April 2006 World Medical Journal Review
Reviewed by Richard F. Lockey, M.D., Editor-In-Chief
1. INCREASED GLUCOCORTICOID RECEPTOR ß ALTERS STEROID RESPONSE IN GLUCOCORTICOID-INSENSITIVE ASTHMA
BAL cells of 7 patients with glucocorticoid (GC)-sensitive asthma and 8 patients with GC-insensitive asthma were examined to define the functional role of glucocorticoid receptor (GCR) ß (a splicing variant and dominant negative inhibitor of the classic GCRa) in controlling GCRa nuclear translocation and transactivation at a molecular level. Significantly reduced nuclear translocation of GCRa in response to GC was present in GC-insensitive asthma. These same subjects had significantly increased levels of cytoplasmic and nuclear GCRß. RNA silencing of GCRß mRNA in BAL macrophages from these same subjects enhanced dexamethasone-induced GCRa transactivation. Editor's comment: Measurable differences in GC receptor activity are present in GC-insensitive asthma. Goleva E, et al. Am J Respir Crit Care Med 2006; 173: 607.
2. THE EFFECT OF TELITHROMYCIN IN ACUTE EXACERBATIONS OF ASTHMA
A total of 278 adults with asthma were enrolled within 24 hours after an acute exacerbation requiring short-term medical care. They were randomly assigned to receive 10 days of oral telithromycin 800 mg daily or placebo in addition to usual care. The primary efficacy end points were a change from baseline over the treatment period in symptoms as recorded by the patient and A.M. peak expiratory flow (PEF). Presence of Chlamydophila pneumoniae or Mycoplasma pneumoniae was assed by the polymerase chain reaction and culture. Patients on telithromycin had a significantly greater reduction of symptoms than those on placebo, but no significant difference in A.M. PEF. Sixty-one percent had evidence of infection with C. pneumoniae, M. pneumoniae or both, but there was no relationship between bacteriologic status and response to asthma treatment. Editor's comment: Are C. pneumoniae and, M. pneumoniae important in the
pathogenenesis of asthma? Is the effect of telithromycin antibacterial or anti-inflammatory? Is the response to this antibiotic similar to other macrolides? The debate goes on! Johnston SF, et al. N Engl J Med 2006; 354: 1589. Little FF, (editorial), p.1632.
3. BUILDING HEALTH: AN EPIDEMIOLOGICAL STUDY OF "SICK BUILDING SYNDROME" (SBS)
SBS was studied in a cross sectional data analysis of the physical environment of a selection of buildings added to individual data from the Whitehall II study -- an ongoing health survey of office-based civil servants. A self-report questionnaire was used to capture 10 symptoms of SBS and psychosocial work stress. In total, 4,052 participants, 42-62 yrs, working in 44 buildings were included in the study. Positive, but non-significant, relations were found with airborne bacteria, inhalable dust, dry bulb temperature, relative humidity, and having some control over the local physical environment. Greater effects were found with features of the psychosocial work environment, including high job demands and low support. Only psychosocial work characteristics and control over the physical environment were independently associated with symptoms in the multivariate analysis. Editor's comment: "Sick Building Syndrome" is a misnomer. This syndrome would be better termed "Building Related Complaints." Marmot AF, et al. Occup Environ Med 2006; 63: 283.
4. SAFETY AND IMMUNOGENICITY OF AN INACTIVATED SUBVIRION INFLUENZA A (H5N1) VACCINE.
The authors conducted a multicenter, double-blind, two-stage study involving 451 healthy adults 18-64 yr who were randomly assigned to receive various IM doses of a subvirion influenza A (H5N1) vaccine ("Bird Flu") or placebo. There were no major safety problems and the highest antibody responses were among those subjects who received 45 µg (43 % response) and 90 µg (58% response). Editor's comment: The 58% response is lower than ideal, but good news for a virus which could cause a world-wide flu epidemic. Treanor JJ, et al. N Engl J Med 2006; 345: 1343.
5. NEUROPSYCHOLOGICAL AND RENAL EFFECTS OF DENTAL AMALGAM IN CHILDREN and NEUROBEHAVIORAL EFFECTS OF DENTAL AMALGAM IN CHILDREN
Both studies are randomized clinical trials. The first study compares neuropsychological and renal function of children (6 to 10 yrs at baseline) whose dental caries were restored using amalgam or mercury free materials. The second study assesses the safety of dental amalgam vs. resin composite restorations in children, (8 to 10 yrs at baseline). The first study followed patients for 5 yrs and the second for 7 yrs. Both conclude that dental amalgam is safe and does not affect neuropsychological outcomes, renal disease or have any adverse neurobehavioral effects. Editor's comment: This paper concludes that amalgam restorations are safe! Bellinger DC, et al. JAMA 2006; 295: 1775. DeRouen TA, et al. p. 1784.
6. A META-ANALYSIS OF THE EFFECT OF HIGH WEIGHT ON ASTHMA
A Medline search (1966 to October, 2004), supplemented by a manual search of reference lists and literature, was used for this meta-analysis cohort study that examined high body weight at birth or during childhood and future asthma. The combined results from 4 studies that met inclusion criteria and examined the effect of high body weight during middle childhood on the outcomes of subsequent asthma showed a 50% increase in relative risk (RR 1.5, 95% CI 1.2 to 1.8). The combined results from 9 studies that examined the effect of high birth weight on subsequent asthma had a pooled RR of 1.2 (95% CL 1.1 to 1.3). There was consistency among the studies. Editor's comment: Excessive weight affects many diseases, including asthma. Flaherman V, Rutherford GW. Arch Dis Child 2006; 91: 334.
7. DOES ANTIBIOTIC EXPOSURE DURING INFANCY LEAD TO DEVELOPMENT OF ASTHMA? A SYSTEMATIC REVIEW AND META-ANALYSIS?
Eight studies (four prospective and four retrospective) examined the association between exposure to at least one course of antibiotics and development of childhood asthma. The authors conclude that exposure to at least one course of antibiotics during the first year of life seems to be a risk factor for childhood asthma. Likewise, there is a slight dose-response association for each additional course of antibiotics. Editor's comment: Conclusions from this study are consistent with the "hygiene hypothesis." Marra F, et al. Chest 2006; 129: 610.
8. AN EXCELLENT REVIEW ON SEVERE ASTHMA
Asthma is the theme of this issue of the JACI. Articles include: Severe Asthma: An Overview; Understanding the Pathophysiology of Severe Asthma to Generate New Therapeutic Opportunities; Managing Severe Asthma; Severity and Control of Severe Asthma; Update on Glucocorticoid Action and Resistance; Severity, Control, and Responsiveness in Asthma; and Severe asthma. Editor's comment: Although there is some redundancy, these are excellent reviews about the pathophysiology and treatment of severe asthma. Moore WC et al, p-487; Holgate ST et al, p-496; Wenzel S, Szefler SJ, p-508; Bateman ED, p-519; Ito K, et al, p-522; Stoloff SW, Boushey HA, p-544; Foley S, Hamid Q, p-714. J Allergy Clin Immunol 2006; 117:
Severe Asthma: An Overview
Understanding the Pathophysiology of Severe Asthma to Generate New Therapeutic Opportunities
Managing Severe Asthma: No abstract is available.
Severity and Control of Severe Asthma: No abstract is available.
Update on Glucocorticoid Action and Resistance
Severity, Control, and Responsiveness in Asthma
Severe asthma: No abstract is available.
9. INTERESTING COLLECTION OF REVIEW ARTICLES ON DRUG ALLERGY
These articles include: Drug-Induced Hypersensitivity Syndrome (DIHS): A Reaction Induced by a Complex Interplay Among Herpesviruses and Antiviral and Antidrug Immune Responses; Toxic Epidermal Necrolysis and Stevens Johnson Syndrome: Our Current Understanding; Pharmacological Interaction of Drugs with Immune Receptors: The p-i Concept; Immune Mechanisms in Drug Allergy; and Recent Advances in the Development of Anti-allergic Drugs. Editor's comment: Progress is being made to better understand the complexity and pathogenesis of drug allergy. Shiohara T, et al, p-1; French LE, p-9; Pichler WJ, et al, p-17; Roujeau J, p-27; Nagai H, et al, p-35. Allergology International 2006; 55.
10. ANTIINFLAMMATORY EFFECTS OF SALMETEROL/FLUTICASONE PROPIONATE IN COPD
Bronchial biopsies and induced sputum were collected from 140 current and former smokers (mean age, 64 yr) with moderate to severe COPD. They were randomized in a 13-wk, double-blind study to placebo or salmeterol/fluticasone propionate 50/500 µg (n = 67) twice daily. Biopsies were repeated at 12-wk. and sputa at 8- and 13-wk. Combination therapy was associated with a reduction in biopsy CD8+ cells, not CD68+ cells. Sputum differential (but not total) neutrophils reduced progressively. The combination also significantly reduced biopsy CD45+ and CD4+ cells, cells expressing genes for tumor necrosis factor–a and IFN-? and sputum total eosinophils. Changes were accompanied by a 173-ml improvement in prebronchodilator FEV1. Editor's comment: The combination of salmeterol/fluticasone are anti-inflammatory for COPD. Barnes NC, et al. Am J Respir Crit Care Med 2006; 173: 736.
11. REVIEW ARTICLE ON EXTRAPULMONARY EFFECTS OF INHALED NITRIC OXIDE: MECHANISMS AND IMPLICATIONS.
These articles include: The Biological Chemistry of Nitric Oxide as It Pertains to the Extrapulmonary Effects of Inhaled Nitric Oxide; Extrapulmonary Effects of Inhaled Nitric Oxide: Role of Reversible S-Nitrosylation of Erythrocytic Hemoglobin; Immunoregulatory and Antimicrobial Effects of Nitrogen Oxides; Regulation of Respiration and Endothelial Gene Expression by S-Nitrosothiols in Health and Disease; and Summary: Systemic Effects of Inhaled Nitric Oxide. Editor's comment: This is an excellent review on the extrapulmonary effects of inhaled nitric oxide. Gow AJ, p-150; McMahon TJ, Doctor A, p-153; Mannick JB, p-161; Palmer LA, p-166; Gaston B, p-170. Proc Am Thorac Soc 2006; 3.
