Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation

ADAM17 (a disintegrin and metalloproteinase 17) is ubiquitously expressed and cleaves membrane proteins, such as epidermal growth factor receptor (EGFR) ligands, l-selectin, and TNF, from the cell surface, thus regulating responses to tissue injury and inflammation. However, little is currently known about its role in skin homeostasis. We show that mice lacking ADAM17 in keratinocytes (A17(ΔKC)) have a normal epidermal barrier and skin architecture at birth but develop pronounced defects in epidermal barrier integrity soon after birth and develop chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 d after birth, followed by reduced transglutaminase (TGM) activity, transepidermal water loss, up-regulation of the proinflammatory cytokine IL-36α, and inflammatory immune cell infiltration. Activation of the EGFR was strongly reduced in A17(ΔKC) skin, and topical treatment of A17(ΔKC) mice with recombinant TGF-α significantly improved TGM activity and decreased skin inflammation. Finally, we show that mice lacking the EGFR in keratinocytes (Egfr(ΔKC)) closely resembled A17(ΔKC) mice. Collectively, these results identify a previously unappreciated critical role of the ADAM17–EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier and suggest that this pathway could represent a good target for treatment of epidermal barrier defects

Awareness of social care needs in people with epilepsy and intellectual disability

Background: Nearly a quarter of people with intellectual disability (ID) have epilepsy with large numbers experiencing drug-resistant epilepsy, and premature mortality. To mitigate epilepsy risks the environment and social care needs, particularly in professional care settings, need to be met. Purpose: To compare professional care groups as regards their subjective confidence and perceived responsibility when managing the need of people with ID and epilepsy. Method: A multi-agency expert panel developed a questionnaire with embedded case vignettes with quantitative and qualitative elements to understand training and confidence in the health and social determinants of people with ID and epilepsy. The cross-sectional survey was disseminated amongst health and social care professionals working with people with ID in the UK using an exponential non-discriminative snow-balling methodology. Group comparisons were undertaken using suitable statistical tests including Fisher's exact, Kruskal-Wallis, and Mann-Whitney. Bonferroni correction was applied to significant (p < 0.05) results. Content analysis was conducted and relevant categories and themes were identified. Results: Social and health professionals (n = 54) rated their confidence to manage the needs of people with ID and epilepsy equally. Health professionals showed better awareness (p < 0.001) of the findings/recommendations of the latest evidence on premature deaths and identifying and managing epilepsy-related risks, including the relevance of nocturnal monitoring. The content analysis highlighted the need for clearer roles, improved care pathways, better epilepsy-specific knowledge, increased resources, and better multi-disciplinary work. Conclusions: A gap exists between health and social care professionals in awareness of epilepsy needs for people with ID, requiring essential training and national pathways

Awareness of social care needs in people with epilepsy and intellectual disability

Background: Nearly a quarter of people with intellectual disability (ID) have epilepsy with large numbers experiencing drug-resistant epilepsy, and premature mortality. To mitigate epilepsy risks the environment and social care needs, particularly in professional care settings, need to be met. Purpose: To compare professional care groups as regards their subjective confidence and perceived responsibility when managing the need of people with ID and epilepsy. Method: A multi-agency expert panel developed a questionnaire with embedded case vignettes with quantitative and qualitative elements to understand training and confidence in the health and social determinants of people with ID and epilepsy. The cross-sectional survey was disseminated amongst health and social care professionals working with people with ID in the UK using an exponential non-discriminative snow-balling methodology. Group comparisons were undertaken using suitable statistical tests including Fisher’s exact, Kruskal-Wallis, and Mann-Whitney. Bonferroni correction was applied to significant (p < 0.05) results. Content analysis was conducted and relevant categories and themes were identified. Results: Social and health professionals (n = 54) rated their confidence to manage the needs of people with ID and epilepsy equally. Health professionals showed better awareness (p < 0.001) of the findings/recommendations of the latest evidence on premature deaths and identifying and managing epilepsy-related risks, including the relevance of nocturnal monitoring. The content analysis highlighted the need for clearer roles, improved care pathways, better epilepsy-specific knowledge, increased resources, and better multi-disciplinary work. Conclusions: A gap exists between health and social care professionals in awareness of epilepsy needs for people with ID, requiring essential training and national pathways

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes.

addresses: Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Plymouth, UK.The final publication is available at link.springer.com/article/10.1007%2Fs00125-009-1276-0Evidence that the beta cells of human patients with type 1 diabetes can be infected with enterovirus is accumulating, but it remains unclear whether such infections occur at high frequency and are important in the disease process. We have now assessed the prevalence of enteroviral capsid protein vp1 (vp1) staining in a large cohort of autopsy pancreases of recent-onset type 1 diabetic patients and a range of controls

Silencing of Renal DNaseI in Murine Lupus Nephritis Imposes Exposure of Large Chromatin Fragments and Activation of Toll Like Receptors and the Clec4e

Recent studies demonstrate that transformation of mild lupus nephritis into end-stage disease is imposed by silencing of renal DNaseI gene expression in (NZBxNZW)F1 mice. Down-regulation of DNaseI results in reduced chromatin fragmentation, and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals that produce IgG anti-chromatin antibodies. The main focus of the present study is to describe the biological consequences of renal DNaseI shut-down and reduced chromatin fragmentation with a particular focus on whether exposed large chromatin fragments activate Toll like receptors and the necrosis-related Clec4e receptor in murine and human lupus nephritis. Furthermore, analyses where performed to determine if matrix metalloproteases are up-regulated as a consequence of chromatin-mediated Toll like receptors/Clec4e stimulation. Mouse and human mRNA expression levels of DNaseI, Toll like receptors 7–9, Clec4e, pro-inflammatory cytokines and MMP2/MMP9 were determined and compared with in situ protein expression profiles and clinical data. We demonstrate that exposure of chromatin significantly up-regulate Toll like receptors and Clec4e in mice, and also but less pronounced in patients with lupus nephritis treated with immunosuppresants. In conclusion, silencing of renal DNaseI gene expression initiates a cascade of inflammatory signals leading to progression of both murine and human lupus nephritis. Principal component analyses biplot of data from murine and human lupus nephrits demonstrate the importance of DNaseI gene shut down for progression of the organ disease

Resource allocation with MAC layer node cooperation in cognitive radio networks

An algorithm for cooperative Dynamic Spectrum Access in Cognitive Radio networks is presented. The proposed algorithm utilizes Medium Access Control layer mechanisms for message exchange between secondary nodes that operate in license exempt spectrum bands, in order to achieve interference mitigation. A fuzzy logic reasoner is utilized in order to take into account the effect of the coexistence of a large number of users in the interference as well as to cope for uncertainties in the message exchange, caused by the nodes' mobility and the large delays in the updating of the necessary information. The proposed algorithm is applied in Filter Bank Multicarrier, as well as Orthogonal Frequency Division Multiplexing systems, and its performance is evaluated through extensive simulations that cover a wide range of typical scenarios. Experimental results indicate improved behaviour compared to previous schemes, especially in the case of uncertainties that cause underestimation of the interference levels

Transmission power regulation in cooperative Cognitive Radio systems under uncertainties

An algorithm for power control in cooperative Cognitive Radio networks is proposed. The algorithm utilizes Medium Access Control layer mechanisms for message exchange between the nodes, in order to achieve interference mitigation. A fuzzy logic reasoner is used to cope for uncertainties that appear in real life systems, caused from parameters such as non-ideal message exchange or high user mobility. The proposed algorithm is applied in Filter Bank Multicarrier as well as Orthogonal Frequency Division Multiplexing systems under various scenarios and its performance is evaluated through extensive simulations. Experimental results indicate improved behavior compared to previous schemes, especially in the case of uncertainties that cause underestimation of the interference levels

Resource allocation with MAC layer node cooperation in cognitive radio networks

An algorithm for cooperative Dynamic Spectrum Access in Cognitive Radio networks is presented. The proposed algorithm utilizes Medium Access Control layer mechanisms for message exchange between secondary nodes that operate in license exempt spectrum bands, in order to achieve interference mitigation. A fuzzy logic reasoner is utilized in order to take into account the effect of the coexistence of a large number of users in the interference as well as to cope for uncertainties in the message exchange, caused by the nodes&apos; mobility and the large delays in the updating of the necessary information. The proposed algorithm is applied in Filter Bank Multicarrier, as well as Orthogonal Frequency Division Multiplexing systems, and its performance is evaluated through extensive simulations that cover a wide range of typical scenarios. Experimental results indicate improved behaviour compared to previous schemes, especially in the case of uncertainties that cause underestimation of the interference levels. Copyright © 2010 A. Merentitis and D. Triantafyllopoulou