities that had little or no evidence-based data on which to form a conclusion. The role of an organized, targeted weight-loss program either as a single therapy or as a supplement to PAP needs to be clarified. Although bariatric surgery is increasingly performed for refractory medically complicated obesity, its long-term effectiveness in treatment of obstructive sleep apnea in morbidly obese patients is not yet demonstrated. Positional therapy, or methods for preventing sleep in the supine position, has probably been underutilized due to lack of easily measured predictive factors and randomized controlled trials.
255 citations
TL;DR: Recommendations are provided indicating that behavioral interventions are effective in the treatment of bedtime problems and night wakings in young children, producing reliable and significant clinical improvement in sleep parameters.
Abstract: Bedtime problems and frequent night wakings are highly prevalent in infants, toddlers, and preschoolers. Evidence suggests that sleep disruption and/or insufficient sleep have potential deleterious effects on children's cognitive development, regulation of affect, attention, health outcomes, and overall quality of life, as well as secondary effects on parental and family functioning. Furthermore, longitudinal studies have demonstrated that sleep problems first presenting in infancy may become chronic, persisting into the preschool and school-aged years. A solid body of literature now exists supporting the use of empirically-based behavioral management strategies to treat bedtime problems and night wakings in infants, toddlers, and preschoolers. The following practice parameters present recommendations for the use of behavioral (i.e., non-pharmacological) treatments of bedtime problems and night wakings in young children (aged 0 - 4. years 11 months). A companion review paper on which the recommendations are based was prepared by a taskforce appointed by the Standards of Practice Committee (SPC) of the American Academy of Sleep Medicine (AASM), and summarizes the peer-reviewed scientific literature on this topic. The authors of the review paper evaluated the evidence presented by the reviewed studies according to modified Sackett criteria. Using this information and a grading system described by Eddy (i.e., standard, guideline or option), the Standards of Practice Committee and Board of Directors of the American Academy of Sleep Medicine determined levels of treatment recommendation presented in the practice parameters below. These practice parameters provide 3 types of recommendations. First, recommendations are provided indicating that behavioral interventions are effective in the treatment of bedtime problems and night wakings in young children, producing reliable and significant clinical improvement in sleep parameters. Second, recommendations are made regarding specific behavioral therapies, including: (1) unmodified extinction, extinction with parental presence, and preventive parent education are all rated as individually effective therapies in the treatment of bedtime problems and night wakings (Standards), and (2) graduated extinction, bedtime fading/positive routines and scheduled awakenings are rated as individually effective therapies in the treatment of bedtime problems and night wakings but with less certainty (Guidelines). There was insufficient evidence to recommend standardized bedtime routines and positive reinforcement as single therapies. In addition, although behavioral therapies for bedtime problems and night wakings are often combined, there was insufficient evidence available to recommend one individual therapy over another or to recommend an individual therapy over a combination of therapies. Finally, recommendations are provided regarding the beneficial effects of behavioral treatments on secondary outcomes, including daytime functioning (child) and parental well-being.
226 citations
Journal Article•
TL;DR: Moxifloxacin, gatifloxicin, and high-dose levoflOxacin have excellent EBA, only slightly less than for INH, and greater extended EBA; these drugs warrant further study in the treatment of drug-susceptible TB.
Abstract: OBJECTIF: Evaluer l'activite bactericide precoce (EBA) des nouvelles fluoroquinolones (levofloxacine, gatifloxacine et moxifloxacine) chez les patients atteints de tuberculose pulmonaire (TBP). SCHEMA : Essai ouvert randomise. Quarante adultes atteints d'une TBP recemment diagnostiquee et a bacilloscopie positive ont ete attribues a raison de 10 par bras soit a l'isoniazide (INH) 300 mg, soit a la levofloxacine 1000 mg, a la gatifloxacine 400 mg ou a la moxifloxacine 400 mg par jour pendant 7 jours. On a recueilli des expectorations pour culture quantitative pendant 2 jours avant la mise en route de la monotherapie et chaque jour au cours des 7 jours de monotherapie. L'activite bactericide a ete estimee en mesurant la diminution du nombre de bacilles au cours des 2 premiers jours (EBA 0-2) et au cours des 5 derniers jours de la monotherapie (EBA prolongee, EBA 2-7). Le personnel du laboratoire ignorait le traitement attribue. RESULTATS: L'EBA 0-2 de l'INH (0.67 log 10 cfu/ml/ jour) est plus elevee que celle de la moxifloxacine (0.33 log 10 cfu/ml/jour) et de la gatifloxacine (0.35 log 10 cfu/ ml/jour), mais pas que celle de la levofloxacine a 1000 mg par jour (0.45 log 10 cfu/ml/jour) (P = 0.14). L'activite bactericide entre les jours 2 et 7 est similaire pour les trois fluoroquinolones. Dans une comparaison combinant les fluoroquinolones, l'EBA 2-7est superieure a celle de l'INH. CONCLUSION: La moxifloxacine, la gatifloxacine et les fortes doses de levofloxacine ont d'excellentes EBA qui ne sont que legerement inferieures a l'INH et elles ont une EBA prolongee plus importante. Ces medicaments meritent des etudes complementaires dans le traitement de la TB a germes sensibles.
196 citations
TL;DR: A functional role for Syk is delineated in the development of mast cell- and IgE-mediated AHR and airway inflammation, and these results indicate that inhibition of Syk may be a target in the treatment of allergic asthma.
Abstract: Rationale: Spleen tyrosine kinase (Syk) is important for Fc and B-cell receptor–mediated signaling.Objective: To determine the activity of a specific Syk inhibitor (R406) on mast cell activation in vitro and on the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation in vivo.Methods: AHR and inflammation were induced after 10 d of allergen (ovalbumin [OVA]) exposure exclusively via the airways and in the absence of adjuvant. This approach was previously established to be IgE, FceRI, and mast cell dependent. Alternatively, mice were passively sensitized with OVA-specific IgE, followed by limited airway challenge. In vitro, the inhibitor was added to cultures of IgE-sensitized bone marrow–derived mast cells (BMMCs) before cross-linking with allergen.Results: The inhibitor prevented OVA-induced degranulation of passively IgE-sensitized murine BMMCs and inhibited the production of interleukin (IL)-13, tumor necrosis factor α, IL-2, and IL-6 in these sensitized BMMCs. When administ...
99 citations
Baylor College of Medicine1, Boston Children's Hospital2, Johns Hopkins University3, Nationwide Children's Hospital4, Children's Memorial Hospital5, National Jewish Health6, University of Toronto7, Riley Hospital for Children8, Cincinnati Children's Hospital Medical Center9, University of Pittsburgh10, Washington University in St. Louis11
TL;DR: This is the first of a series on pediatric pulmonary disease that will appear as Perspectives in Pediatric Pathology over the coming months, and will include practical issues, such as this protocol for handling lung biopsies, as well as reviews of advances in various areas in pediatric pulmonary pathology.
Abstract: This is the first of a series on pediatric pulmonary disease that will appear as Perspectives in Pediatric Pathology over the coming months. The series will include practical issues, such as this protocol for handling lung biopsies and another on bronchoalveolar lavage in childhood, as well as reviews of advances in various areas in pediatric pulmonary pathology. It has been 11 years since the last Perspectives on pulmonary disease. Much has happened since then in this area, and this collection will highlight some emerging and rapidly advancing areas in pediatric lung disease. These will include a review of molecular mechanisms of lung development, and another of mechanisms of pulmonary vascular development. The surfactant system and its disorders, as well as recent advances in the biology of the pulmonary neuroendocrine system and mechanisms of respiratory viral disease, will be addressed. Articles on pulmonary hypertension, pulmonary neoplasia, and pediatric lung transplantation, with their implications for the pediatric pathologist, are also planned. The contributors to this series are a diverse group with special interests and expertise in these areas. As Dr. William Thurlbeck noted in his foreword to the previous volume, Pulmonary Disease, volume 18 of Perspectives in Pediatric Pathology, pediatric pathology had been largely concerned with phenomenology, rather than with mechanisms, model systems, and experimental investigation. I think he would have been pleased to see the changes that have occurred over the past 10 years in pediatric lung biology and pathology in particular, because these were particularly favored interests of his later years.
92 citations
TL;DR: It is demonstrated that Syk inhibition prevents allergen-induced AHR and airway inflammation after systemic sensitization and challenge, at least in part through alteration of DC function.
Abstract: We evaluated the role of Syk, using an inhibitor, on allergen-induced airway hyperresponsiveness (AHR) and airway inflammation in a system shown to be B cell– and mast cell–independent. Sensitization of BALB/c mice with ovalbumin (OVA) and alum after three consecutive OVA challenges resulted in AHR to inhaled methacholine and airway inflammation. The Syk inhibitor R406 (30 mg/kg, administered orally, twice daily) prevented the development of AHR, increases in eosinophils and lymphocytes and IL-13 levels in bronchoalveolar lavage (BAL) fluid, and goblet cell metaplasia when administered after sensitization and before challenge with OVA. Levels of IL-4, IL-5, and IFN-γ in BAL fluid and allergen-specific antibody levels in serum were not affected by treatment. Because many of these responses may be influenced by dendritic cell function, we investigated the effect of R406 on bone marrow–derived dendritic cell (BMDC) function. Co-culture of BMDC with immune complexes of OVA and IgG anti-OVA together with OVA-sensitized spleen mononuclear cells resulted in increases in IL-13 production. IL-13 production was inhibited if the BMDCs were pretreated with the Syk inhibitor. Intratracheal transfer of immune complex-pulsed BMDCs (but not nonpulsed BMDCs) to naive mice before airway allergen challenge induced the development of AHR and increases in BAL eosinophils and lymphocytes. All of these responses were inhibited if the transferred BMDCs were pretreated with R406. These results demonstrate that Syk inhibition prevents allergen-induced AHR and airway inflammation after systemic sensitization and challenge, at least in part through alteration of DC function.
92 citations
TL;DR: The mechanisms of S. aureus colonization and infection are examined, of which the most important are defective skin barrier function, increased S.aureus adherence, and the decreased innate immune responses found in AD skin.
Abstract: The role of staphylococcal superantigens in the pathophysiology of atopic dermatitis (AD) has been the focus of intense interest during the past decade Although the increased prevalence of Staphylococcus aureus and its bacterial toxins in AD skin is well established, exploitation of the known mechanisms of superantigens in this disease for the development of novel therapies remains an active area of research With the emergence of multi-drug resistant S aureus, the need for a better understanding of the pathophysiology of bacterial superantigens in AD has become increasingly important This review examines the mechanisms of S aureus colonization and infection, of which the most important are defective skin barrier function, increased S aureus adherence, and the decreased innate immune responses found in AD skin The contribution of superantigens to the pathophysiology of AD is then discussed Important immunologic mechanisms in this context include the role of superantigens in promoting T helper-2 skin inflammation, IgE production, T-regulatory cell subversion, expansion and migration of skin-homing T cells, and IgE anti-superantigen production Lastly, these findings are discussed with reference to current therapeutic approaches, of which the most important include anti-inflammatory and antimicrobial medications, and future strategies, which are expected to consist of immune-modulators and synthetic antibacterials
TL;DR: These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in myeloid dendritic cell numbers.
Abstract: Rationale: There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) after repeated airway exposure to allergen in sensitized mice.Methods: Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7, or 11 occasions. Airway function in response to inhaled methacholine was monitored; bronchoalveolar lavage fluid inflammatory cells were counted; and goblet cell metaplasia, peribronchial fibrosis, and smooth muscle hypertrophy were quantitated on tissue sections. Bone marrow–derived dendritic cells were generated after differentiation of bone marrow cells in the presence of growth factors.Results: Sensitization to ovalbumin (OVA) in alum, followed by three airway exposures to OVA, induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis, and peribronchial smooth muscle hypertrophy; increased levels of interleukin (IL)-4, IL-5, IL-13, granulocyte-macrophage colony–stimulating factor, trans...
TL;DR: In this article, the association between cereal-grain exposures (wheat, barley, rye, oats) in the infant diet and development of wheat allergy was examined, and the results showed that delaying initial exposure to cereal grains until after 6 months may increase the risk of developing wheat allergy.
Abstract: OBJECTIVE.Early exposure to solid foods in infancy has been associated with the development of allergy. The aim of this study was to examine the association between cereal-grain exposures (wheat, barley, rye, oats) in the infant diet and development of wheat allergy. METHODS.A total of 1612 children were enrolled at birth and followed to the mean age of 4.7 years. Questionnaire data and dietary exposures were obtained at 3, 6, 9, 15, and 24 months and annually thereafter. The main outcome measure was parent report of wheat allergy. Children with celiac disease autoimmunity detected by tissue transglutaminase autoantibodies were excluded. Wheat-specific immunoglobulin E levels on children reported to have wheat allergy were obtained. RESULTS.Sixteen children (1%) reported wheat allergy. Children who were first exposed to cereals after 6 months of age had an increased risk of wheat allergy compared with children first exposed to cereals before 6 months of age (after controlling for confounders including a family history of allergic disorders and history of food allergy before 6 months of age). All 4 children with detectable wheat-specific immunoglobulin E were first exposed to cereal grains after 6 months. A first-degree relative with asthma, eczema, or hives was also independently associated with an increased risk of wheat-allergy development. CONCLUSIONS.Delaying initial exposure to cereal grains until after 6 months may increase the risk of developing wheat allergy. These results do not support delaying
TL;DR: Findings indicate that HIF stimulation by PHD inhibition ameliorates pathological and physiological consequences of BPD, and improves lung growth and function in prematurely born neonates in vivo.
Abstract: Bronchopulmonary dysplasia (BPD), a chronic lung disease affecting preterm neonates, is associated with significant childhood and adult health problems. Histopathologic features of BPD include impaired vascular and distal airway development. We previously showed that activation of hypoxia-inducible factors (HIFs) by inhibition of prolyl hydroxylase domain-containing proteins (PHDs) is feasible and that it stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis in vitro. We tested the hypothesis that enhancement of angiogenesis by activation of HIFs improves lung growth and function in prematurely born neonates in vivo. Preterm baboons (125 day+14 day pro re nata O2 model, corresponding to 27 human gestational weeks) were treated for 14 days with intravenous (i.v.) FG-4095, a PHD inhibitor. Notably, 77% of diminished total alveolar surface area in untreated controls was recovered by FG-4095 treatment. Functional significance of the structural changes was indicated by improved oxygenation and lung compliance in FG-4095-treated newborns. Surfactant proteins B and C and saturated phosphatidylcholine were unchanged. Incidence of spontaneous ductus arteriosus closure was increased, likely contributing to lower ratio of pulmonary to systemic blood flow in FG-4095 group. These findings indicate that HIF stimulation by PHD inhibition ameliorates pathological and physiological consequences of BPD.
TL;DR: The development of AHR and airway inflammation in sensitized fB-/- mice could be restored after intranasal administration of purified factor B before the airway challenge, and administration of a neutralizing anti-factor B mAb to sensitized mice beforeAirway challenge reduced the development of Allergen sensitivity and inflammation.
Abstract: Exposure to inhaled allergens leads to increases in airway hyperresponsiveness (AHR) and inflammation, associated with increased levels of biologically active fragments derived from the complement C3 and C5 family of proteins. Further, complement activation during allergen challenge in sensitized animals is necessary for the development of AHR and airway inflammation. To define the complement pathway involved, we studied mice deficient in complement factor 4 (C4−/−), a critical component of the classical pathway, or factor B (fB−/−), an essential protein in the alternative complement pathway. WT, C4−/−, and fB−/− mice were sensitized to ovalbumin and subsequently exposed to nebulized ovalbumin (1% in saline) on 3 consecutive days. After allergen sensitization and challenge, fB−/− mice demonstrated significantly lower airway responsiveness to methacholine and less airway inflammation. In contrast, C4−/− mice showed no reduction in AHR and airway inflammation compared with WT mice. Tissue inflammation, goblet cell hyperplasia, and IL-4, IL-5, and IL-13 levels in BAL fluid were significantly reduced in fB−/− mice compared with C4−/− and WT mice. The development of AHR and airway inflammation in sensitized fB−/− mice could be restored after intranasal administration of purified factor B before the airway challenge. In addition, administration of a neutralizing anti-factor B mAb to sensitized mice before airway challenge reduced the development of AHR and airway inflammation. These results demonstrate that in sensitized hosts complement activation through the alternative pathway after allergen exposure is critical to the development of AHR and airway inflammation.
TL;DR: In this paper, a case-control study did not suggest an increased risk for death or intensive care unit admissions with use of long-acting β 2 -agonists and showed that these outcomes were not a direct toxic effect of the drugs and increased the possibility that they resulted from an interaction between relief of symptoms by β 2-agonists and delay in seeking medical care.
Abstract: Short-acting β 2 -agonists are effective in relieving acute symptoms of asthma and in the short-term prevention of symptoms from stimuli, such as exercise. They are ineffective when used on a regular schedule to improve asthma control. Long-acting β 2 -agonists, on the other hand, provide sustained bronchodilation and improve asthma control. Regular use of long-acting β 2 -agonists is not associated with significant tolerance to their bronchodilator action, impairment in the response to albuterol, decreased baseline pulmonary function, increased response to methacholine, or increased risk of adverse cardiac events. Case-control studies do not suggest an increased risk for death or intensive care unit admissions with use of long-acting β 2 -agonists. In prospective studies in which there has been an increase in asthma deaths or serious asthma exacerbations, this increased risk has not been observed in subjects using inhaled corticosteroids. Where increased deaths have occurred in relation to either short- or long-acting β 2 -agonists, the events have not occurred equally throughout the exposed population. This suggests that these outcomes were not a direct toxic effect of the drugs and increases the possibility that they resulted from an interaction between relief of symptoms by β 2 -agonists and delay in seeking medical care.
TL;DR: It is suggested that neutrophils sequestered in the lung become fundamentally different from those resident in the circulation, and this difference is distinct from in vitro activation with endotoxin.
Abstract: Although the accumulation of neutrophils in the lungs and airways is common to many inflammatory lung diseases, including acute lung injury, the alterations that neutrophils undergo as they leave t...
TL;DR: In this article, the authors examined the immunologic response to three doses of dog extract expressed as their Can f 1 content, and found a significant dose-dependent response in suppression of titrated skin prick tests and suppression of the late cutaneous response.
Abstract: Background The immunologic response to immunotherapy with dog extract is not well characterized Objective The purpose of this study was to examine the immunologic response to 3 doses of dog extract expressed as their Can f 1 content Methods Cluster immunotherapy was administered to 28 patients with dog allergy who were randomly assigned to 1 of 4 treatment arms: placebo or acetone-precipitated extract containing 06 μg, 30 μg, or 150 μg Can f 1 per 05 mL maintenance dose Studies included titrated skin prick tests, the late cutaneous response, titrated nasal challenge with dog extract, and serum allergen-specific IgE and IgG 4 Dog allergen-stimulated lymphocyte proliferation was performed with measurement of secreted cytokines by ELISA and of intracellular cytokines by flow cytometry Results There was a significant dose-dependent response in suppression of titrated skin prick tests and suppression of the late cutaneous response There was a significant increase from baseline in dog-specific IgG 4 in both the high-dose and low-dose groups and a dose-dependent suppression of secreted TNF-α and increase in secreted TGF-β There was a dose-dependent trend in suppression of secreted IL-4 with a significant decrease from baseline in the high-dose group There were no significant changes in symptom scores; lymphocyte proliferation; secreted IFN-γ, IL-10, or IL-5; or intracellular cytokine production Conclusion The dose-response in immunologic parameters after immunotherapy with dog extract is similar to that previously demonstrated with cat extract Clinical implications The greatest and most consistent response is seen with a dose containing 15 μg Can f 1
TL;DR: AATD remains a devastating illness for many of those affected as reflected in a high incidence of transplantation for liver and lung disease, and the clinical characteristics of diseased individuals in North America are reviewed.
Abstract: Background: α1-Antitrypsin deficiency (AATD) is an uncommon genetic disease which occurs in 1–2.5% of Americans with chronic obstructive pulmonary disease (COPD). Little
TL;DR: The results demonstrate that the new plasma derived α1-PI (Zemaira) is bioequivalent to the currently available product Prolastin, is well tolerated, and safe with respect to the risk of viral transmission.
Abstract: Augmentation therapy with a plasma derived alpha l-Proteinase Inhibitor (alpha1 -PI) has been demonstrated to be effective in restoring serum Alpha1 -antitrypsin (AAT)* levels in individuals with AAT Deficiency (note: alpha1 PI and AAT are synonymous). The objective of this study was to demonstrate that the steady-state trough serum alphal-PI levels, achieved by a new plasma derived alpha,-PI (Zemaira, study drug, ZLB Behring LLC, King of Prussia, Pennsylvania, USA), were bioequivalent to those achieved by the currently available alpha-PI therapy, Prolastin (control drug, Bayer Corporation, Berkeley, California, USA), and maintained weekly trough serum antigenic alpha1-PI levels above the protective threshold of 11 microM. This multi-center, controlled study randomized a total of 44 subjects to receive either study or control drug for a 10-week double-blind phase. The control group was then crossed over to receive the study drug for the remainder of the study (14 weeks). The difference in mean trough serum antigenic alpha1-PI level between the treatment groups was 1.45 microM (90% CI-2.77, -0.13), signifying bioequivalence. The mean trough serum antigenic alpha1-PI level in the study drug group was greater than the therapeutic threshold of 11 microM, achieving a level of 17.7 microM during the steady-state period. Treatment-related adverse events (AEs) were seen in 7% and 21% of study and control drug treated subjects, respectively. No documented viral transmission occurred. These results demonstrate that the new plasma derived alpha1-PI (Zemaira) is bioequivalent to the currently available product Prolastin, is well tolerated, and safe with respect to the risk of viral transmission.
TL;DR: The purpose of this survey was to describe the current status of pediatric consultation-liaison (C-L) services in the United States.
Patent•
18 Oct 2006TL;DR: In this article, conditions for conditionally immortalizing stem cells including adult and embryonic stem cells, the cells produced by such methods, therapeutic and laboratory or research methods of using such cells, and methods to identify compounds related to cell differentiation and development or to treat diseases are described.
Abstract: Disclosed are methods for conditionally immortalizing stem cells, including adult and embryonic stem cells, the cells produced by such methods, therapeutic and laboratory or research methods of using such cells, and methods to identify compounds related to cell differentiation and development or to treat diseases, using such cells. A mouse model of acute myeloid leukemia (AML) and cells and methods related to such mouse model are also described.
TL;DR: Dietary administration of 2-methoxyestradiol prevented the development of preneoplastic lesions independent of progression stage and identified TSG-6 as a potential marker that could be used for early diagnosis and prognosis of cancerous or precancerous lesions.
Abstract: Purpose: 2-Methoxyestradiol, an estrogenic metabolite, is in clinical trials for the treatment of hormone-refractory prostate cancer. However, neither the chemopreventive role nor the mechanism of 2-methoxyestradiol–induced biological activities is fully understood. Experimental Design: Eight- and 24-week-old transgenic adenocarcinoma of mouse prostate (TRAMP) mice were fed a diet containing 50 mg 2-methoxyestradiol/kg body weight for 16 and 8 weeks, respectively. Chemopreventive efficacy was evaluated by magnetic resonance imaging, determining the prostate-seminal vesicle complex volume and histologic analysis of prostate tumor or tissue. Tumor invasion assays were used to show the role of tumor necrosis factor-α–stimulated gene (TSG-6), a 2-methoxyestradiol–up-regulated gene identified by DNA array analysis. Expression of TSG-6 was analyzed in a human tissue array containing different grades of prostate tumors. Results: Dietary administration of 2-methoxyestradiol prevented the development of preneoplastic lesions independent of progression stage. TSG-6 was low or undetectable in prostate cancer cells (LNCaP, PC-3, and DU145) and TRAMP tumors but up-regulated in response to 2-methoxyestradiol. Immunohistochemistry of the human prostate tumor array showed a decrease in TSG-6–positive cells with increasing grade relative to normal prostate (P = 0.0001). Although overexpression of TSG-6 inhibited invasion of androgen-independent cells (P = 0.007), antisense TSG-6 reversed this effect. Conclusions: To the best of our knowledge, this is the first report showing the potential of 2-methoxyestradiol as a chemopreventive agent. We have also identified TSG-6 as a potential marker that could be used for early diagnosis and prognosis of cancerous or precancerous lesions.
TL;DR: It is concluded that both personal and secondhand exposure to tobacco smoke in childhood are likely to accelerate the onset of symptoms in AAT deficient patients and Respiratory infections in childhood may also contribute to this risk.
Abstract: BACKGROUND In an early study of highly symptomatic patients with PI*Z alpha-1 antitrypsin deficiency (AAT), tobacco smoking was identified as a risk factor by comparing the age of symptom onset in smokers and nonsmokers. Age of symptom onset has not been well studied in relationship to other environmental exposures. METHODS Environmental exposures were assessed in 313 PI*Z adults through retrospective self-administered questionnaire. Age of onset of symptoms with and without these exposures were analyzed through survival analysis. RESULTS Personal smoking was the most important risk factor, associated with earlier onset of cough and wheeze, and showed a dose-dependent relationship with the onset of dyspnea. Childhood environmental tobacco smoke (ETS) exposure was independently associated with younger age of onset of cough. Earlier onset of wheeze was also associated with childhood respiratory infections and family history of emphysema. The report of childhood respiratory infections was associated with childhood ETS exposure, but no statistically significant interactions were noted. CONCLUSIONS We conclude that both personal and secondhand exposure to tobacco smoke in childhood are likely to accelerate the onset of symptoms in AAT deficient patients. Respiratory infections in childhood may also contribute to this risk.
Medical University of South Carolina1, George Washington University2, Case Western Reserve University3, Henry Ford Health System4, University of Cincinnati5, University of North Carolina at Chapel Hill6, Cleveland Clinic7, Johns Hopkins University8, National Jewish Health9, Georgetown University10, University of Pennsylvania11, Icahn School of Medicine at Mount Sinai12
TL;DR: The phenotypic features and clinical outcomes of sarcoidosis in sibling pairs show minimal concordance, with the possible exception that the presence of ocular or liver involvement in the first sibling with a diagnosis of sarCOidosis makes involvement of these organs more likely in other affected siblings.
Patent•
15 Nov 2006TL;DR: In this article, the authors present methods for therapy of cystic fibrosis and other conditions such as cancer using agents capable of increasing thiol-containing compound transport via a transporter system (i.e., MDR-1 or MRP-2).
Abstract: Methods for therapy of cystic fibrosis and other conditions such as cancer are provided. The methods comprise one or more agents capable of increasing thiol-containing compound transport via a transporter system (i.e., ABC transporters such as MDR-1 or MRP-2) in cells. Other embodiments include the use of agents to modulate transport of thiol-containing compounds within the cell. Therapeutic methods involve the administration of such agents to a patient afflicted with cystic fibrosis, cancer and/or another condition responsive to stimulation of thiol-containing compound transport.
TL;DR: Data indicate that RANTES plays a role in the regulation of airway function after repeated allergen challenge, in part through modulation of levels of IFN-gamma and IL-12.
Abstract: RANTES (CC chemokine ligand 5) contributes to airway inflammation through accumulation of eosinophils, but the exact role of RANTES (CCL5) is not defined. C57BL/6 mice, sensitized by injection of ovalbumin (OVA) on Days 1 and 14, were challenged with OVA on Days 28, 29, and 30 (3 challenges, short-term–challenge model) or on Days 28, 29, 30, 36, 40, 44, and 48 (7 challenges, repeated–challenge model) and evaluated 48 h later. Anti-mouse RANTES was given intravenously, and recombinant mouse RANTES or PBS was given intratracheally. These reagents were given on Days 28, 29, and 30 in the short-term–challenge study and on Days 44 and 48 in the repeated-challenge study. After short-term challenge, there were no effects after administration of anti-RANTES or RANTES. In the repeated-challenge study, although control mice showed a decrease in airway hyperresponsiveness, administration of anti-RANTES sustained and enhanced airway hyperresponsiveness and increased goblet cell numbers. In contrast, administration of RANTES normalized airway function but reduced goblet cell numbers. IL-12 and IFN-γ levels in BAL decreased in the anti-RANTES group and increased in the RANTES group. IFN-γ–producing CD4 T cells in lung, and IFN-γ production from lung T cells in response to OVA in the anti-RANTES group, were significantly decreased but were increased in the RANTES group. Anti–IFN-γ, administered with RANTES, decreased the effects of RANTES on AHR after repeated challenge. These data indicate that RANTES plays a role in the regulation of airway function after repeated allergen challenge, in part through modulation of levels of IFN-γ and IL-12.
TL;DR: It is suggested that dexamethasone can stimulate G1-S phase cell cycle transition in human airway fibroblasts obtained from asthmatics, which leads to enhanced airway remodelling in some individuals remains to be determined.
Abstract: Corticosteroids are the first line of therapy for asthma. Whether they alter the progression of airway remodelling in asthma is, as yet, unknown. To determine whether corticosteroids could alter the fibroblast cell cycle the current authors studied the effect of dexamethasone on cultured airway fibroblasts obtained from nine mild-to-moderate, steroid-naive asthmatics (forced expiratory volume in one second 78+/-4% predicted), and seven normal controls. Fibroblasts were cultured from endobronchial biopsies obtained via bronchoscopy. Cells were exposed to dexamethasone (10(-9)-10(-7) M) and studied at 72 h to determine differences in progression through the cell cycle. In asthmatic fibroblasts, dexamethasone, at concentrations of 10(-8)M and 10(-7)M, nearly doubled the number of cells in the S phase (17.8+/-3.0% and 18.4+/-3.1%, respectively) compared with untreated fibroblasts (10.3+/-1.4%). There was no significant effect in normal control fibroblasts. Dexamethasone induced hyperphosphorylation of the tumour suppressor, retinoblastoma (RB) in asthmatic fibroblasts; fibroblasts from normal controls had significantly less hyperphosphorylation of RB. No difference in protein expression of the CCAAT/enhancer binding protein alpha between the two groups was detected. This study suggests that dexamethasone can stimulate G1-S phase cell cycle transition in human airway fibroblasts obtained from asthmatics. Whether this leads to enhanced airway remodelling in some individuals remains to be determined.
National Institutes of Health1, American College of Physicians2, Harvard University3, Georgetown University4, Icahn School of Medicine at Mount Sinai5, Henry Ford Health System6, Johns Hopkins University7, Medical University of South Carolina8, National Jewish Health9, University of Cincinnati10, University of Iowa11, University of Pennsylvania12
TL;DR: Simulation is conducted to compare the trend tests and the robust trend tests under various genetic models and the results are applied to detect candidate-gene association using an example from a case-control aetiologic study of sarcoidosis.
Abstract: Trend tests for genetic association using a matched case-control design are studied, which allows for a variable number of controls per case. However, the tests depend on the scores based on the underlying genetic model, thus it may result in substantial loss of power when the model is misspecified. Since the mode of inheritance may be unknown for complex diseases, robust trend tests in matched case-control studies are developed. Simulation is conducted to compare the trend tests and the robust trend tests under various genetic models. The results are applied to detect candidate-gene association using an example from a case-control aetiologic study of sarcoidosis.
TL;DR: Increasing the rate of infusion of IGIV-C, 10% by 75% up to 0.14 mL/kg/min (840 mg/ kg/h) was well tolerated, suggesting safe administration of IGiva, 10%, at this rate, and resulted in a shortened overall infusion time.
Abstract: The incidence and severity of infusion-related adverse events (AEs) after infusions of IGIV-C, 10%, (Gamunex) at 0.14 mL/kg/min versus 0.08 mL/kg/min (standard rate) were compared. Patients with confirmed PID received two infusions 3-4 weeks apart with IGIV-C, 10% 400-600 mg/kg. Patients received their first infusion at 0.08 or 0.14 mL/kg/min and their second infusion 3-4 weeks later at the alternate rate, at an established step-wise rate increase. Ninety-seven of 100 patients remained valid for safety assessment. There were three infusion-related reactions at the standard rate and five at the increased rate. The incidence of all reported AEs was similar for both rates. Despite the time required for step-wise increases in infusion rate, the increased rate resulted in a shortened overall infusion time. Increasing the rate of infusion of IGIV-C, 10% by 75% up to 0.14 mL/kg/min (840 mg/kg/h) was well tolerated, suggesting safe administration of IGIV-C, 10% at this rate.