Wheezing and asthma often begin in early childhood, but it is difficult to predict whether or not a wheezy infant will develop asthma. There is an ongoing debate about whether treatment with inhaled corticosteroids (ICSs) at the first signs of wheezing in very young children will prevent the development of asthma and worsening of pulmonary function later in childhood. This randomized, double-blind, controlled comparison of continuous treatment with inhaled fluticasone propionate 100 μg versus placebo twice daily was started in 173 young children who had previously manifested at least 2 documented episodes of wheezing (or 1 severe wheezing episode). These children were then followed until age 5 years with reduction of the dosage of the inhaled medication if warranted by the clinical situation. It was found that at age 5 years the children in the 2 treatment groups did not differ significantly in the proportion of children with current wheeze, physician-diagnosed asthma, or use of asthma medication. The lung function and airway reactivity were also not significantly different in the 2 treatment groups. There was also no difference between the 2 groups in the frequency of children in whom open-label ICS treatment was used because of increasing asthma symptoms. The authors concluded that early, continuous use of inhaled fluticasone propionate for wheezing in preschool children had no effect on the occurrence of asthma or wheeze later in childhood and did not prevent lung function decline or reduce airway reactivity. These findings are in concert with that of another recent study that showed no residual beneficial effect of ICS treatment of preschool children at increased risk for asthma (N Engl J Med 2006;354:1985-97). (Murray et al. Lancet 2006;368:754-62.) In some patients, severe pemphigus vulgaris (PV) is not controlled with the usual treatment, which includes corticosteroids, immunosuppressive agents, and intravenous immunoglobulin (IVIg). This study assessed the effects of adding treatment with rituximab (Ritux), an anti-CD20 monoclonal antibody, in severe PV. Ritux, 375 mg/kg, was given intravenously in 2 cycles, initially along with IVIg, in 11 patients with severe PV not previously controlled with the usual therapy. The patients then received Ritux and IVIg injections monthly. There was a prompt remission of PV lesions in 9 of the 11 patients treated with Ritux, lasting 22 to 37 months. Levels of IgG4 anti-keratinocyte antibodies also decreased considerably with Ritux treatment, with levels of such antibodies subsequently correlated with PV clinical disease activity. Circulating B-cell levels also decreased markedly. The findings in this uncontrolled investigation look quite promising in a severe, potentially fatal disease, warranting a future expanded, controlled study. Our knowledge of the pathogenesis of PV may also be enhanced by these findings. (Ahmed et al. N Eng J Med 2006;355:1772-9.) Although immunization with the inactivated influenza (Flu) vaccine has been recommended for all children aged 6 to 23 months in the United States, there have not been large-scale studies of the safety of such immunization in this age group. The current study was a retrospective cohort comparison of the frequency of diagnoses listed in medically attended events in a managed care setting during a 14-day period following Flu immunization in 45,356 children, aged 6 to 23 months, during the period 1991-2003. These findings were compared with the frequency of diagnoses in medically attended events during control periods 15 to 28 days before and 15 to 28 days after the Flu vaccine injections in the same children. The investigators found that only a diagnosis of gastritis/duodenitis was listed significantly more often in the 14 days after immunization (odds ratio, 5.50). However, the increased frequency of gastritis/duodenitis in days 1 to 14 was found to be less impressive and not significant after chart review. Thirteen diagnoses, including respiratory infection, asthma, and otitis media, were made less frequently during the postimmunization period than during the control periods in the same children. The authors concluded that there were very few medically attended events, none of which was serious, significantly associated with receipt of the inactivated Flu vaccine by these young children. These findings should also reassure parents that such Flu immunization does not trigger or aggravate asthma in young children. (Hambidge et al. JAMA 2006;296:1990-7.) Overproduction of mucus is a central feature of asthma and is thought to involve IL-13, epidermal growth factor receptor (EGFR), and transcription factor FOXA2. To elucidate how these pathways work together, the investigators established a primary normal human bronchial epithelial (NHBE) cell culture system with IL-13–induced mucus production and gene transcript expression changes similar to those seen in IL-13–treated mice. IL-13 did not stimulate release of the EGFR ligand TGF-α, but inhibition of constitutive release of TGF-α from NHBE cells reduced both constitutive and IL-13–induced mucin production. Microarray analysis revealed that IL-13 and the EGFR pathways had almost completely independent effects on transcript expression. EGFR activity had extensive effects, including altered expression of many transcripts associated with cell metabolism, survival, transcription, and differentiation. One of the few common effects of IL-13 and EGFR signaling was decreased expression of FOXA2, which is known to prevent mucus production. As such, these data show that IL-13 and EGFR pathways make critical but quite distinct contributions to gene regulation in airway epithelial cells, yet they both inhibit the production of FOXA2, a known negative regulator of mucus production. (Zhen et al. Am J Respir Cell Mol Biol. 2006. In press [doi:10.1165/rcmb.2006-0180OC].) Specific downregulation of deleterious genes is highly desirable in numerous diseases and has attracted considerable attention with the application of RNA interference (RNAi) in preclinical studies. RNAi is a natural mechanism of post-transcriptional gene silencing by means of sequence-specific mRNA degradation, triggered by small double-stranded RNAs. Because this mechanism can be efficiently induced in vivo by expressing target-complementary short hairpin RNA (shRNA) from nonviral and viral vectors, RNAi is attractive for human therapeutics. In this paper, the long-term effects of sustained high-level shRNA expression in livers of adult mice was examined. High levels of shRNA expression in hepatocytes after intravenous infusion was achieved with an optimized shRNA delivery vector based on adeno-associated virus type 8 (AAV8). Notably, the majority of vectors resulted in dose-dependent liver injury and ultimately caused death. Morbidity was associated with the downregulation of liver-derived microRNAs, indicating possible competition of the latter with shRNAs for limiting cellular factors required for the processing of various small RNAs. These findings indicate that RNAi strategies for human disease will have to proceed with significant caution, especially focused on optimizing shRNA dose and sequence. (Grimm et al. Nature 2006;441:537-41.) Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract that is caused in part by a dysregulated immune response to intestinal flora. The cytokine IL-12, which is critical for activation of natural killer (NK) cells and T cells to produce IFN-γ, has been shown to be important in disease pathogenesis, as demonstrated by the ability of anti–IL-12p40 to improve IBD in murine models and in patients. However, it has recently been appreciated that the cytokine IL-23 also shares the IL-12p40 subunit and thus that prior conclusions about the specific role of IL-23 have to be interpreted with caution. Now, 2 separate publications draw considerable attention to IL-23 in IBD. In the first paper, investigators examined the role of IL-23 in murine models of IBD. In particular, 2 models of Helicobacter hepaticus–triggered T cell–dependent colitis—one involving anti–IL-10 receptor monoclonal antibody treatment of infected T-cell–sufficient hosts and the other involving CD4+ T cell transfer into infected recombinase gene-deficient recipients—were examined. The data demonstrate that IL-23 and not IL-12 was essential for the development of maximal intestinal disease. Furthermore, IBD was shown to be dependent on the synergistic triggering of intestinal inflammation by IL-23–induced IL-17 and IFN-γ. In the second paper, the genetic factors that contribute to IBD were analyzed using a genome-wide association study. Interestingly, a highly significant association between Crohn's disease and the IL-23 receptor gene on chromosome 1p31 was identified. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) was shown to confer strong protection against Crohn's disease, and additional noncoding IL-23 receptor variants were independently associated with disease. Replication studies confirmed IL-23 receptor associations in independent cohorts of patients with Crohn disease or ulcerative colitis. Taken together, these results prioritize the IL-23 signaling pathway as a therapeutic target in IBD. (Kullberg et al. J Exp Med 2006;2485-94. Duerr et al. Science 2006 Oct 26 [epub ahead of print].)