Epicutaneous sensitization in the development of food allergy: What is the evidence and how can this be prevented?

There is increasing evidence regarding the importance of allergic sensitization through the skin. In this review, we provide an overview of the atopic march and immune mechanism underlying the sensitization and effector phase of food allergy. We present experimental models and human data that support the concept of epicutaneous sensitization and how this forms one half of the dual-allergen exposure hypothesis. We discuss specific important elements in the skin (FLG and other skin barrier gene mutations, Langerhans cells, type 2 innate lymphoid cells, IL-33, TSLP) that have important roles in the development of allergic responses as well as the body of evidence on environmental allergen exposure and how this can sensitize an individual. Given the link between skin barrier impairment, atopic dermatitis, food allergy, allergic asthma, and allergic rhinitis, it is logical that restoring the skin barrier and prevention or treating atopic dermatitis would have beneficial effects on prevention of related allergic diseases, particularly food allergy. We present the experimental and human studies that have evaluated this approach and discuss various factors which may influence the success of these approaches, such as the type of emollient chosen for the intervention, the role of managing skin inflammation, and differences between primary and secondary prevention of atopic dermatitis to achieve the desired outcome.     

The great mimicker: Phenotypic overlap between constitutional mismatch repair deficiency and Tuberous Sclerosis complex

Constitutional mismatch repair deficiency is a rare cancer predisposition syndrome caused by biallelic mutations in one of the four mismatch repair genes. Patients are predisposed to various tumors including hematological malignancies, brain tumors and colorectal carcinomas. Phenotypic overlap with Neurofibromatosis-1 is well known, with most patients presenting with café-au-lait macules. Other common features include axillary and/or inguinal freckling and intracranial MRI foci of high T2W/FLAIR signal intensity similar to the typical FASI seen in Neurofibromatosis-1. In this cohort of eight patients with constitutional mismatch repair deficiency we describe overlapping phenotypical features with Tuberous Sclerosis complex. In addition to “ash-leaf like” hypomelanotic macules (five patients), we detected intracranial tuber-like lesions (three patients), renal cysts (three patients) and renal angiomyolipomas (two patients). All our patients also had Neurofibromatosis-1 like features, mainly café-au-lait macules. This study suggests that features of Tuberous sclerosis especially when overlapping with those of Neurofibromatosis 1 or malignancies atypical for these syndromes should raise the possibility of constitutional mismatch repair deficiency. Correct diagnosis is essential for appropriate genetic counseling and pre-emptive cancer surveillance.     

Interleukin-9 is involved in host protective immunity to intestinal nematode infection

Murine studies have demonstrated that, as with other nematodes, infection with the intestinal nematode Trichinella spiralis is associated with a pronounced intestinal mastocytosis, eosinophilia and an elevation in serum levels of total IgE. Both interleukin (IL)-4 and IL-5 are clearly important in the generation of IgE responses and eosinophilia, respectively, but the control of mucosal mastocytosis in vivo is not as well defined. Mucosal mast cells appear to be particularly important with regard to T. spiralis infections as there is good evidence to suggest their involvement in expulsion of the parasite from the host. In this study we examined the effect of the overproduction of the Th2 cytokine IL-9 on infection with this nematode. We demonstrate that naive IL-9-transgenic mice have an intense intestinal mastocytosis and high serum levels of mouse mast cell protease-1. Moreover, upon infection high titers of parasite-specific IgG1 were observed with a heightened mast cell response, which was associated with the rapid expulsion of T. spiralis from the gut. Furthermore, as depression of this mast cell response, using anti-c-kit antibodies, resulted in the inability of these mice to expel the parasite, this study clearly demonstrates an activity of IL-9 on mucosal mastocytosis and the host protective immune response in vivo.     

Absence of TP53 alterations in pheochromocytomas and medullary thyroid carcinomas

The role of the TP53 gene in the development of inherited and sporadic pheochromocytomas and medullary thyroid carcinomas (MTC) has not been clarified because of conflicting reports and limitations in the assays used to detect mutations. To determine the frequency of TP53 alterations in these tumors, 22 pheochromocytomas and 29 MTCs were screened for loss of heterozygosity (LOH) on 17p with four markers. Single-strand-conformation-variant (SSCV) analysis of exons 4–9 of the TP53 gene was performed in 20 of the pheochromocytomas and in 22 of the MTCs. The expression of p53 was determined by immunohistochemistry in 19 pheochromocytomas and in 17 MTCs using two antibodies (D01 and D07) on frozen and paraffin-embedded tissues. Four of the 22 pheochromocytomas and none of the MTCs showed LOH on 17p. No mutations were detected in any of the tumors screened by SSCV analysis. Immunohistochemical staining of frozen and paraffin-embedded tumor sections did not show p53 overexpression in any of the tumors examined. Our findings indicate that mutations in the TP53 gene are an uncommon event in the tumorigenesis of pheochromocytomas and medullary thyroid carcinomas. Genes Chromosom. Cancer 20:24–29, 1997. © 1997 Wiley-Liss, Inc.     

Solid Polymer Electrolytes Based on Copolymers of Cyclic Carbonate Acrylate and n‐Butylacrylate

Solid polymer electrolytes (SPEs) are prepared by mixing poly(2‐oxo‐1,3‐dioxolan‐4‐yl)methyl acrylate‐random‐n‐butylacrylate) [P(cyCA‐r‐nBA)] statistical copolymers with bis(trifluoromethane)sulfonimide lithium salt. The P(cyCA‐r‐nBA) copolymers are synthesized by reversible addition‐fragmentation chain transfer polymerization and different molar masses as well as copolymer composition are targeted in order to study the influence of the molecular parameters on the thermal, mechanical, and electrochemical properties of the SPEs obtained after mixing the copolymers with lithium salts. In the investigated experimental window, it is shown that the thermal and mechanical properties of the SPEs mainly depend on the composition of the copolymer and are poorly influenced by the molar mass. In sharp contrast, the ionic conductivities are more deeply influenced by the molar mass than by the composition of the copolymers. In this respect ionic conductivity values ranging from 4.2 × 10^?6 S cm^?1 for the lower molar mass sample to 8 × 10^?8 S cm^?1 for the higher molar mass one are measured at room temperature for the investigated SPEs.     

Improved provider preparedness through an 8-part genetics and genomic education program

PurposeLarge-scale genetics education appropriate for general practice providers is a growing priority. We describe the content and impact of a mandatory system-wide program implemented at Sanford Health.MethodsThe Imagenetics Initiative at Sanford Health developed a 2-year genetics education program with quarterly web-based modules that were mandatory for all physicians and advanced practice providers. Scores of 0 to 5 were calculated for each module on the basis of the number of objectives that the participants reported as fulfilled. In addition, the participants completed surveys before starting and after finishing the education program, which included a 7-item measure scored 7 to 28 on the perceived preparedness to practice genetics.ResultsBetween 2252 and 2822 Sanford Health employees completed each of the 8 quarterly education modules. The ratings were highest for the module about using genomics to improve patient management (mean score = 4.3) and lowest for the module about different types of genetic tests and specialists. The mean perceived preparedness scores increased from 15.7 at pre-education to 19.1 at post-education (P < .001).ConclusionWeb-based genetics education was highly effective in increasing health care providers’ confidence about using genetics. Both comfort with personal knowledge and confidence regarding access to the system’s genomic medicine experts increased significantly. The results demonstrate how scalable approaches can improve provider preparedness.     

Construction and evaluation of a eukaryotic expression plasmid for stable delivery using attenuated Salmonella

An approach to enhancing the stability of eukaryotic expression plasmids for delivery using attenuated Salmonella has been evaluated. The expression apparatus and beta-galactosidase gene from the expression plasmid, pCMVbeta, was cloned into the low copy number plasmid pLG339. The resulting construct, pLGbetaGAL, was shown to have a lower copy number than pCMVbeta in Salmonella enterica var Typhimurium aroA strain SL7207. Furthermore, beta-galactosidase-specific antibody was induced in mice following intramuscular inoculation with pLGbetaGAL as naked DNA. Following oral administration of mice with SL7207/pCMVbeta, recombinants could not be detected in tissues 3 days after inoculation. In comparison, SL7207/pLGbetaGAL recombinant bacteria could be detected in the Peyer's patches and spleens indicating that the Salmonella strain was stable. However, both SL7207/pCMVbeta and SL7207/pLGbetaGAL failed to induce beta-galactosidase-specific IgG in vivo. The mechanism by which attenuated Salmonella are able to release heterologous DNA for antigen processing and presentation is not yet understood. These results suggest that the mechanism needs to be further elucidated in order to rationally improve the system.