Assessing the New and Emerging Treatments for Atopic Dermatitis.

The newer and emerging treatments for atopic dermatitis (AD) focus on blockade of inflammatory cytokines, especially those that derive from T helper cell type 2 (TH2) and are associated with a pathway of immunoglobulin E (IgE) sensitization. Among the proinflammatory cytokines that have been identified as promising therapeutic targets are chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2), IgE, thymic stromal lymphopoietin (TSLP), and several monoclonal antibodies that block key cytokine pathways in the innate immune response. Two agents that have been studied in phase III clinical trials are the boronbased phosphodiesterase-4 (PDE-4) inhibitor, crisaborole, and dupilumab, an antibody that inhibits the interleukin-4/ IL-13 receptor α chain.

Review of Critical Issues in the Pathogenesis of Atopic Dermatitis.

About a decade age, loss-of-function mutations in the filaggrin molecule were first implicated in the pathogenesis of ichthyosis vulgaris and, subsequently, of atopic dermatitis and other atopic diseases. Since then, intensive study of the role of filaggrin null mutations have led to other milestones in understanding the pathologic pathways in these diseases, including the initiation, maintenance, and promotion of the disease processes. The result has been new and emerging clinical and pharmacologic strategies for early identification of and intervention in atopic diseases.

Update on Epidemiology, Diagnosis, and Disease Course of Atopic Dermatitis.

Studies of the prevalence of atopic dermatitis (AD) have provided insights into associated environmental risk factors, demonstrating the complex interactions between the presence of filaggrin (FLG) gene defects and environment. Among other important findings is that elevated transepidermal water loss (TEWL) in newborns is a strong predictor of AD, regardless of FLG status. Recently recognized predictors of disease course and severity include onset of AD signs and symptoms before 12 months of age and the presence of an FLG mutation and concomitant immunoglobulin E sensitization early in life.

Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations.

Iron intakes and status of 2-year-old children in the Cork BASELINE Birth Cohort Study.

Young children are at risk of iron deficiency and subsequent anaemia, resulting in long-term consequences for cognitive, motor and behavioural development. This study aimed to describe the iron intakes, status and determinants of status in 2-year-old children. Data were collected prospectively in the mother-child Cork BASELINE Birth Cohort Study from 15 weeks' gestation throughout early childhood.

The role of the CCN family of proteins in blood cancers.

Haematopoiesis is the term used to describe the production of blood cells. This is a tightly regulated hierarchical system in which mature circulating blood cells develop from a small population of haematopoietic stem (HSC) and progenitor cells within the microenvironment of the bone marrow. Molecular and genetic abnormalities arising in these stem cells lead to a block in the normal programme of proliferation and differentiation and result in the development of the blood cancers known as the leukaemias and lymphomas.

Publishing FAIR Data: An Exemplar Methodology Utilizing PHI-Base.

Pathogen-Host interaction data is core to our understanding of disease processes and their molecular/genetic bases. Facile access to such core data is particularly important for the plant sciences, where individual genetic and phenotypic observations have the added complexity of being dispersed over a wide diversity of plant species vs. the relatively fewer host species of interest to biomedical researchers.

Skin barrier impairment at birth predicts food allergy at 2 years of age.

Background: Transcutaneous exposure to food allergens can lead to food sensitization (FS)/food allergy (FA). We measured skin barrier function in early infancy and related it to the later development of FS/FA at age 2 years.

Objective: We sought to examine the relationship between early life skin barrier function and FA in infancy.

Too Much, Too Little or Just Enough: A Goldilocks Effect for IL-13 and Skin Barrier Regulation?

The mechanistic relationship between IL-4/IL-13 and skin barrier function has been of interest since the filaggrin discovery and the subsequent in vitro demonstration that IL-4 and IL-13 downregulate filaggrin expression in cultured keratinocytes. Hönzke and colleagues explore these interactions further. The effects of IL-4/ll-13 may be context dependent, with differing roles in homeostasis and in disease.

How does tolerability of double balloon enteroscopy compare to other forms of endoscopy?

Background And Aims: Gastrointestinal endoscopy can be difficult for patients to tolerate. Studies on endoscopic tolerability mainly focus on gastroscopy or colonoscopy with a paucity of data on double balloon enteroscopy (DBE). We aimed to prospectively evaluate tolerability in patients undergoing several forms of endoscopy including DBE.

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci).

PhytoPath: an integrative resource for plant pathogen genomics.

PhytoPath (www.phytopathdb.org) is a resource for genomic and phenotypic data from plant pathogen species, that integrates phenotypic data for genes from PHI-base, an expertly curated catalog of genes with experimentally verified pathogenicity, with the Ensembl tools for data visualization and analysis.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

Background: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres.

Objectives: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs.

Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations.

Background: Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown.

Using the pathogen-host interactions database (PHI-base) to investigate plant pathogen genomes and genes implicated in virulence.

New pathogen-host interaction mechanisms can be revealed by integrating mutant phenotype data with genetic information. PHI-base is a multi-species manually curated database combining peer-reviewed published phenotype data from plant and animal pathogens and gene/protein information in a single database.

Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity.

Background: Atopic dermatitis (AD) is an inflammatory skin condition that can occur in early life, predisposing to asthma development in a phenomenon known as the atopic march. Although genetic and environmental factors are known to contribute to AD and asthma, the mechanisms underlying the atopic march remain poorly understood. Filaggrin loss-of-function mutations are a major genetic predisposer for the development of AD and progression to AD-associated asthma.

Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes.

Background: Atopic dermatitis (AD) is characterized by epidermal barrier failure and immune-mediated inflammation. Evidence on AD as a potential risk factor for inflammatory comorbidities is scarce.

Objectives: We sought to test the hypothesis that prevalent AD is a risk factor for incident rheumatoid arthritis (RA) and inflammatory bowel disease (IBD; Crohn disease [CD], ulcerative colitis [UC]) and is inversely related to type 1 diabetes (T1D) and to investigate established RA, IBD, and T1D susceptibility loci in AD.

Activating CARD14 Mutations Are Associated with Generalized Pustular Psoriasis but Rarely Account for Familial Recurrence in Psoriasis Vulgaris.

Caspase recruitment family member 14 (CARD14, also known as CARMA2), is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Gain-of-function CARD14 mutations have been documented in familial forms of psoriasis vulgaris (PV) and pityriasis rubra pilaris (PRP). More recent investigations have also implicated CARD14 in the pathogenesis of pustular psoriasis.

Neonatal adiposity increases the risk of atopic dermatitis during the first year of life.

Background: Early nutrition and adiposity have been linked to atopic dermatitis (AD) development.

Objective: We sought to describe risk factors for AD in the first year of life in infants participating in the Cork BASELINE birth cohort study (n = 1537).

Methods: Prospective data on early-life events, infant feeding, and nutritional and environmental exposures were collected at 15 weeks' gestation, birth, and 2, 6, and 12 months of age.

Recent advances in the pathobiology and management of Kasabach-Merritt phenomenon.

Kasabach-Merritt Phenomenon (KMP) refers to the clinical constellation of thrombocytopenia, consumptive coagulopathy and purpura associated with Kaposiform haemangioedothelioma or tufted angioma, but not the more common infantile haemangioma. It shows a variable and unpredictable response to traditional pharmacological agents, such as steroids, vincristine or interferon alpha 2a or 2b. More recently, the interaction between platelets and endothelial cells and the proangiogenic phenotype that results has been recognized to underly the pathogenesis of this disorder.

Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin.

Background: Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported.

Objective: We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis.