The Journal of Allergy and Clinical Immunology RSS feed: Current Issue. An official publication of the American Academy of Allergy, Asthma, and Immunology, The Journal of Allergy and Clinical Immunology brings timely clinical papers, instructive case reports, and detailed examinations of state-of-the-art equipment and techniques to clinical allergists, immunologists, dermatologists, internists, and other physicians concerned with clinical manifestations of allergies in their practice. Articles cover such topics as allergic and immunologic diseases, the latest therapies and treatment programs, occupational/industrial allergy, and studies of antigens, allergens, and the environment. With an impact factor of 8.115, the journal ranks 1st of 17 in the Allergy category; ranked 9th of 119 in the Immunology category on the 2008 Journal Citation Reports®, published by Thomson Reuters. The Journal of Allergy and Clinical Immunology is also recommended for initial purchase in the Brandon-Hill study, Selected List of Books and Journals for the Small Medical Library.http://www.jacionline.org/?rss=yesElsevier Inc.en © 2008 Published by Elsevier Inc. All rights reserved. The Journal of Allergy and Clinical Immunology0091-67491226December 2008 © 2008 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.jacionline.org/article/PIIS0091674908020629/abstract?rss=yesCover 110.1016/S0091-6749(08)02062-9The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2OFCOFChttp://www.jacionline.org/article/PIIS0091674908019246/abstract?rss=yesKnowledge of the human genome and the application of array-based technology has allowed identification of single-nucleotide polymorphisms (SNPs) which are associated with increased risk for many diseases. Several previous studies had established an association between SNPs on chromosome 17q21 and the risk for asthma. Bouzigon and colleagues (N Engl J Med 2008; Oct 15 [epub ahead of print]) re-examined this association, comparing various asthma phenotypes to 38 SNPs located within a region of that chromosome. Their patient data was drawn from 1621 individuals from 388 families included in the Epidemiological Study on the Genetics and Environment of Asthma. Eleven of these SNPs were significantly associated with asthma. However, this association held only for those subjects of all ages who had the onset of their asthma at or before age 4 years. Furthermore, the association between these SNPs and asthma risk was limited to those who had passive tobacco smoke exposure in early life. There are several genes within the region of the implicated SNPs, including ORMDL3, which might have a role in viral infections, and GSDML, which may be involved in the growth and differentiation of epithelial cells. Nevertheless, the mechanism of the increased risk has not been determined. The results of this study further emphasize that asthma is not a single disease, but rather a number of gene/environment interactions presenting with clinical similarities.News Beyond Our PagesMarc E. Rothenberg, Harold S. Nelson10.1016/j.jaci.2008.10.039The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2News beyond our pages10411042http://www.jacionline.org/article/PIIS0091674908019192/abstract?rss=yesPrimary immunodeficiencies (PIDs) were long thought to be exclusively recessive traits — autosomal recessive (AR) in most cases, with a few X-linked recessive (XR) diseases. In recent years, autosomal dominant (AD), mitochondrial, polygenic, and even somatic PIDs have been described. However, AR remains the most frequent inheritance pattern among recently described PIDs. Some PIDs have been shown to be genetically heterogeneous. Mendelian susceptibility to mycobacterial diseases (MSMD) displays a high level of genetic heterogeneity. There are 6 MSMD-causing genes, including 1 X-linked gene (nuclear factor-κB–essential modulator [NEMO]) and 5 autosomal genes (IFN-γ receptor 1 [IFNGR1], IFN-γ receptor 2 [IFNGR2], signal transducer and activator of transcription 1 [STAT1], IL-12 p40 subunit [IL12P40], and IL-12 receptor β-subunit [IL12RB1]). The X-linked trait is XR; STAT1 deficiency is AD; the IFNGR2, IL12P40 subunit, and IL12RB1 deficiencies are AR; and IFNGR1 deficiency may be AD or AR. Two of the AR traits (IFNGR1, IFNGR2) may be subdivided into complete and partial deficiencies, and 3 AR complete deficiencies (IFNGR1, IFNGR2, IL12RB1) may be subdivided into disorders with and without cell surface expression. Finally, there are 2 types of AD STAT1 deficiency, depending on whether the mutation impairs phosphorylation or DNA binding. Thirteen genetic disorders conferring MSMD have been described, involving 1 XR, 3 AD (2 genes), and 9 AR traits (4 genes). However, no genetic etiology has yet been identified for about half of all patients with MSMD. We expect to identify new XR and AD causes of MSMD, but new AR etiologies of MSMD are also likely to be discovered. The investigation of children from areas in which consanguineous marriages are common will probably facilitate the description of many more AR traits.The genetic heterogeneity of mendelian susceptibility to mycobacterial diseasesSaleh Al-Muhsen, Jean-Laurent Casanova10.1016/j.jaci.2008.10.037The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Clinical reviews in allergy and immunology10431051http://www.jacionline.org/article/PIIS0091674908021817/abstract?rss=yesThe genetic heterogeneity of mendelian susceptibility to mycobacterial diseases10.1016/j.jaci.2008.11.001The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Continuing Medical Education examination10521053http://www.jacionline.org/article/PIIS0091674908018903/abstract?rss=yesIgE antibodies play a central role in the pathogenesis of atopic diseases and in host immunity against parasitic infections. IgE has potent activities on mast cells and basophils. IgE class switching is a very tightly controlled process, and serum IgE levels are very low compared with other immunoglobulin isotypes. Transcription factors that activate or inhibit the IgE gene promoter, as well as TH1 and TH2 cytokines are important in the regulation of IgE levels. Hyper-IgE syndrome; Wiskott-Aldrich syndrome; immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX); Omenn syndrome; and atypical complete DiGeorge syndrome are primary immune deficiencies that are associated with elevated serum IgE levels. Increased IgE levels in IPEX, Wiskott-Aldrich syndrome and Omenn syndrome are likely related to increased TH2 cytokine production caused by decreased a number or function of CD4+CD25+forkhead box protein P3+ regulatory T cells. The link between signal transducer and activator of transcription 3 mutations and elevated serum IgE levels in hyper-IgE syndrome is unclear. Insight into IgE regulation provided by the study of primary immune deficiencies with elevated IgE has important implications for allergic diseases.Primary immune deficiencies with aberrant IgE productionEsra Ozcan, Luigi D. Notarangelo, Raif S. Geha10.1016/j.jaci.2008.10.023The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Mechanisms of allergic diseases10541062http://www.jacionline.org/article/PIIS0091674908018733/abstract?rss=yesPrimary immune deficiencies with aberrant IgE production10.1016/j.jaci.2008.10.020The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Continuing Medical Education examination10631064http://www.jacionline.org/article/PIIS0091674908019143/abstract?rss=yesNow able to treat or cure many of the most serious forms of primary immunodeficiency, clinical immunologists are increasingly concerned about the long-term outcomes and quality of life issues their patients live with as a result of medical intervention. There is no better way to illustrate a very happy result of immunologic reconstitution than the Journal cover picture of life photographs of a patient with common variable immunodeficiency who was diagnosed at 11 years of age and begun on monthly intravenous immunoglobulin replacement therapy. She went on to accomplish her dreams with a college degree, medical degree, and specialty board certification. Dr Jennifer Pate now gives to other patients the healing power she was able to obtain by maintaining her own health with regular immunologic treatments. Dr Pate validates the hypothesis that definitive treatment of patients with primary immunodeficiency will enable them to live life to the fullest and take their place in society.Treatment of immunodeficiency: Long-term outcome and quality of lifeWilliam T. Shearer, Luigi D. Notarangelo, Linda M. Griffith10.1016/j.jaci.2008.10.033The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Editorial10651068http://www.jacionline.org/article/PIIS0091674908016850/abstract?rss=yesThe identification of the molecular bases of more than 130 primary immunodeficiency diseases has prompted the use of mutation analysis in the diagnostic approach to these patients. Here we discuss the importance of and the limitations associated with molecular diagnosis of these disorders and emphasize the need that mutation analysis be accompanied by appropriate evidence that the identified genetic defect has pathologic consequences on RNA/protein expression and function.Is it necessary to identify molecular defects in primary immunodeficiency disease?Luigi D. Notarangelo, Ricardo Sorensen10.1016/j.jaci.2008.08.038The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Current perspectives10691073http://www.jacionline.org/article/PIIS0091674908017399/abstract?rss=yesRecent insights into the relevance of the epidermal barrier function and its interaction with components of the innate and adaptive immune responses in patients with atopic dermatitis (AD) give rise to a number of novel potential treatment options. In particular, the identification of loss-of-function mutations in the barrier protein filaggrin and of a diminished expression of certain antimicrobial peptides in AD skin stimulates new concepts to think beyond the TH1/TH2 paradigm. This review will focus on these most recent discoveries and will discuss new and corresponding proof-of-concept trials in patients with AD. It will further speculate on novel ways to restore the homeostasis among the 3 major components in AD skin suspected to be clinically relevant.Atopic dermatitis: Therapeutic concepts evolving from new pathophysiologic insightsThomas Jung, Georg Stingl10.1016/j.jaci.2008.09.042The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Update review10741081http://www.jacionline.org/article/PIIS009167490801734X/abstract?rss=yesOmenn syndrome (OS) was reported until recently as a distinct form (phenotype and genotype) of severe combined immunodeficiency (SCID). Similar to other patients with SCID, patients with OS present early in infancy with viral or fungal pneumonitis, chronic diarrhea, and failure to thrive. Unlike typical SCID, patients with OS have enlarged lymphoid tissue, severe erythroderma, increased IgE levels, and eosinophilia. The inflammation observed in these patients is believed to be triggered by clonally expanded T cells, which are predominantly of the TH2 type. These abnormal T cells, in the absence of proper regulation by other components of the immune system, secrete a host of cytokines that promote autoimmune as well as allergic inflammation. The emergence of these T-cell clones occurs in patients with hypomorphic mutations in recombination activating gene 1 or 2, but not in patients with deleterious mutations in these enzymes which render them inactive. Recently, OS was also identified in a growing list of other leaky SCIDs with mutations in RNA component of mitochondrial RNA processing endoribonuclease, adenosine deaminase, IL-2 receptor γ, IL-7 receptor α, ARTEMIS, and DNA ligase 4. This new information revealed OS is a distinct inflammatory process that can be associated with genetically diverse leaky SCIDS.Omenn syndrome: Inflammation in leaky severe combined immunodeficiencyAnna Villa, Luigi D. Notarangelo, Chaim M. Roifman10.1016/j.jaci.2008.09.037The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Rostrum10821086http://www.jacionline.org/article/PIIS0091674908018411/abstract?rss=yesAllogeneic hematopoietic cell transplantation (HCT) has been used for 40 years to ameliorate or cure primary immune deficiency (PID) diseases, including severe combined immunodeficiency (SCID) and non-SCID PID. There is a critical need for evaluation of the North American experience of different HCT approaches for these diseases to identify best practices and plan future investigative clinical trials. Our survey of incidence and prevalence of PID in North American practice sites indicates that such studies are feasible. A conference of experts in HCT treatment of PID has recommended (1) a comprehensive cross-sectional and retrospective analysis of HCT survivors with SCID; (2) a prospective study of patients with SCID receiving HCT, with comparable baseline and follow-up testing across participating centers; (3) a pilot study of newborn screening for SCID to identify affected infants before compromise by infection; and (4) studies of the natural history of disease in patients who do or do not receive HCT for the non-SCID diseases of Wiskott-Aldrich syndrome and chronic granulomatous disease. To accomplish these goals, collaboration by a consortium of institutions in North America is proposed. Participation of immunologists and HCT physicians having interest in PID and experts in laboratory methods, clinical outcomes assessment, databases, and analysis will be required for the success of these studies.Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: Current status and critical needsLinda M. Griffith, Morton J. Cowan, Donald B. Kohn, Luigi D. Notarangelo, Jennifer M. Puck, Kirk R. Schultz, Rebecca H. Buckley, Mary Eapen, Naynesh R. Kamani, Richard J. O'Reilly, Robertson Parkman, Chaim M. Roifman, Kathleen E. Sullivan, Alexandra H. Filipovich, Thomas A. Fleisher, William T. Shearer, workshop participants10.1016/j.jaci.2008.09.045The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Workshop summary10871096http://www.jacionline.org/article/PIIS0091674908015479/abstract?rss=yesChronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation. In addition, we have observed a number of diverse autoimmune conditions in our CGD population, suggesting that patients with CGD are at an elevated risk for development of autoimmune disorders. In this report, we describe antiphospholipid syndrome, recurrent pericardial effusion, juvenile idiopathic arthritis, IgA nephropathy, cutaneous lupus erythematosus, and autoimmune pulmonary disease in the setting of CGD. The presence and type of autoimmune disease have important treatment implications for patients with CGD.Chronic granulomatous disease as a risk factor for autoimmune diseaseSuk See De Ravin, Nora Naumann, Edward W. Cowen, Julia Friend, Dianne Hilligoss, Martha Marquesen, James E. Balow, Karyl S. Barron, Maria L. Turner, John I. Gallin, Harry L. Malech10.1016/j.jaci.2008.07.050The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Case study10971103http://www.jacionline.org/article/PIIS0091674908018745/abstract?rss=yesImmune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare autoimmune genetic disorder caused by mutation of the FOXP3 gene, a key regulator of the immune response. Initial clinical manifestations leading physicians to consider IPEX are early-onset severe enteropathy (mostly associated with eczema, elevated IgE levels, and eosinophilia) and/or insulin-dependent diabetes. To provide hints for a prompt diagnosis, Gambineri et al (p 1105) studied 14 children with new or previously identified mutations within the FOXP3 gene. The typical IPEX symptoms, especially enteropathy, were reported particularly in patients carrying mutations within FOXP3 functional domains or FOXP3 null mutations. However, patients carrying similar mutations did not always show the same disease courses, and they often responded quite differently to therapy. Surprisingly, FOXP3 protein expression on patients' T cells did not correlate with disease severity; unless the underlying mutation completely prevented gene expression, FOXP3-positive T cells were detected (ex vivo and/or induced by activation in vitro) also in severely affected patients (see Figure). These results indicate that expression of FOXP3 is a poor predictor of IPEX, whereas early recognition of clinical markers and genetic analysis of FOXP3 mutations are essential to ensure an accurate diagnosis and avoid delay in the treatment.The Editors' ChoiceDonald Y.M. Leung, Stanley J. Szefler, Associate Editors of the JACI10.1016/j.jaci.2008.10.021The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2The Editors' choice11041104http://www.jacionline.org/article/PIIS0091674908017223/abstract?rss=yesBackground: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune genetic disorder caused by mutation of the forkhead box protein 3 gene (FOXP3), a key regulator of immune tolerance.Objective: We sought to provide clinical and molecular indicators that facilitate the understanding and diagnosis of IPEX syndrome.Methods: In 14 unrelated affected male subjects who were given diagnoses of IPEX syndrome based on FOXP3 gene sequencing, we determined whether particular FOXP3 mutations affected FOXP3 protein expression and correlated the molecular and clinical data.Results: Molecular analysis of FOXP3 in the 14 subjects revealed 13 missense and splice-site mutations, including 7 novel mutations. Enteropathy, generally associated with endocrinopathy and eczema, was reported in all patients, particularly in those carrying mutations within FOXP3 functional domains or mutations that altered protein expression. However, similar genotypes did not always result in similar phenotypes in terms of disease presentation and severity. In addition, FOXP3 protein expression did not correlate with disease severity.Conclusion: Severe autoimmune enteropathy, which is often associated with increased IgE levels and eosinophilia, is the most prominent early manifestation of IPEX syndrome. Nevertheless, the disease course is variable and somewhat unpredictable. Therefore genetic analysis of FOXP3 should always be performed to ensure an accurate diagnosis, and FOXP3 protein expression analysis should not be the only diagnostic tool for IPEX syndrome.Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: Inconsistent correlation between forkhead box protein 3 expression and disease severityEleonora Gambineri, Lucia Perroni, Laura Passerini, Lucia Bianchi, Claudio Doglioni, Franco Meschi, Riccardo Bonfanti, Yves Sznajer, Alberto Tommasini, Anita Lawitschka, Anne Junker, Desiree Dunstheimer, Peter H. Heidemann, Giantonio Cazzola, Marco Cipolli, Wilhelm Friedrich, Dragana Janic, Nadira Azzi, Erick Richmond, Silvia Vignola, Arrigo Barabino, Giuseppe Chiumello, Chiara Azzari, Maria-Grazia Roncarolo, Rosa Bacchetta10.1016/j.jaci.2008.09.027The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Editors' choice articles11051112.e1http://www.jacionline.org/article/PIIS0091674908015480/abstract?rss=yesBackground: Boys with X-linked ectodermal dysplasia and immunodeficiency caused by mutations of nuclear factor-κB essential modulator have defects in innate and adaptive immunity, and some have colitis.Objective: We sought to determine whether curing the immune defect in such patients by means of allogeneic hematopoietic stem cell transplantation abolishes the susceptibility to colitis.Methods: A boy with X-linked hypohydrotic ectodermal dysplasia with immunodeficiency underwent allogeneic transplantation from a matched unaffected sibling identified by means of preimplantation genetic diagnosis. Toll-like receptor (TLR) function was assessed by measuring TLR agonist–induced cytokine production in whole blood tested in vitro. B-cell proliferation was measured by means of tritiated thymidine incorporation. Natural killer cell function was examined in PBMCs by means of K562 target cell lysis. Colitis severity was assessed clinically based on corticosteroid requirement and histology of large intestinal biopsy specimens.Results: Defects in cytokine production in response to TLR agonists, CD40-mediated proliferation, and natural killer cell cytotoxicity were all corrected after hematopoietic stem cell transplantation. Despite successful hematopoietic and immune reconstitution, the patient continued to have flares of colitis, often associated with bacterial infection.Conclusions: Our findings strongly suggest that nuclear factor-κB essential modulator deficiency intrinsic to the intestinal epithelium is sufficient to predispose to colitis, despite robust correction of immune defects.Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-κB essential modulator deficiencySung-Yun Pai, Ofer Levy, Haifa H. Jabara, Jonathan N. Glickman, Liat Stoler-Barak, Jessica Sachs, Samuel Nurko, Jordan S. Orange, Raif S. Geha10.1016/j.jaci.2008.08.026The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Editors' choice articles11131118.e1http://www.jacionline.org/article/PIIS0091674908017211/abstract?rss=yesBackground: CXCR3 is a chemokine receptor that plays important roles in mediating chemotactic signals and modulating the activation of lymphocytes. We have previously conducted a case-control study by using a candidate gene approach to investigate the association of CXCR3 polymorphisms with the risk of asthma. Results from the epidemiologic study showed that a common nucleotide variant in the CXCR3 intron (rs2280964G>A) was associated with disease susceptibility (1006 cases and 384 control subjects; odds ratio, 0.81; 95% CI, 0.69-0.94; P = .007).Objective: The aim of our study was to evaluate the epidemiologic study and provide functional evidence for the association of rs2280964G>A with asthma by investigating the effects of intronic variant on chemokine-mediated phenotypes of human-derived T cells.Methods: We used cell line–based in vitro and human primary T cell–based ex vivo studies to examine the functional consequences of the intronic polymorphism, focusing on the regulation of gene expression, splicing, and immune responsiveness toward activating signals.Results: We present functional evidence indicating that the rs2280964A allele significantly correlates with decreased CXCR3 gene expression, which would lead to variation in immune cell responses to chemokine-cytokine signals in vitro and ex vivo that includes a decrease in chemotactic activity.Conclusion: These findings, in conjunction with those of our previous epidemiologic studies, might implicate a functional link between a common nucleotide variant of a chemokine receptor gene, CXCR3, and a cause for a complex-trait disease, asthma.A common intronic variant of CXCR3 is functionally associated with gene expression levels and the polymorphic immune cell responses to stimuliJung-Won Choi, Choon-Sik Park, Minyoung Hwang, Hye-Young Nam, Hun Soo Chang, Seong Gyu Park, Bok-Ghee Han, Kuchan Kimm, Hyung Lae Kim, Bermseok Oh, Yeonjung Kim10.1016/j.jaci.2008.09.026The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Editors' choice articles11191126.e7http://www.jacionline.org/article/PIIS0091674908017247/abstract?rss=yesBackground: Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity.Objectives: We sought to examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing.Methods: In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome.Results: The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy (P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% [P = .003] and 37% [P = .003], respectively) and interference with activity scores (32% [P = .01] and 40% [P = .001], respectively) that were most evident in those with positive asthma predictive indices.Conclusions: In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezingLeonard B. Bacharier, Brenda R. Phillips, Robert S. Zeiger, Stanley J. Szefler, Fernando D. Martinez, Robert F. Lemanske, Christine A. Sorkness, Gordon R. Bloomberg, Wayne J. Morgan, Ian M. Paul, Theresa Guilbert, Marzena Krawiec, Ronina Covar, Gary Larsen, Michael Mellon, Mark H. Moss, Vernon M. Chinchilli, Lynn M. Taussig, Robert C. Strunk, Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute10.1016/j.jaci.2008.09.029The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Original article11271135.e8http://www.jacionline.org/article/PIIS0091674908019234/abstract?rss=yes“What's in a name? That which we call a roseBy any other name would smell as sweet…”William Shakespeare, Romeo and Juliet, 1594 In this issue of the Journal, Bacharier et al from the Childhood Asthma Research and Education (CARE) network of the National Heart Lung and Blood Institute address an important common question in their Acute Intervention Management Strategies trial: “How can we best treat intermittent wheezing episodes in young children?” Wheezing illnesses are common and may affect as many as 50% of preschool children, resulting in substantial impact on the children, their families, and the health care system. In this study, episodic use of an inhaled wet nebulized corticosteroid (budesonide) or an oral leukotriene receptor antagonist (montelukast) did not affect the primary outcome parameter, proportion of episode-free days, but did significantly decrease morbidity in the children during the wheezing episodes. In the year before study entry, the children had an average of 3.4 episodes of “wheezing illness,” missed an average of 4.8 days from school or daycare, and received 1 course of oral corticosteroids (median, 1.0; range, 0.02-2.0). The current study was powered for the primary outcome on the basis of data from a previous study of preschool children with recurrent acute asthma episodes. In that study, children had frequent, severe wheezing episodes with an average of more than 12 episodes per year, requiring 8 to 9 courses of oral corticosteroids per year. Given the relatively few episodes per child in the current study, it would have been surprising to fulfill the requirement for a significant change in the defined primary outcome of episode-free days or in a secondary outcome such as number of courses of oral corticosteroids.Asthma in the preschool child: Still a rose by any other name?Allan B. Becker10.1016/j.jaci.2008.10.038The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Editorial11361137http://www.jacionline.org/article/PIIS0091674908017235/abstract?rss=yesBackground: Clinical trials in children with moderate-to-severe persistent asthma are limited.Objective: We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing.Methods: The budesonide dose (with salmeterol [50 μg] twice daily) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma. After a budesonide-stable period of 6 weeks, children were randomized in a double-masked, parallel, multicenter study to receive once-nightly azithromycin, montelukast, or matching placebos plus the established controlling dose of budesonide (minimum, 400 μg twice daily) and salmeterol twice daily. Primary outcome was time from randomization to inadequate asthma control after sequential budesonide dose reduction.Results: Of 292 children screened, only 55 were randomized. Inadequate adherence to study medication (n = 80) and improved asthma control under close medical supervision (n = 49) were the major reasons for randomization failure. A futility analysis was requested by the Data Safety Monitoring Board. In data available for analyses, no differences were noted for either treatment compared with placebo in time to inadequate control status (median: azithromycin, 8.4 weeks [95% confidence limit, 4.3-17.3]; montelukast, 13.9 weeks [95% confidence limit, 4.7-20.6]; placebo, 19.1 weeks [95% confidence limit, 11.7-infinity]), with no difference between the groups (log-rank test, P = .49). The futility analysis indicated that even if the planned sample size was reached, the results of this negative study were unlikely to be different, and the trial was prematurely terminated.Conclusion: Based on these results, neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid–sparing alternative in children with moderate-to-severe persistent asthma.Azithromycin or montelukast as inhaled corticosteroid–sparing agents in moderate-to-severe childhood asthma studyRobert C. Strunk, Leonard B. Bacharier, Brenda R. Phillips, Stanley J. Szefler, Robert S. Zeiger, Vernon M. Chinchilli, Fernando D. Martinez, Robert F. Lemanske, Lynn M. Taussig, David T. Mauger, Wayne J. Morgan, Christine A. Sorkness, Ian M. Paul, Theresa Guilbert, Marzena Krawiec, Ronina Covar, Gary Larsen, Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute10.1016/j.jaci.2008.09.028The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Original article11381144.e4http://www.jacionline.org/article/PIIS0091674908017284/abstract?rss=yesBackground: Chronic rhinosinusitis (CRS) is characterized by persistent mucosal inflammation and frequent exacerbations.Objective: To determine whether innate epithelial responses to cigarette smoke or bacterial or viral pathogens may be abnormal in CRS leading to an inappropriate inflammatory response.Methods: Primary nasal epithelial cells (PNECs) were grown from middle turbinate biopsies of 9 healthy controls and 11 patients with CRS. After reaching 80% to 90% confluence, PNECs were exposed to medium or cigarette smoke extract (CSE) 5% (vol/vol) for 1 hour, washed, then stimulated with staphylococcal lipoteichoic acid, LPS, or double-stranded RNA (dsRNA). After 24 hours, gene expression was quantified by QRT-PCR.Results: At baseline, PNECs revealed elevated TNF-α and growth-related oncogene-α (a C-X-C chemokine)/CXCL1 (GRO-α) (4-fold increase, P = .02; and 16-fold increase, P = .004, respectively) in subjects with CRS compared with controls with normal levels of IL-1β, IL-6, IL-8/CXCL8, human β-defensin-2, monocyte chemoattractant protein 2/CCL8, monocyte chemoattractant protein 3/CCL7, and regulated upon activation, normal T-cell expressed and secreted (RANTES)/CCL5. Immunostaining of nasal biopsies, however, revealed comparable epithelial staining for TNF-α, GRO-α, and RANTES. There were no differences in mRNA induction by CSE, TNF-α, lipoteichoic acid, LPS, or dsRNA alone. The combination of CSE+dsRNA induced exaggerated RANTES (12,115-fold vs 1500-fold; P = .03) and human β-defensin-2 (1120-fold vs 12.5-fold; P = .05) in subjects with CRS. No other genes were differentially induced. Furthermore, CSE+dsRNA induced normal levels of IFN-β, IFN-λ1, and IFN-λ2/3 mRNA in subjects with CRS.Conclusion: Cigarette smoke extract plus dsRNA induces exaggerated epithelial RANTES expression in patients with CRS. We propose that an analogous response to cigarette smoke plus viral infection may contribute to acute exacerbations and eosinophilic mucosal inflammation in CRS.Cigarette smoke combined with Toll-like receptor 3 signaling triggers exaggerated epithelial regulated upon activation, normal T-cell expressed and secreted/CCL5 expression in chronic rhinosinusitisMoshe Yamin, Eric H. Holbrook, Stacey T. Gray, Rachel Harold, Nicolas Busaba, Avinash Sridhar, Katia J. Powell, Daniel L. Hamilos10.1016/j.jaci.2008.09.033The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Rhinitis, sinusitis, and upper airway disease11451153.e3http://www.jacionline.org/article/PIIS0091674908017259/abstract?rss=yesBackground: Orally administered, food-specific immunotherapy appears effective in desensitizing and potentially permanently tolerizing allergic individuals.Objective: We sought to determine whether milk oral immunotherapy (OIT) is safe and efficacious in desensitizing children with cow's milk allergy.Methods: Twenty children were randomized to milk or placebo OIT (2:1 ratio). Dosing included 3 phases: the build-up day (initial dose, 0.4 mg of milk protein; final dose, 50 mg), daily doses with 8 weekly in-office dose increases to a maximum of 500 mg, and continued daily maintenance doses for 3 to 4 months. Double-blind, placebo-controlled food challenges; end-point titration skin prick tests; and milk protein serologic studies were performed before and after OIT.Results: Nineteen patients, 6 to 17 years of age, completed treatment: 12 in the active group and 7 in the placebo group. One dropped out because of persistent eczema during dose escalation. Baseline median milk IgE levels in the active (n = 13) versus placebo (n = 7) groups were 34.8 kUa/L (range, 4.86–314 kUa/L) versus 14.6 kUa/L (range, 0.93–133.4 kUa/L). The median milk threshold dose in both groups was 40 mg at the baseline challenge. After OIT, the median cumulative dose inducing a reaction in the active treatment group was 5140 mg (range 2540-8140 mg), whereas all patients in the placebo group reacted at 40 mg (P = .0003). Among 2437 active OIT doses versus 1193 placebo doses, there were 1107 (45.4%) versus 134 (11.2%) total reactions, with local symptoms being most common. Milk-specific IgE levels did not change significantly in either group. Milk IgG levels increased significantly in the active treatment group, with a predominant milk IgG4 level increase.Conclusions: Milk OIT appears to be efficacious in the treatment of cow's milk allergy. The side-effect profile appears acceptable but requires further study.A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergyJustin M. Skripak, Scott D. Nash, Hannah Rowley, Nga H. Brereton, Susan Oh, Robert G. Hamilton, Elizabeth C. Matsui, A. Wesley Burks, Robert A. Wood10.1016/j.jaci.2008.09.030The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Food, drug, insect sting allergy, and anaphylaxis11541160http://www.jacionline.org/article/PIIS0091674908017405/abstract?rss=yesBackground: Reported incidences of anaphylaxis range from 3.2 to 20 per 100,000 population. The incidence and trend over time has meaningful public health implications but has not been well characterized because of a lack of a standard definition and deficiencies in reporting of events.Objective: We sought to determine the incidence and cause of anaphylaxis over a 10-year period.Methods: We performed a population-based incidence study that was conducted in Rochester, Minnesota, from 1990 through 2000. Anaphylaxis episodes were identified on the basis of symptoms and signs of mast cell and basophil mediator release plus mucocutaneous, gastrointestinal tract, respiratory tract, or cardiovascular system involvement.Results: Two hundred eleven cases of anaphylaxis were identified (55.9% in female subjects). The mean age was 29.3 years (SD, 18.2 years; range, 0.8-78.2 years). The overall age- and sex-adjusted incidence rate was 49.8 (95% CI, 45.0-54.5) per 100,000 person-years. Age-specific rates were highest for ages 0 to 19 years (70 per 100,000 person-years). Ingested foods accounted for 33.2% (70 cases), insect stings accounted for 18.5% (39 cases), medication accounted for 13.7% (29 cases), radiologic contrast agent accounted for 0.5% (1 case), “other” causes accounted for 9% (19 cases), and “unknown” causes accounted for 25.1% (53 cases). The “other” group included cats, latex, cleaning agents, environmental allergens, and exercise. There was an increase in the annual incidence rate during the study period from 46.9 per 100,000 persons in 1990 to 58.9 per 100,000 persons in 2000 (P = .03).Conclusion: The overall incidence rate is 49.8 per 100,000 person-years, which is higher than previously reported. The annual incidence rate is also increasing. Food and insect stings continue to be major inciting agents for anaphylaxis.The etiology and incidence of anaphylaxis in Rochester, Minnesota: A report from the Rochester Epidemiology ProjectWyatt W. Decker, Ronna L. Campbell, Veena Manivannan, Anuradha Luke, Jennifer L. St. Sauver, Amy Weaver, M. Fernanda Bellolio, Eric J. Bergstralh, Latha G. Stead, James T.C. Li10.1016/j.jaci.2008.09.043The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Food, drug, insect sting allergy, and anaphylaxis11611165http://www.jacionline.org/article/PIIS0091674908018708/abstract?rss=yesEpidemiologic studies have confirmed a steady increase in the rate of occurrence of asthma, allergic rhinitis, and eczema in recent decades. The magnitude of this increase is so great that the term “epidemic” is correctly used to describe it. The rate of occurrence of anaphylaxis has also reportedly increased during this time, but the magnitude of this increase is more difficult to ascertain with certainty, and it might or might not warrant the designation “epidemic.”Anaphylaxis epidemic: Fact or fiction?F. Estelle R. Simons, Hugh A. Sampson10.1016/j.jaci.2008.10.019The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Editorial11661168http://www.jacionline.org/article/PIIS0091674908015455/abstract?rss=yesBackground: Human hypomorphic nuclear factor-κB essential modulator (NEMO) mutations cause diverse clinical and immunologic phenotypes, but understanding of their scope and mechanistic links to immune function and genotype is incomplete.Objective: We created and analyzed a database of hypomorphic NEMO mutations to determine the spectrum of phenotypes and their associated genotypes and sought to establish a standardized NEMO reconstitution system to obtain mechanistic insights.Methods: Phenotypes of 72 individuals with NEMO mutations were compiled. NEMO L153R and C417R were investigated further in a reconstitution system. TNF-α or Toll-like receptor (TLR)–5 signals were evaluated for nuclear factor-κB activation, programmed cell death, and A20 gene expression.Results: Thirty-two different mutations were identified; 53% affect the zinc finger domain. Seventy-seven percent were associated with ectodermal dysplasia, 86% with serious pyogenic infection, 39% with mycobacterial infection, 19% with serious viral infection, and 23% with inflammatory diseases. Thirty-six percent of individuals died at a mean age of 6.4 years. CD40, IL-1, TNF-α, TLR, and T-cell receptor signals were impaired in 15 of 16 (94%), 6 of 7 (86%), 9 of 11 (82%), 9 of 14 (64%), and 7 of 18 (39%), respectively. Hypomorphism-reconstituted NEMO-deficient cells demonstrated partial restoration of NEMO functions. Although both L153R and C417R impaired TLR and TNF-α–induced NF-κB activation, L153R also increased TNF-α–induced programmed cell death with decreased A20 expression.Conclusion: Distinct NEMO hypomorphs define specific disease and genetic characteristics. A reconstitution system can identify attributes of hypomorphisms independent of an individual's genetic background. Apoptosis susceptibility in L153R reconstituted cells defines a specific phenotype of this mutation that likely contributes to the excessive inflammation with which it is clinically associated.Hypomorphic nuclear factor-κB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversityEric P. Hanson, Linda Monaco-Shawver, Laura A. Solt, Lisa A. Madge, Pinaki P. Banerjee, Michael J. May, Jordan S. Orange10.1016/j.jaci.2008.08.018The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Original articles11691177.e16http://www.jacionline.org/article/PIIS0091674908013729/abstract?rss=yesBackground: Cartilage hair hypoplasia is an autosomal recessive type of metaphyseal chondrodysplasia, caused by mutations in the ribonuclease mitochondrial RNA processing (RMRP) gene. Typical features of cartilage hair hypoplasia include short stature, a predisposition to malignancy, and a variable degree of impairment of cellular immunity.Objective: We sought to describe the heterogeneity of clinical and immunologic phenotype in 12 consecutive patients with RMRP mutations who were referred to 2 different institutions for immunologic evaluation.Methods: We have retrospectively analyzed the clinical and laboratory features in 12 patients with molecular defects in the RMRP gene. T-cell repertoire was investigated by quantitating Vβ families' expression and analyzing their diversity. T-cell receptor excision circle analysis was used to study thymic output.Results: All 12 patients had significant immune abnormalities, leading to severe immune deficiency in 9. CD8 lymphocytopenia was identified as a novel phenotype associated with RMRP mutations. Significant, even intrafamilial, phenotypic heterogeneity was observed. In 3 cases, severe immunodeficiency was the only phenotypic manifestation associated with RMRP mutations, a novel finding. Mutations leading to significant immune defects were most often located in the promoter, and the first case of a compound heterozygote for 2 such mutations is reported.Conclusion: This report broadens the spectrum of phenotypes associated with RMRP mutations and suggests that mutations in this gene should be considered when evaluating patients with combined immune deficiency, regardless of the presence of other manifestations.Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutationsFotini D. Kavadas, Silvia Giliani, Yiping Gu, Evelina Mazzolari, Andrea Bates, Eleonora Pegoiani, Chaim M. Roifman, Luigi D. Notarangelo10.1016/j.jaci.2008.07.036The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Original articles11781184http://www.jacionline.org/article/PIIS0091674908019131/abstract?rss=yesBackground: Between 1981 and 1995, 20 children with severe combined immunodeficiency (SCID; median age at transplant, 6.5 [range, 0.5-145] mo, 12 with serious infection) were treated with haploidentical T cell–depleted (anti-CD6 antibody) bone marrow (median number of 5.7 [0.8-18.8] × 108 nucleated cells/kg) from mismatched related donors (MMRDs), and 5 children with SCID (median age at transplant, 1.8 [0.5-5.0] mo, 1 with serious infection) were given unmanipulated bone marrow from matched related donors (MRDs). No conditioning or graft-versus-host disease (GvHD) prophylaxis was used.Objective: To assess the outcomes of patients with SCID who received bone marrow from MMRDs or MRDs.Methods: We reviewed the medical records of these 25 consecutive patients with SCID (4 with Omenn syndrome).Results: Of the 20 patients who received bone marrow from MMRDs, 12 engrafted, 10 survived at a median age of 15.2 [10.0-19.1] years, 4 had chronic GvHD (lung, intestine, skin), 5 required intravenous immunoglobulin, and 8 attended school or college. Two of 5 patients who died had chronic GvHD, and 2 developed lymphoproliferative disease. Of the 5 patients who received bone marrow from MRDs, 5 engrafted, 5 survived at a median age of 23.3 [18.5-26] years, 1 had chronic GvHD (lung, skin), 2 required intravenous immunoglobulin, and 4 attended school or college.Conclusions: Treatment of critically ill patients with SCID with anti-CD6 antibody T cell–depleted MMRD marrow resulted in an overall 50% long-term survival of patients (83% survival of those engrafted). The principal barriers to long-term survival were delay in diagnosis, life-threatening infection, failure to engraft, and chronic GvHD. Educational goals were achieved in most of the survivors.Long-term outcomes of nonconditioned patients with severe combined immunodeficiency transplanted with HLA-identical or haploidentical bone marrow depleted of T cells with anti-CD6 mAbNiraj C. Patel, Javier Chinen, Howard M. Rosenblatt, Imelda C. Hanson, Betty S. Brown, Mary E. Paul, Stuart L. Abramson, Jerome Ritz, William T. Shearer10.1016/j.jaci.2008.10.030The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Original articles11851193http://www.jacionline.org/article/PIIS0091674908013146/abstract?rss=yesBackground: Partial DiGeorge syndrome (pDGS) presents with thymic hypoplasia and a variable decrease in T-cell numbers. Although lymphocyte proliferation to mitogens is generally preserved, it is uncertain whether the development of specific cellular immunity in pDGS is similarly preserved.Objective: We sought to study the development of antigen-specific T-cell responses in patients with pDGS with regard to their initial CD3 T-cell counts.Methods: A retrospective review of 93 patients with pDGS followed at Texas Children's Hospital Allergy and Immunology Clinic from 1991 to 2006 was performed. Serial lymphocyte proliferation to Candida and tetanus antigens was longitudinally analyzed. Antigen-specific lymphoproliferation was compared with initial patient CD3 T-cell counts of less than the 10th percentile (n = 63), the 10th to 50th percentile (n = 20), and greater than the 50th percentile (n = 10) of age-matched normal control values. Tetanus-specific IgG levels and the number of tetanus immunizations were also studied.Results: The median CD3 T-cell counts at baseline in all 3 groups were as follows: 10th percentile, 1188 cells/mm3 (range, 168-3272 cells/mm3); 10th to 50th percentile, 2816 cells/mm3 (range, 1484-4155 cells/mm3); greater than 50th percentile, 4246 cells/mm3 (range, 2573-6481 cells/mm3). Thirty-one (46%) of 68 patients with pDGS who received at least 3 tetanus vaccines had persistent Candida and tetanus-specific cellular immunity, and 24 (35%) did not have immunity to either antigen. Most (22/24) of these patients had CD3 T-cell counts at presentation of less than the 10th percentile of normal values. Protective tetanus-specific IgG titers (>0.10 IU/mL) were detected in all patients tested from the age of 2 to 85 months (n = 72).Conclusion: Some patients with pDGS with low CD3 T-cell counts might not have specific Candida and tetanus cellular immunity.Development of specific T-cell responses to Candida and tetanus antigens in partial DiGeorge syndromeCarla M. Davis, Vikas S. Kancherla, Ashwini Reddy, Wenyaw Chan, Hung-Wen Yeh, Lenora M. Noroski, Howard Rosenblatt, William T. Shearer, Javier Chinen10.1016/j.jaci.2008.06.039The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Original articles11941199http://www.jacionline.org/article/PIIS0091674908018642/abstract?rss=yesBackground: Resistin-like molecule (Relm) α is a secreted protein and a hallmark signature gene for alternatively activated macrophages. Relm-α is highly induced by allergic inflammatory triggers and perceived to promote tissue repair. Yet the function of Relm-α remains unknown.Objective: We sough to determine the role of Relm-α in dextran sodium sulfate (DSS)–induced colonic injury.Methods: The cellular source of Relm-α was determined after oral DSS-induced colitis. Retnla−/− mice were generated, subjected to DSS treatment, and monitored for disease progression (clinical and histopathologic features). Cytokine production in the supernatants of ex vivo colon cultures, and of LPS-stimulated macrophages incubated with Relm-α was assessed. Relm-α was administered intraperitoneally, and the cellular recruitment to the peritoneum was assessed.Results: After innate intestinal stimulation with DSS, Relm-α was highly expressed by eosinophils and epithelial cells. Retnla gene–targeted mice were protected from DSS-induced colitis (eg, decreased diarrhea, rectal bleeding, colon shortening, disease score, and histopathologic changes). Relm-α coactivated IL-6 and TNF-α release and inhibited IL-10 release from LPS-activated bone marrow–derived macrophages. Consistent with these finding, colon cultures of DSS-treated Retnla−/− mice produced decreased IL-6 and increased IL-10 ex vivo. Furthermore, Retnla−/− mice had substantially decreased c-Jun N-terminal kinase phosphorylation in vivo. In vivo administration of Relm-α initiated cellular recruitment to the peritoneum, and Relm-α was able to induce eosinophil chemotaxis in vitro.Conclusions: These findings demonstrate a central proinflammatory role for Relm-α in colonic innate immune responses, identifying a novel pathway for regulation of macrophage activation.Resistin-like molecule α enhances myeloid cell activation and promotes colitisAriel Munitz, Amanda Waddell, Luqman Seidu, Eric T. Cole, Richard Ahrens, Simon P. Hogan, Marc E. Rothenberg10.1016/j.jaci.2008.10.017The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Rapid publication12001207.e1http://www.jacionline.org/article/PIIS0091674908016862/abstract?rss=yesBackground: Both active and passive smoking are considered to be risk factors for asthma development. However, the precise mechanisms involved remain elusive. Recently, thymic stromal lymphopoietin (TSLP) has been shown to play a key role in the development of TH2-type allergic inflammation in patients with asthma.Objective: The aim of this study was to investigate whether there was a causal relationship between cigarette smoke exposure and TSLP expression in the lung.Methods: We examined the effects of repeated intranasal exposure of cigarette smoke extract (CSE) on TSLP mRNA and protein expression in the mouse lung by means of real-time PCR, Western blotting, and immunohistochemistry. We also examined the effects of intranasal exposure of CSE plus ovalbumin (OVA) on TH2-type immune responses and lung pathology.Results: Repeated exposure of CSE induced TSLP mRNA and protein expression, which was inhibited by treatment with antioxidative N-acetylcysteine and by TNF-α receptor I deficiency. In addition, the intranasal exposure of CSE simultaneously with OVA induced OVA-specific TH2-type immune responses and airway inflammation, which were inhibited by the blockade of the TSLP activity.Conclusion: CSE induced TSLP expression in the mouse lung in an oxidative stress–dependent and TNF-α receptor I–dependent manner, and when challenged simultaneously with an antigen, CSE promoted the development of airway inflammation in association with TH2-type immune responses.Cigarette smoke extract induces thymic stromal lymphopoietin expression, leading to TH2-type immune responses and airway inflammationYuki Nakamura, Masanori Miyata, Tetsuro Ohba, Takashi Ando, Kyosuke Hatsushika, Fumiko Suenaga, Naomi Shimokawa, Yuko Ohnuma, Ryohei Katoh, Hideoki Ogawa, Atsuhito Nakao10.1016/j.jaci.2008.09.022The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Original article12081214http://www.jacionline.org/article/PIIS0091674908011718/abstract?rss=yesTo the Editor: Severe combined immune deficiency (SCID) is a heterogeneous group of inherited diseases characterized by significantly impaired immunity leading to death in infancy unless treated with bone marrow transplantation (BMT). When successful, BMT provides full immune reconstitution and long-term survival. However, a common and potentially fatal complication of BMT is acute graft-versus-host disease (aGvHD). Once it occurs, aGvHD poses a therapeutic challenge mainly because of the paucity of effective alternatives to methylprednisolone (MP) and cyclosporin A. Other treatment modalities including antithymocyte globulin, monoclonal antibodies, denileukin diftitox, or pentostatin have shown limited success.High-dose methylprednisolone is effective in the management of acute graft-versus-host disease in severe combined immune deficiencyRaz Somech, Fotini D. Kavadas, Adelle Atkinson, Eyal Grunebaum, Chaim M. Roifman10.1016/j.jaci.2008.06.023The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Letters to the Editor12151216http://www.jacionline.org/article/PIIS0091674908013079/abstract?rss=yesTo the Editor: About 150 primary immunodeficiencies (PIDs) have been described, with more than 100 genetic etiologies identified, as reviewed by Casanova and Abel. Most known PIDs are rare and first manifest symptoms in infancy or early childhood. They confer predisposition to various clinical phenotypes, including infection and cancer. Most PIDs predispose affected children to infectious diseases, the nature and range of which depend on the condition. Autosomal recessive IL-12 receptor β1 (IL-12Rβ1) deficiency is the most common cause of hereditary predisposition to mycobacterial diseases and salmonellosis in otherwise healthy patients, as reviewed by Filipe-Santos et al. Many PIDs also confer predisposition to cancer, whether because of impaired control of oncogenic viruses, impaired DNA repair, or both. The best known example is ataxia-telangiectasia (A-T), which is associated with a high rate of lymphoma and leukemia, as reviewed by Lavin et al. Known PIDs are typically rare, with a prevalence between 1/100,000 and 1/1,000,000 cases per live births. We report the first patient with 2 hereditary PIDs: IL-12Rβ1 deficiency and A-T.Simultaneous presentation of 2 rare hereditary immunodeficiencies: IL-12 receptor β1 deficiency and ataxia-telangiectasiaMohammad Ehlayel, Ludovic de Beaucoudrey, Francesca Fike, Shareef A. Nahas, Jacqueline Feinberg, Jean-Laurent Casanova, Richard A. Gatti10.1016/j.jaci.2008.07.005The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Letters to the Editor12171219http://www.jacionline.org/article/PIIS0091674908015583/abstract?rss=yesTo the Editor: Omenn syndrome (OS) is a fatal variant of severe combined immunodeficiency (SCID), unless treated with allogeneic bone marrow transplant (BMT). Initially OS was associated with mutations in the recombination activating gene (RAG) 1 and 2. Subsequently, we and others identified mutations in genes such as RNA component of ribonuclease mitochondrial RNA, adenosine deaminase, IL-2 receptor γ, and IL-7 receptor α in patients with OS. We report here, for the first time, the occurrence of OS in a patient with a novel mutation in the DNA ligase IV gene, which was corrected after allogeneic bone marrow transplant.Omenn syndrome is associated with mutations in DNA ligase IVEyal Grunebaum, Andrea Bates, Chaim M. Roifman10.1016/j.jaci.2008.08.031The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Letters to the Editor12191220http://www.jacionline.org/article/PIIS0091674908018769/abstract?rss=yesTo the Editor: Chronic mucocutaneous candidiasis (CMCC) is a heterogeneous group of disorders with a common manifestation of persistent or recurrent candidial and fungal infections of the skin, nails, and mucous membranes. The best delineated entity, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), is caused by mutations in the autoimmune regulator (AIRE) gene. However, AIRE mutations are found in only about a third of cases with CMCC in our institution. In a search for genetic predisposition to CMCC in patients without APECED, we studied the protein tyrosine phosphatase nonreceptor 22 (PTPN22), 1858T, a variant of the lymphoid protein tyrosine phosphatase (LYP) R620W.Association of the lymphoid protein tyrosine phosphatase, R620W variant, with chronic mucocutaneous candidiasisAmit Nahum, Andrea Bates, Nigel Sharfe, Chaim M. Roifman10.1016/j.jaci.2008.10.027The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Letters to the Editor12201222http://www.jacionline.org/article/PIIS0091674908013535/abstract?rss=yesTo the Editor: We have recently identified and characterized a novel mast cell (MC) activation pathway initiated by contact with activated T cells. It has been reported that this pattern of activation is associated with phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase and p38. We showed that the cytokines IL-8 and oncostatin M are released from MCs after contact with activated T cells and that this process is subject to MAPK inhibition. The best characterized upstream regulator of the MAPK system is the small guanosine triphosphate (GTP)–binding protein Ras. This protein has critical functions in many cell types; however, in MCs its functions are not entirely understood. Therefore, and on the basis of our previous findings, we decided to study the spatiotemporal pattern of Ras activation in MCs stimulated by activated T cells.Stimulation of human mast cells by activated T cells leads to N-Ras activation through Ras guanine nucleotide releasing protein 1Irit Shefler, Yoseph A. Mekori, Adam Mor10.1016/j.jaci.2008.07.024The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Letters to the Editor12221225http://www.jacionline.org/article/PIIS0091674908013547/abstract?rss=yesTo the Editor: Asthma is the most common chronic disease in children across all developed countries. Although the cause of the disease remains unknown, it is recognized as a complex genetic disorder with an environmental component. As with many other complex diseases, a long list of genes has been associated with asthma through linkage and candidate gene association studies, the majority of which do not replicate. The first genome-wide association study of asthma predisposition was recently published. In that study 317,000 single nucleotide polymorphisms (SNPs) were typed in 994 patients with childhood-onset asthma, resulting in the identification of a novel locus on chromosome 17q12-q21 containing multiple genes and associated markers. Expression analysis in lymphoblastoid cell lines revealed that ORMDL3 expression was strongly correlated with the asthma-associated variants, leading the authors to conclude that it was the most likely candidate gene at this locus.ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestryPatrick M.A. Sleiman, Kiran Annaiah, Marcin Imielinski, Jonathan P. Bradfield, Cecilia E. Kim, Edward C. Frackelton, Joseph T. Glessner, Andrew W. Eckert, F. George Otieno, Erin Santa, Kelly Thomas, Ryan M. Smith, Wendy Glaberson, Maria Garris, Sigfus Gunnlaugsson, Rosetta M. Chiavacci, Julian Allen, Jonathan Spergel, Robert Grundmeier, Michael M. Grunstein, Mark Magnusson, Hans Bisgaard, Struan F.A. Grant, Hakon Hakonarson10.1016/j.jaci.2008.06.041The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Letters to the Editor12251227http://www.jacionline.org/article/PIIS009167490801364X/abstract?rss=yesTo the Editor: Several studies have focused on the effect of acute mental stress with regard to the functional activity of immune cells, including T cells, natural killer cells, and eosinophils, suggesting psychoneuroendocrine mechanisms. The effect of acute mental stress on the functional activity of human basophils, however, thus far is not clear.The functional activity of basophil granulocytes is modulated by acute mental stress and sympathetic activation in vivo and in vitroUlrike Raap, Gerhard Schmid-Ott, Manuela Bruder, Katja Wichmann, Alexander Kapp, Thomas Werfel10.1016/j.jaci.2008.07.031The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Letters to the Editor12271229http://www.jacionline.org/article/PIIS0091674908013699/abstract?rss=yesTo the Editor: Tomatoes (Lycopersicum esculentum, botanical family of Solanaceae) are a well-documented source of IgE-mediated food allergy, but only 1 report has suggested the possibility of an occupational respiratory allergy to tomato allergens. Herein we report the clinical and immunologic findings in a tomato greenhouse worker who had occupational asthma and rhinitis.Tomato-induced occupational asthma in a greenhouse workerOlivier Vandenplas, Carine Sohy, Vinciane D'Alpaos, Carine Nootens, Joël Thimpont, Daniela Weigand, Stephan Scheurer10.1016/j.jaci.2008.07.035The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Letters to the Editor12291231http://www.jacionline.org/article/PIIS0091674908016667/abstract?rss=yesTo the Editor: Streptococcus pneumoniae is a major cause of pneumonia, septicemia, and meningitis. It causes great morbidity and mortality throughout the world. In particular, young children, the elderly, and immunocompromised individuals are susceptible to pneumococcal infections. Host protection against pneumococcal infections is mediated by antibodies against pneumococcal surface proteins and capsular polysaccharides (caps-PSs). Caps-PSs are a main determinant of virulence of S pneumoniae, and antibodies to caps-PSs are protective against infection with S pneumoniae. Some pneumococcal surface proteins, such as pneumococcal surface protein A (PspA), are also considered virulence factors.The human polysaccharide- and protein-specific immune response to Streptococcus pneumoniae is dependent on CD4+ T lymphocytes, CD14+ monocytes, and the CD40–CD40 ligand interactionLeen Moens, Greet Wuyts, Louis Boon, Marcel T. den Hartog, Jan L. Ceuppens, Xavier Bossuyt10.1016/j.jaci.2008.09.006The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Letters to the Editor12311233http://www.jacionline.org/article/PIIS009167490801676X/abstract?rss=yesTo the Editor: Measles-mumps-rubella (MMR) vaccination is a very safe and effective health intervention. However, hypersensitivity reactions to this vaccine have been reported by various authors. In the past, allergic reactions were attributed to egg proteins. Because the majority of severe reactions were observed in egg-tolerant individuals, sensitization to other components was evaluated, and gelatin allergy was demonstrated.Dextran-specific IgG response in hypersensitivity reactions to measles-mumps-rubella vaccineGiovanna Zanoni, Antonio Puccetti, Marzia Dolcino, Rita Simone, Andrea Peretti, Antonio Ferro, Giuseppe Tridente10.1016/j.jaci.2008.09.015The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Letters to the Editor12331235http://www.jacionline.org/article/PIIS0091674908013663/abstract?rss=yesTo the Editor: In a recent very interesting review, Dr Fantuzzi discussed the functions of adiponectin and put forward several important questions about the role of the protein. In this correspondence I will propose an explanation of why high adiponectin levels can be seen in conjunction with insulin resistance and inflammation.Adiponectin: A defense protein in catabolismCarl Johan Behre10.1016/j.jaci.2008.07.032The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Correspondence12361236http://www.jacionline.org/article/PIIS0091674908018502/abstract?rss=yesTo the Editor: The recently published updated practice parameters for allergic rhinitis titled “The diagnosis and management of rhinitis: an updated practice parameter” contained incorrect information within Table VIII. Specifically, the table inaccurately states that the age limit for OMNARIS (ciclesonide) is 12 years. Per the US Food and Drug Administration–approved package insert for OMNARIS, the product is indicated for the treatment of nasal symptoms associated with seasonal allergic rhinitis in adults and children 6 years and older and 12 years and older for perennial allergic rhinitis. The approved dose is 2 sprays per nostril once daily (200 μg daily dose).Allergic rhinitis practice parameter update: Correction to information regarding OMNARIS (ciclesonide) nasal sprayJohn G. Karafilidis, William T. Andrews10.1016/j.jaci.2008.10.010The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Correspondence12361236http://www.jacionline.org/article/PIIS0091674908018575/abstract?rss=yesWith regard to the August 2008 supplement entitled “The Diagnosis and Management of Rhinitis: An Updated Practice Parameter” (J Allergy Clin Immunol 2008;122(suppl):S1-S84), the Joint Task Force on Practice Parameters has modified and further refined the “Sample Rhinitis Medication Action Plan” (Fig 5), shown below.Correction10.1016/j.jaci.2008.10.005The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Correction12371237http://www.jacionline.org/article/PIIS0091674908015613/abstract?rss=yesThe cold ethanol precipitation method developed by Cohn in the 1940s yields almost pure IgG suitable for intramuscular immunoglobulin or subcutaneous immunoglobulin (SCIG) administration with little modification other than inactivating or removing pathogens. These preparations are concentrated (16% wt/vol) and contain 5% to 10% of the IgG as large aggregates causing potentially fatal systemic anaphylactoid reactions if administered intravenously. Intravenous immunoglobulin (IVIG) products contain 1% or less of the total IgG in small aggregates and have a final concentration of 3% to 12%. IVIG products differ in their excipients (preservatives and inhibitors of IgG aggregation) and physical/chemical characteristics (eg, lyophilized powder or liquid and pH). Each product has a slightly different adverse reaction profile, although there are very few published comparisons of one product with another.Intravenous immunoglobulin: Adverse reactions and managementFrancisco A. Bonilla10.1016/j.jaci.2008.08.033The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Clinical pearls12381239http://www.jacionline.org/article/PIIS0091674908021015/abstract?rss=yesEditor in Chief DONALD Y. M. LEUNG, MD, PhD Denver, Colo Deputy Editor STANLEY J. SZEFLER, MD Denver, ColoIndex Editorial Board10.1016/S0091-6749(08)02101-5The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-212401240http://www.jacionline.org/article/PIIS0091674908021027/abstract?rss=yesIndex Copyright10.1016/S0091-6749(08)02102-7The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-212411241http://www.jacionline.org/article/PIIS0091674908021064/abstract?rss=yesAbdulkerim H (see Pistiner et al). 2008;122:274-9 Abe J, Ebata R, Jibiki T, Yasukawa K, Saito H, Terai M. Elevated granulocyte colony-stimulating factor levels predict treatment failure in patients with Kawasaki disease. 2008;122:1008-13Author index∗10.1016/S0091-6749(08)02106-4The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-212421264http://www.jacionline.org/article/PIIS0091674908021076/abstract?rss=yesAcetaminophen Blame acetaminophen (Rothenberg and Nelson). 2008;122:844 (News beyond our pages)Subject index∗10.1016/S0091-6749(08)02107-6The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-212651294http://www.jacionline.org/article/PIIS0091674908020678/abstract?rss=yes The genetic heterogeneity of mendelian susceptibility to mycobacterial diseasesA Brief Overview of This Month's JACI10.1016/S0091-6749(08)02067-8The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2FrontmatterA3A4http://www.jacionline.org/article/PIIS009167490802068X/abstract?rss=yesNews beyond our pages1041 Marc E. Rothenberg, MD, PhD, and Harold S. Nelson, MD, EditorsTable of contents10.1016/S0091-6749(08)02068-XThe Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2FrontmatterA6A6http://www.jacionline.org/article/PIIS0091674908020691/abstract?rss=yes This month's theme: New insights, discoveries, and controversies in primary immunodeficiencyThis month's theme10.1016/S0091-6749(08)02069-1The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2FrontmatterA6A6http://www.jacionline.org/article/PIIS0091674908020708/abstract?rss=yes The cover picture of this thematic issue of the Journal devoted to primary immunodeficiency tells the story of human triumph over a serious medical condition, accomplishment of dreams despite hardships, and enjoyment of an excellent quality of life. Jennifer Pate, MD, found out that she had common variable immunodeficiency (CVID) at 11 years of age when her parents brought her to the Allergy and Immunology Clinic at Texas Children's Hospital because of recurrent serious infections. Replacement therapy with monthly intravenous immunoglobulin and careful follow-up at the clinic gave her the boost to lead an active adolescent and young adult life and to go on to be a responsible member of society as a board-certified psychiatrist. Dr Pate is an example of the treatment that clinical immunologists hope to provide for their patients with immunodeficiency.About the cover10.1016/S0091-6749(08)02070-8The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2FrontmatterA6A6http://www.jacionline.org/article/PIIS009167490802071X/abstract?rss=yes The Journal of Allergy and Clinical Immunology posts in-press articles online in advance of their appearance in the print edition of the Journal. They are available at the JACI Web site at www.jacionline.org at the “Articles in Press” link, as well as at Elsevier's ScienceDirect Web site, www.sciencedirect.com. Each print article will acknowledge the e-publication date (the date when the article first appeared online). As soon as an article is published online, it is fully citable through use of its Digital Object Identifier (DOI). Please visit the JACI Web site and view our hot-off-the-wire articles through the “Articles in Press” link.In-press articles10.1016/S0091-6749(08)02071-XThe Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2FrontmatterA8A8http://www.jacionline.org/article/PIIS0091674908020721/abstract?rss=yes Editors' Choice (p 1104)Symbols used in the Table of Contents10.1016/S0091-6749(08)02072-1The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2FrontmatterA8A8http://www.jacionline.org/article/PIIS0091674908020733/abstract?rss=yesEditor in Chief DONALD Y. M. LEUNG, MD, PhD Denver, Colo Deputy Editor STANLEY J. SZEFLER, MD Denver, ColoEditorial Board10.1016/S0091-6749(08)02073-3The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2FrontmatterA22A22http://www.jacionline.org/article/PIIS0091674908020769/abstract?rss=yesCommunications regarding original articles and editorial management should be addressed to Donald Y. M. Leung, MD, PhD, Editor in Chief, The Journal of Allergy and Clinical Immunology, National Jewish Medical and Research Center, 1400 Jackson St (J324), Denver, CO 80206; phone 303-398-1963; fax 303-270-2269.Information for Readers10.1016/S0091-6749(08)02076-9The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Reader servicesA24A24http://www.jacionline.org/article/PIIS0091674908020770/abstract?rss=yesDear colleagues: The U.S. House of Representatives has 20 standing committees. The American Thoracic Society (ATS) has about 30. The AAAAI has 104 committees.Newsview-AAAAI10.1016/S0091-6749(08)02077-0The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Reader servicesA27A29http://www.jacionline.org/article/PIIS0091674908020794/abstract?rss=yesOnline AAAAI/ACAAI Certification/Maintenance of Certification Board Review Course All the content of the live course offered in April 2008 is now available for purchase online. Visit www.aaaai.org/members.stm and select “Online Board Review Course.” Funded through an educational grant from Teva Specialty Pharmaceuticals.CME Activities Calendar10.1016/S0091-6749(08)02079-4The Journal of Allergy and Clinical Immunology 122, 6 (2008)2008-12-01The Journal of Allergy and Clinical Immunology2008-12-011226S0091-6749(08)X0013-2Reader servicesA31A32