Food allergies are immune-mediated, complex disorders, which are the source of increasing health concern worldwide. The goal of this review is to present an updated summary of the food allergy (FA) burden among children and adults across different populations, focusing on research from the past 5Β years. FAs impact a growing number of global residents-particularly those residing in higher-income, industrialized regions. Moreover, growing epidemiologic evidence suggests that the population health burden of non-IgE-mediated FAs, such as food protein-induced enterocolitis syndrome, may also be higher than previously reported. FA is a complex trait that impacts infants, children, as well as adults across the globe. The population health burden of both IgE- and non-IgE-mediated FAs is likely to grow in the absence of rapid advances and widespread implementation of effective FA prevention and treatment interventions. Systematic epidemiological research initiatives are needed, both nationally and globally, to better understand and reduce the burden of these allergic diseases.
Allergy and its manifestations were first appreciated in the 1870β s. Today, the mechanism by which specific substances elicit allergic reactions remains poorly understood. This is problematic from a healthcare perspective because the prevalence of allergic disease and its societal costs are substantial. Regarding mechanistic understanding of allergy, a new proposal, The Acari Hypothesis, has been forwarded. The Hypothesis, borne from consideration of alpha-gal syndrome, postulates that acarians, i.e., mites and ticks, are operative agents of allergy. By way of their pathogenic payloads and salivary pattern recognition receptor(s), acarians potentiate in human hosts the generation of IgE against acarian dietary elements. Those elements account for most, if not all, known human allergens. Inasmuch as acarian-human interactions occur on human epithelial surfaces, it is to be expected factors that influence the presence and/or operation of acarians on those surfaces influence the expression of allergic diseases. In this report, it is proposed that two adaptations of catarrhine primates, i.e., Old World monkeys, apes and humans, evolved to deter acarian species: firstly, the expansion of eccrine glands across the entirety of body surface area, and, secondly, the secretion of sweat by those glands. Contemporary hygienic practices that reduce and/or disrupt the operation of eccrine glands are likely responsible for the increase in allergic disease seen today.
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology β’
The prevalence and awareness of food allergy (FA) among US adults is arguably at a historical high, both with respect to primary immunoglobulin E-mediated food hypersensitivity and other food-triggered conditions that operate through a variety of immunologic mechanisms (eg, pollen-FA syndrome, alpha-gal syndrome, food protein-induced enterocolitis syndrome, eosinophilic esophagitis). Worryingly, not only are many adults retaining childhood-onset food allergies as they age into adulthood, it seems that many adults are experiencing adult-onset allergies to previously tolerated foods, with correspondingly adverse physical, and psychological health impacts. Consequently, this review aims to summarize what is currently known about the epidemiology and population-level burden of FA among adult populations in North America and around the globe. This article also provides insights into the natural history of these conditions and what we need to know as we look to the future to support effective care and prevent FA.
Hypersensitivity to galactose-Ξ±-1,3-galactose (Ξ±-gal) is an informative example of a pathologic IgE-mediated process. By way of their saliva, ticks are able to sensitize humans to tick dietary elements that express Ξ±-gal. Mites, which along with ticks constitute the phyletic subclass Acari, feed on proteinaceous foodstuffs that represent most, if not all, human allergens. Given: (1) the gross nature of the pathophysiological reactions of allergy, especially anaphylaxis, (2) the allergenicity of acarian foodstuffs, and (3) the relatedness of ticks and mites, it has been hypothesized that human-acarian interactions are cardinal to the pathogenesis of allergy. In this report, a means by which such interactions contribute to that pathogenesis is proposed.
Anaphylaxis is a poorly understood immune process in which a Th2-/IgE-mediated adaptive response commandeers cellular machinery, typically reserved for defense against multicellular ectoparasites, to activate against otherwise benign molecules. Its clinical manifestations consist of rapid pathophysiological reflexes that target epithelial surfaces. The galactose-Ξ±-1,3-galactose hypersensitivity response is a compelling model of anaphylaxis for which causation has been demonstrated. At the core of the model, a tick bite sensitizes a recipient to a tick foodstuff. As proposed herein, the model likely informs on the origin of all allergic inflammation; namely, allergy is not intended to protect against seemingly harmless and irrelevant materials, but is, instead, intended to rid epithelial surfaces of pathogen-bearing Acari, i.e., mites and ticks. The demonstrated adjuvant activity of acarian gastrointestinal secretions, when paired with the polyphagous diet of mites, renders acarians eminently suited to accounting, mechanistically, for many, if not all, human allergies.
Hussain M, Daignault S, Agarwal N, Grivas PD, Siefker-Radtke AO, et al.
Cancer β’
Epidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated. Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m(2) ) on day 1 plus gemcitabine (1000 mg/m(2) ) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m(2) ) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to-event endpoints. Eighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CIβ=β37%-76%) and 61.4% for arm B (95% CIβ=β48%-74%). The median progression-free survival times were 8.5 months for arm A (95% CIβ=β5.7-10.4 months) and 7.6 months for arm B (95% CIβ=β6.1-8.7 months). The median overall survival times were 17.4 months for arm A (95% CIβ=β12.8 months to unreached) and 14.3 months for arm B (95% CIβ=β11.6-22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death. GC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes.
The journal of allergy and clinical immunology. In practice β’
Idiopathic anaphylaxis is a perplexing problem that accounts for approximately 30% to 60% of cases of anaphylaxis in ambulatory adults and perhaps 10% of cases in children. Advances in our knowledge of idiopathic anaphylaxis have occurred over the past decade with the elucidation of mast cell activating disorders and the discovery of episodes of anaphylaxis caused by galactose-alpha-1,3-galactose. Most patients do well because fatalities can usually be prevented with proper therapy, and many individuals, for reasons not understood, undergo spontaneous remission.
The Journal of clinical endocrinology and metabolism β’
Pituitary adenomas cause clinical manifestations because of mass effects and excess hormone production. This group of tumors represents a tractable target for gene therapy because they are rarely metastatic and because reductions in tumor size and function, in addition to those achieved after surgery, may be of clinical benefit. In this report we describe a strategy for targeting the expression of toxic genes to pituitary cells using adenoviral vectors. Pituitary hormone promoters (human GH or glycoprotein hormone alpha-subunit) were used to express either a marker gene [beta-galactosidase (beta-gal)] or a toxic gene [herpes simplex virus thymidine kinase (TK)]. In GH-producing GH3 cells and in alpha-subunit-producing pituitary tumor cell lines, recombinant adenoviruses containing either the alpha-subunit promoter (Ad alpha Gal; AdaTK) or the GH promoter (AdGHGal; AdGHTK) were expressed at-high levels. Using histological studies and assays for beta-gal activity, expression was shown to persist for at least 21 days, and it was relatively selective for pituitary cell lines. Cytotoxicity studies were performed using the TK-containing vectors and treatment with ganciclovir. Both AdGHTK and AdaTK caused greater than 95% cytotoxicity of GH3 and alphaT3 cells, respectively, at a viral dose (multiplicity of infection, 5 plaque-forming units/cell) that induced minimal toxicity using control viruses. Little cellular toxicity was seen using a nonpituitary cell line (T47D breast tumor cells). The AdGHTK virus also caused marked reduction in the size of GH3 cell tumors that were propagated in nude mice. These studies suggest that adenoviral vectors carrying human pituitary gland specific promoters may be useful for developing gene therapy strategies for the treatment of pituitary adenomas.
