Atopic dermatitis and IgE-mediated food allergy: Common biologic targets for therapy and prevention.

OBJECTIVE: To highlight common mechanistic targets for the treatment of atopic dermatitis (AD) and IgE-mediated food allergy (IgE-FA) with potential to be effective for both diseases and prevent atopic progression. DATA SOURCES: Data sources were PubMed searches or National Clinical Trials (NCT)-registered clinical trials related to AD, IgE-FA, and other atopic conditions, especially focused on the pediatric population. STUDY SELECTIONS: Human seminal studies and/or articles published in the past decade were emphasized with reference to preclinical models when relevant. NCT-registered clinical trials were filtered by inclusion of pediatric subjects younger than 18 years with special focus on children younger than 12 years as a critical period when AD and IgE-FA diseases may often be concurrent. RESULTS: AD and IgE-FA share several pathophysiologic features, including epithelial barrier dysfunction, innate and adaptive immune abnormalities, and microbial dysbiosis, which may be critical for the clinical progression between these diseases. Revolutionary advances in targeted biologic therapies have shown the benefit of inhibiting type 2 immune responses, using dupilumab (anti-interleukin-4Rα) or omalizumab (anti-IgE), to potentially reduce symptom burden for both diseases in pediatric populations. Although the potential for biologics to promote disease remission (AD) or sustained unresponsiveness (IgE-FA) remains unclear, the refinement of biomarkers to predict infants at risk for atopic disorders provides promise for prevention through timely intervention. CONCLUSION: AD and IgE-FA exhibit common features that may be leveraged to develop biologic therapeutic strategies to treat both conditions and even prevent atopic progression. Future studies should be designed with consistent age stratification in the pediatric population and standardized regimens of adjuvant oral immunotherapy or dose escalation (IgE-FA) to improve cross-study interpretation.

Prevention of IgE-Mediated Food Allergy: Emerging Strategies Through Maternal and Neonatal Interventions.

Whereas the early introduction of highly allergenic foods has been shown to be effective at preventing the onset of food allergy (FA) in high-risk infants, sensitization to food antigens can occur prior to complementary food introduction, and thus, additional earlier FA prevention strategies are urgently needed. Currently, aside from early introduction of peanut and egg, no therapies are strongly recommended by international professional allergy societies for the primary prevention of FA. This review focuses on maternal- and neonatal-directed interventions that are being actively investigated and developed, including maternal dietary factors and supplementation, specific elimination diets, breastfeeding, cow's milk formula supplementation, microbiome manipulations, bacterial lysate therapy, and skin barrier therapies. Evaluating how these factors and various prenatal/early life environmental exposures may impact the development of FA is crucial for accurately counseling caregivers in the prevention of FA.

Impact of a Documented Penicillin Allergy on Antibiotic Selection in Pediatric Patients With Osteomyelitis.

Penicillin allergy labels are common in hospitalized patients, and there is a frequent misconception that these patients cannot receive cephalosporins. Through retrospective review, we found that patients with reported penicillin allergies were significantly less likely to receive first-line therapy for acute hematogenous osteomyelitis.

IL-17-Dependent Dysregulated Cutaneous Immune Homeostasis in the Absence of the Wiskott-Aldrich Syndrome Protein.

Wiskott-Aldrich Syndrome (WAS) is characterized by recurrent infections, thrombocytopenia, and eczema. Here, we show that WASp-deficient mice on a BALB/c background have dysregulated cutaneous immune homeostasis with increased leukocyte accumulation in the skin, 1 week after birth. Increased cutaneous inflammation was associated with epithelial abnormalities, namely, altered keratinization, abnormal epidermal tight junctional morphology and increased trans-epidermal water loss; consistent with epidermal barrier dysfunction. Immune and physical barrier disruption was accompanied by progressive skin dysbiosis, highlighting the functional significance of the disrupted cutaneous homeostasis. Interestingly, the dysregulated immunity in the skin preceded the systemic elevation in IgE and lymphocytic infiltration of the colonic lamina propria associated with WASp deficiency. Mechanistically, the enhanced immune cell accumulation in the skin was lymphocyte dependent. Elevated levels of both Type 2 (IL-4, IL-5) and Type 17 (IL-17, IL-22, IL-23) cytokines were present in the skin, as well as the 'itch' factor IL-31. Unexpectedly, the canonical WAS-associated cytokine IL-4 did not play a role in the immune dysfunction. Instead, IL-17 was critical for skin immune infiltration and elevation of both Type 2 and Type 17 cytokines. Our findings reveal a previously unrecognized IL-17-dependent breakdown in immune homeostasis and cutaneous barrier integrity in the absence of WASp, targeting of which may provide new therapeutic possibilities for the treatment of skin pathologies in WAS patients.

A membrane-translocating peptide penetrates into bilayers without significant bilayer perturbations.

Using a high throughput screen, we have identified a family of 12-residue long peptides that spontaneously translocate across membranes. These peptides function by a poorly understood mechanism that is very different from that of the well-known, highly cationic cell penetrating peptides such as the tat peptide from HIV. The newly discovered translocating peptides can carry polar cargoes across synthetic bilayers and across cellular membranes quickly and spontaneously without disrupting the membrane. Here we report on the biophysical characterization of a representative translocating peptide from the selected family, TP2, as well as a negative control peptide, ONEG, from the same library. We measured the binding of the two peptides to lipid bilayers, their secondary structure propensities, their dispositions in bilayers by neutron diffraction, and the response of the bilayer to the peptides. Compared to the negative control, TP2 has a greater propensity for membrane partitioning, although it still binds only weakly, and a higher propensity for secondary structure. Perhaps most revealing, TP2 has the ability to penetrate deep into the bilayer without causing significant bilayer perturbations, a property that may help explain its ability to translocate without bilayer permeabilization.

The electrical response of bilayers to the bee venom toxin melittin: evidence for transient bilayer permeabilization.

Melittin is a 26-residue bee venom peptide that folds into amphipathic α-helix and causes membrane permeabilization via a mechanism that is still disputed. While an equilibrium transmembrane pore model has been a central part of the mechanistic dialogue for decades, there is growing evidence that a transmembrane pore is not required for melittin's activity. In part, the controversy is due to limited experimental tools to probe the bilayer's response to melittin. Electrochemical impedance spectroscopy (EIS) is a technique that can reveal details of molecular mechanism of peptide activity, as it yields direct, real-time measurements of membrane resistance and capacitance of supported bilayers. In this work, EIS was used in conjunction with vesicle leakage studies to characterize the response of bilayers of different lipid compositions to melittin. Experiments were carried out at low peptide to lipid ratios between 1:5000 and 1:100. The results directly demonstrate that the response of the bilayer to melittin at these concentrations cannot be explained by an equilibrium transmembrane pore model.

The effectiveness of neuromuscular warm-up strategies, that require no additional equipment, for preventing lower limb injuries during sports participation: a systematic review.

BACKGROUND: Lower limb injuries in sport are increasingly prevalent and responsible for large economic as well as personal burdens. In this review we seek to determine which easily implemented functional neuromuscular warm-up strategies are effective in preventing lower limb injuries during sports participation and in which sporting groups they are effective. METHODS: Seven electronic databases were searched from inception to January 2012 for studies investigating neuromuscular warm-up strategies and injury prevention. The quality of each included study was evaluated using a modified version of the van Tulder scale. Data were extracted from each study and used to calculate the risk of injury following application of each evaluated strategy. RESULTS: Nine studies were identified including six randomized controlled trials (RCT) and three controlled clinical trials (CCT). Heterogeneity in study design and warm-up strategies prevented pooling of results. Two studies investigated male and female participants, while the remaining seven investigated women only. Risk Ratio (RR) statistics indicated 'The 11+' prevention strategy significantly reduces overall (RR 0.67, confidence interval (CI) 0.54 to 0.84) and overuse (RR 0.45, CI 0.28 to 0.71) lower limb injuries as well as knee (RR 0.48, CI 0.32 to 0.72) injuries among young amateur female footballers. The 'Knee Injury Prevention Program' (KIPP) significantly reduced the risk of noncontact lower limb (RR 0.5, CI 0.33 to 0.76) and overuse (RR 0.44, CI 0.22 to 0.86) injuries in young amateur female football and basketball players. The 'Prevent Injury and Enhance Performance' (PEP) strategy reduces the incidence of anterior cruciate ligament (ACL) injuries (RR 0.18, CI 0.08 to 0.42). The 'HarmoKnee' programme reduces the risk of knee injuries (RR 0.22, CI 0.06 to 0.76) in teenage female footballers. The 'Anterior Knee Pain Prevention Training Programme' (AKP PTP) significantly reduces the incidence of anterior knee pain (RR 0.27, CI 0.14 to 0.54) in military recruits. CONCLUSIONS: Effective implementation of practical neuromuscular warm-up strategies can reduce lower extremity injury incidence in young, amateur, female athletes and male and female military recruits. This is typically a warm-up strategy that includes stretching, strengthening, balance exercises, sports-specific agility drills and landing techniques applied consistently for longer than three consecutive months. In order to optimize these strategies, the mechanisms for their effectiveness require further evaluation.