A systematic review of factors influencing treatment adherence in chronic inflammatory skin disease – strategies for optimizing treatment outcome

Adherence describes how a patient follows a medical regime recommended by a healthcare provider. Poor treatment adherence represents a complex and challenging problem of international healthcare systems, as it has a substantial impact on clinical outcomes and patient safety and constitutes an important financial burden. Since it is one of the most common causes of treatment failure, it is extremely important for physicians to reliably distinguish between non‐adherence and non‐response. This systematic review aims to summarize the current literature on treatment adherence in dermatology, focusing on chronic inflammatory skin diseases such as psoriasis, atopic dermatitis and acne. A systematic literature search was performed using the PubMed Database, including articles from 2008 to 2018. Low treatment adherence is a multidimensional phenomenon defined by the interplay of numerous factors and should under no circumstances be considered as the patient's fault alone. Factors influencing treatment adherence in dermatology include patient characteristics and beliefs, treatment efficacy and duration, administration routes, disease chronicity and the disease itself. Moreover, the quality of the physician‐patient relationship including physician‐time available for the patient plays an important role. Understanding patients’ adherence patterns and the main drivers of non‐adherence creates opportunities to improve adherence in the future. Strategies to increase treatment adherence range from reminder programs to simplifying prescriptions or educational interventions. Absolute adherence to treatment may not be realistically achievable, but efforts need to be made to raise awareness in order to maximize adherence as far as possible

Psoriasis bei Dupilumab-behandeltem atopischem Ekzem

Dupilumab ist ein monoklonaler Antikörper, der an die gemeinsame α‑Kette des IL(Interleukin)-4- und IL-13-Rezeptors bindet und den Th(T-Helferzelle)2-Signalweg blockiert, der bei der Entstehung des atopischen Ekzems eine Schlüsselrolle spielt. Wir berichten über den Fall eines 40-jährigen Patienten, der nach 6 Wochen Dupilumab-Therapie eine histologisch gesicherte Psoriasis entwickelte. Das eigenmächtige, abrupte Absetzen der ungewöhnlichen, nicht leitliniengerechten oralen Steroidtherapie und die Blockade des Th2-Signalwegs durch Dupilumab dürften die entscheidenden Auslösefaktoren für die erstmalige Ausbildung der Psoriasis bei unserem Patienten gewesen sein

A20-Deficient Mast Cells Exacerbate Inflammatory Responses In Vivo

Mast cells are implicated in the pathogenesis of inflammatory and autoimmune diseases. However, this notion based on studies in mast cell-deficient mice is controversial. We therefore established an in vivo model for hyperactive mast cells by specifically ablating the NF-kappa B negative feedback regulator A20. While A20 deficiency did not affect mast cell degranulation, it resulted in amplified pro-inflammatory responses downstream of IgE/Fc epsilon RI, TLRs, IL-1R, and IL-33R. As a consequence house dust mite- and IL-33-driven lung inflammation, late phase cutaneous anaphylaxis, and collagen-induced arthritis were aggravated, in contrast to experimental autoimmune encephalomyelitis and immediate anaphylaxis. Our results provide in vivo evidence that hyperactive mast cells can exacerbate inflammatory disorders and define diseases that might benefit from therapeutic intervention with mast cell function

Defining an Essence of Structure Determining Residue Contacts in Proteins

The network of native non-covalent residue contacts determines the three-dimensional structure of a protein. However, not all contacts are of equal structural significance, and little knowledge exists about a minimal, yet sufficient, subset required to define the global features of a protein. Characterisation of this “structural essence” has remained elusive so far: no algorithmic strategy has been devised to-date that could outperform a random selection in terms of 3D reconstruction accuracy (measured as the Ca RMSD). It is not only of theoretical interest (i.e., for design of advanced statistical potentials) to identify the number and nature of essential native contacts—such a subset of spatial constraints is very useful in a number of novel experimental methods (like EPR) which rely heavily on constraint-based protein modelling. To derive accurate three-dimensional models from distance constraints, we implemented a reconstruction pipeline using distance geometry. We selected a test-set of 12 protein structures from the four major SCOP fold classes and performed our reconstruction analysis. As a reference set, series of random subsets (ranging from 10% to 90% of native contacts) are generated for each protein, and the reconstruction accuracy is computed for each subset. We have developed a rational strategy, termed “cone-peeling” that combines sequence features and network descriptors to select minimal subsets that outperform the reference sets. We present, for the first time, a rational strategy to derive a structural essence of residue contacts and provide an estimate of the size of this minimal subset. Our algorithm computes sparse subsets capable of determining the tertiary structure at approximately 4.8 Å Ca RMSD with as little as 8% of the native contacts (Ca-Ca and Cb-Cb). At the same time, a randomly chosen subset of native contacts needs about twice as many contacts to reach the same level of accuracy. This “structural essence” opens new avenues in the fields of structure prediction, empirical potentials and docking

First update of the living European guideline (EuroGuiDerm) on atopic eczema

First update of the living European guideline (EuroGuiDerm) on atopic eczem

Nkx3.2 Promotes Primary Chondrogenic Differentiation by Upregulating Col2a1 Transcription

Background: The Nkx3.2 transcription factor promotes chondrogenesis by forming a positive regulatory loop with a crucial chondrogenic transcription factor, Sox9. Previous studies have indicated that factors other than Sox9 may promote chondrogenesis directly, but these factors have not been identified. Here, we test the hypothesis that Nkx3.2 promotes chondrogenesis directly by Sox9-independent mechanisms and indirectly by previously characterized Sox9-dependent mechanisms. Methodology/Principal Findings: C3H10T1/2 pluripotent mesenchymal cells were cultured with bone morphogenetic protein 2 (BMP2) to induce endochondral ossification. Overexpression of wild-type Nkx3.2 (WT-Nkx3.2) upregulated glycosaminoglycan (GAG) production and expression of type II collagen a1 (Col2a1) mRNA, and these effects were evident before WT-Nkx3.2-mediated upregulation of Sox9. RNAi-mediated inhibition of Nkx3.2 abolished GAG production and expression of Col2a1 mRNA. Dual luciferase reporter assays revealed that WT-Nkx3.2 upregulated Col2a1 enhancer activity in a dose-dependent manner in C3H10T1/2 cells and also in N1511 chondrocytes. In addition, WT-Nkx3.2 partially restored downregulation of GAG production, Col2 protein expression, and Col2a1 mRNA expression induced by Sox9 RNAi. ChIP assays revealed that Nkx3.2 bound to the Col2a1 enhancer element. Conclusions/Significance: Nkx3.2 promoted primary chondrogenesis by two mechanisms: Direct and Sox9-independen

European guideline (EuroGuiDerm) on atopic eczema – part II: non-systemic treatments and treatment recommendations for special AE patient populations

The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti-inflammatory treatment, antimicrobial and antipruritic treatment and UV photo- therapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietaryinterventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for paediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published sepa- rately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a sec- tion on guideline methodology. Received: 17 February 2022; Accepted: 3 June 202

Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal Synaptic Potentiation and Pain Hypersensitivity

Electrophysiological and behavioral experiments in mice reveal that a cGMP-dependent kinase amplifies neurotransmitter release from peripheral pain sensors, potentiates spinal synapses, and leads to exaggerated pain

Dissecting the First Transcriptional Divergence During Human Embryonic Development

The trophoblast cell lineage is specified early at the blastocyst stage, leading to the emergence of the trophectoderm and the pluripotent cells of the inner cell mass. Using a double mRNA amplification technique and a comparison with transcriptome data on pluripotent stem cells, placenta, germinal and adult tissues, we report here some essential molecular features of the human mural trophectoderm. In addition to genes known for their role in placenta (CGA, PGF, ALPPL2 and ABCG2), human trophectoderm also strongly expressed Laminins, such as LAMA1, and the GAGE Cancer/Testis genes. The very high level of ABCG2 expression in trophectoderm, 7.9-fold higher than in placenta, suggests a major role of this gene in shielding the very early embryo from xenobiotics. Several genes, including CCKBR and DNMT3L, were specifically up-regulated only in trophectoderm, indicating that the trophoblast cell lineage shares with the germinal lineage a transient burst of DNMT3L expression. A trophectoderm core transcriptional regulatory circuitry formed by 13 tightly interconnected transcription factors (CEBPA, GATA2, GATA3, GCM1, KLF5, MAFK, MSX2, MXD1, PPARD, PPARG, PPP1R13L, TFAP2C and TP63), was found to be induced in trophectoderm and maintained in placenta. The induction of this network could be recapitulated in an in vitro trophoblast differentiation model

β1-integrins signaling and mammary tumor progression in transgenic mouse models: implications for human breast cancer

Consistent with their essential role in cell adhesion to the extracellular matrix, integrins and their associated signaling pathways have been shown to be involved in cell proliferation, migration, invasion and survival, processes required in both tumorigenesis and metastasis. β1-integrins represent the predominantly expressed integrins in mammary epithelial cells and have been proven crucial for mammary gland development and differentiation. Here we provide an overview of the studies that have used transgenic mouse models of mammary tumorigenesis to establish β1-integrin as a critical mediator of breast cancer progression and thereby as a potential therapeutic target for the development of new anticancer strategies