Glucocorticoid metabolism and function in ageing skin

Increased demographic proportions of elderly individuals are driving research into healthy lifespan. Excessive circulating glucocorticoids (GC) often cause hypertension, osteoporosis, central obesity, muscle weakness, skin thinning and poor wound healing (e.g. Cushing’s Syndrome) – conditions common in ageing. The GC-activating enzyme 11-beta hydroxysteroid dehydrogenase type 1 (11β-HSD1) displays increased activity in bone cells from older vs. younger donors. Here, we report similar findings in the organ most noticeably affected by ageing – skin. 11β-HSD1 activity was increased in skin from older vs. younger donors with increased expression in dermal fibroblasts from the former. GC induced activity exclusively in cells from older individuals, further increasing dermal GC-generating ability. We demonstrate 11β-HSD1-specific regulation of novel GC target genes that may be dysregulated during ageing which correlate with enzyme activity. Finally, studies characterizing the skin phenotype of aged 11β-HSD1-null mice reveal exciting morphological similarities to skin from young mice. GC therapy is common for elderly skin disorders (e.g. xerosis, pemphigoid and psoriasis). However, elderly patients are more susceptible to side-effects including thinning, bruising, tearing and infection. We identify 11β-HSD1 as a novel therapeutic target to minimize GC-induced side-effects in the elderly, improve the phenotype of ageing skin and limit associated pathologies

The prediction and monitoring of toxicity associated with long-term systemic glucocorticoid therapy

Glucocorticoids are often required for adequate control of inflammation in many serious inflammatory diseases; common indications for long-term treatment include polymyalgia rheumatica, giant cell arteritis, asthma and chronic obstructive pulmonary disease. Long-term glucocorticoid therapy is, however, associated with many adverse effects involving skin, gastro-intestinal, eye, skeletal muscle, bone, adrenal, cardio-metabolic and neuropsychiatric systems. This balance between benefits and risks of glucocorticoids is important for clinical practice and glucocorticoid-related adverse effects can significantly impair health-related quality of life. Understanding the nature and mechanisms of glucocorticoid-related adverse effects may inform how patients are monitored for toxicity and identify those groups, such as older people, that may need closer monitoring. For clinical trials in diseases commonly treated with glucocorticoids, standardised measurement of glucocorticoid-related adverse effects would facilitate future evidence synthesis and meta-analysis

Time-Dependent Framework for Analyzing Emergency Intervention Travel Times and Risk Implications due to Earthquakes. Bucharest Case Study

Earthquakes can generate a significant number of casualties within seconds, as well as high economic losses. The lack of rapid and coordinated emergency intervention can contribute to much greater losses. In this paper we develop a framework taking advantage of the ArcGis Network Analyst extension, able to account for post-earthquake conditions and reflect travel times. By combining 1) network characteristics with 2) direct seismic damage information, 3) models to determine road obstruction potential, 4) traffic information and time-dependent post-earthquake modeling but also 5) emergency intervention facilities (hospitals or fire stations) and considerations regarding their functional limitations, this framework can provide important support for the management of emergency intervention but also for risk reduction planning. Main results consist of maps showing travel times for various scenarios and moments after an earthquake, inaccessible areas, vital roads for access or an identification of important facilities. As case study we chose Bucharest, one of Europe’s most endangered capitals considering the seismic risk level. The city was and could be considerably affected by earthquakes in the Vrancea Seismic Zone, being characterized by a high number of vulnerable buildings and by one of the greatest typical traffic congestion levels in the world. Compared to previous network studies for Bucharest, the new approach is more complex and customable, providing means for real-time integration and time-dependent analysis. Results, for a worst-case scenario, prove that the risks could be even greater than expected, but also what should be done to mitigate them, such as the construction of a new hospital in the western part of the city, ensuring safe delimited routes for emergency vehicles or expanding the treatment capacity of actual hospitals—some of which also need seismic retrofitting. Results of this study will be integrated in the revised version of the National Conception for Post-Earthquake Response—an operational framework which will lead to risk mitigation through the improvement of post-disaster reaction

Network-risk: an open GIS toolbox for estimating the implications of transportation network damage due to natural hazards, tested for Bucharest, Romania

Abstract. Due to their widespread and continuous expansion, transportation networks are considerably exposed to natural hazards such as earthquakes, floods, landslides or hurricanes. The vulnerability of specific segments and structures among bridges, tunnels, pumps or storage tanks can translate not only into direct losses but also into significant indirect losses at the systemic level. Cascading effects such as post-event traffic congestion, building debris or tsunamis can contribute to an even greater level of risk. To support the effort of modeling the natural hazards' implications at the full transportation network scale, we developed a new applicable framework, relying on (i) GIS to define, analyze and represent transportation networks; (ii) methods for determining the probability of network segments to fail due to natural-hazard effects; (iii) Monte Carlo simulation for multiple scenario generation; (iv) methods to analyze the implications of connectivity loss on emergency intervention times and transit disruption; and (v) correlations with other vulnerability and risk indicators. Currently, the framework is integrated into ArcGIS Desktop as a toolbox entitled “Network-risk”, which makes use of the ModelBuilder functions and is free to download and modify. Network-risk is an attempt to bring together interdisciplinary research with the goal of creating an automated solution to deliver insights on how a transportation network can be affected by natural hazards, directly and indirectly, assisting in risk evaluation and mitigation planning. In this article we present and test Network-risk at the full urban scale for the road network of Bucharest. This city is one of Europe's most exposed capitals to earthquakes, with high seismic-hazard values and a vulnerable building stock but also significant traffic congestion problems not yet accounted for in risk analyses and risk reduction strategies. Document type: Articl

A Whiff of Sulfur: One Wind a Day Keeps the Doctor Away

Reactive Sulfur Species (RSS), such as allicin from garlic or sulforaphane from broccoli, are fre-quently associated with biological activities and possible health benefits in animals and humans. Among these Organic Sulfur Compounds (OSCs) found in many plants and fungi, the Volatile Sulfur Compounds (VSCs) feature prominently, not only because of their often-pungent smell, but also because they are able to access places which solids and solutions cannot reach that easily. Indeed, inorganic RSS such as hydrogen sulfide (H2S) and sulfur dioxide (SO2 ) can be used to lit-erally fumigate entire rooms and areas. Similarly, metabolites of garlic, such as allyl methyl sulfide (AMS), are formed metabolically in humans in lower concentrations and reach the airways from inside the body as part of one’s breath. Curiously, H2S is also formed in the gastrointestinal tract by gut bacteria, and the question of if and for which purpose this gas then crosses the barriers and enters the body is indeed a delicate matter for equally delicate studies. In any case, nature is surprisingly rich in such VSCs, as fruits (for instance, the infamous durian) demonstrate, and therefore these VSCs represent a promising group of compounds for further studies

The effects of attachment style on coping with visible skin conditions and responsiveness to a compassion based self-help intervention

No abstract available

Topical 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition Corrects Cutaneous Features of Systemic Glucocorticoid Excess in Female Mice

Glucocorticoid (GC) excess drives multiple cutaneous adverse effects, including skin thinning and poor wound healing. The ubiquitously expressed enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates mouse corticosterone from 11-dehydrocorticosterone (and human cortisol from cortisone). We previously demonstrated elevated 11β-HSD1 activity during mouse wound healing, but the interplay between cutaneous 11β-HSD1 and systemic GC excess is unexplored. Here, we examined effects of 11β-HSD1 inhibition by carbenoxolone (CBX) in mice treated with corticosterone (CORT) or vehicle for 6 weeks. Mice were treated bidaily with topical CBX or vehicle (VEH) 7 days before wounding and during wound healing. CORT mice displayed skin thinning and impaired wound healing but also increased epidermal integrity. 11β-HSD1 activity was elevated in unwounded CORT skin and was inhibited by CBX. CORT mice treated with CBX displayed 51%, 59%, and 100% normalization of wound healing, epidermal thickness, and epidermal integrity, respectively. Gene expression studies revealed normalization of interleukin 6, keratinocyte growth factor, collagen 1, collagen 3, matrix metalloproteinase 9, and tissue inhibitor of matrix metalloproteinase 4 by CBX during wound healing. Importantly, proinflammatory cytokine expression and resolution of inflammation were unaffected by 11β-HSD1 inhibition. CBX did not regulate skin function or wound healing in the absence of CORT. Our findings demonstrate that 11β-HSD1 inhibition can limit the cutaneous effects of GC excess, which may improve the safety profile of systemic steroids and the prognosis of chronic wounds

Automated quantification of 3D wound morphology by machine learning and optical coherence tomography in type 2 diabetes

Background: Driven by increased prevalence of type 2 diabetes and ageing populations, wounds affect millions of people each year, but monitoring and treatment remain limited. Glucocorticoid (stress hormones) activation by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) also impairs healing. We recently reported that 11β-HSD1 inhibition with oral AZD4017 improves acute wound healing by manual 2D optical coherence tomography (OCT), although this method is subjective and labour-intensive. Objectives: Here, we aimed to develop an automated method of 3D OCT for rapid identification and quantification of multiple wound morphologies. Methods: We analysed 204 3D OCT scans of 3 mm punch biopsies representing 24 480 2D wound image frames. A u-net method was used for image segmentation into 4 key wound morphologies: early granulation tissue, late granulation tissue, neo-epidermis, and blood clot. U-net training was conducted with 0.2% of available frames, with a mini-batch accuracy of 86%. The trained model was applied to compare segment area (per frame) and volume (per scan) at days 2 and 7 post-wounding and in AZD4017 compared to placebo. Results: Automated OCT distinguished wound tissue morphologies, quantifying their volumetric transition during healing, and correlating with corresponding manual measurements. Further, AZD4017 improved epidermal re-epithelialisation (by manual OCT) with a corresponding trend towards increased neo-epidermis volume (by automated OCT). Conclusion: Machine learning and OCT can quantify wound healing for automated, non-invasive monitoring in real-time. This sensitive and reproducible new approach offers a step-change in wound healing research, paving the way for further development in chronic wounds

Inhibition of the glucocorticoid‐activating enzyme 11β‐hydroxysteroid dehydrogenase type 1 drives concurrent 11‐oxygenated androgen excess

Aldo‐keto reductase 1C3 (AKR1C3) is a key enzyme in the activation of both classic and 11‐oxygenated androgens. In adipose tissue, AKR1C3 is co‐expressed with 11β‐hydroxysteroid dehydrogenase type 1 (HSD11B1), which catalyzes not only the local activation of glucocorticoids but also the inactivation of 11‐oxygenated androgens, and thus has the potential to counteract AKR1C3. Using a combination of in vitro assays and in silico modeling we show that HSD11B1 attenuates the biosynthesis of the potent 11‐oxygenated androgen, 11‐ketotestosterone (11KT), by AKR1C3. Employing ex vivo incubations of human female adipose tissue samples we show that inhibition of HSD11B1 results in the increased peripheral biosynthesis of 11KT. Moreover, circulating 11KT increased 2–3 fold in individuals with type 2 diabetes after receiving the selective oral HSD11B1 inhibitor AZD4017 for 35 days, thus confirming that HSD11B1 inhibition results in systemic increases in 11KT concentrations. Our findings show that HSD11B1 protects against excess 11KT production by adipose tissue, a finding of particular significance when considering the evidence for adverse metabolic effects of androgens in women. Therefore, when targeting glucocorticoid activation by HSD11B1 inhibitor treatment in women, the consequently increased generation of 11KT may offset beneficial effects of decreased glucocorticoid activation