No / Peripheral intracrine sex steroid synthesis from adrenal precursors dehydroepiandrosterone (DHEA) and DHEA-sulfate has evolved in humans. We sought to establish if there are differences in intracrine, paracrine, and endocrine regulation of sex steroids by primary cultures of human skin epidermal keratinocytes and dermal fibroblasts. Microarray analysis identified multifunctional genes modulated by steroids, quantitative RT-PCR (qRT-PCR) mRNA expression, enzymatic assay aromatase activity, scratch assay cell migration, immunocytochemistry α-smooth muscle actin (α-SMA), and collagen gel fibroblast contraction. All steroidogenic components were present, although only keratinocytes expressed the organic anion organic anion transporter protein (OATP) 2B1 transporter. Both expressed the G-protein-coupled estrogen receptor (GPER1). Steroids modulated multifunctional genes, up-regulating genes important in repair and aging [angiopoietin-like 4 (ANGPTL4), chemokine (C-X-C motif) ligand 1 (CXCL1), lamin B1 (LMNB1), and thioredoxin interacting protein (TXNIP)]. DHEA-sulfate (DHEA-S), DHEA, and 17β-estradiol stimulated keratinocyte and fibroblast migration at early (4 h) and late (24–48 h) time points, suggesting involvement of genomic and nongenomic signaling. Migration was blocked by aromatase and steroid sulfatase (STS) inhibitors confirming intracrine synthesis to estrogen. Testosterone had little effect, implying it is not an intermediate. Steroids stimulated fibroblast contraction but not α-SMA expression. Mechanical wounding reduced fibroblast aromatase activity but increased keratinocyte activity, amplifying the bioavailability of intracellular estrogen. Cultured fibroblasts and keratinocytes provide a biologically relevant model system to investigate the complex pathways of sex steroid intracrinology in human skin.—Pomari, E., Valle, L. D., Pertile, P., Colombo, L., and Thornton, M. J. Intracrine sex steroid synthesis and signaling in human epidermal keratinocytes and dermal fibroblasts.

No / Significance: Epigenetic regulatory mechanisms are essential for epidermal homeostasis and contribute to the pathogenesis of many skin diseases, including skin cancer and psoriasis. However, while the epigenetic regulation of epidermal homeostasis is now becoming active area of research, the epigenetic mechanisms controlling the wound healing response remain relatively untouched. Recent Advances: Substantial progress achieved within the last two decades in understanding epigenetic mechanisms controlling gene expression allowed defining several levels, including covalent DNA and histone modifications, ATP-dependent and higher-order chromatin chromatin remodeling, as well as noncoding RNA- and microRNA-dependent regulation. Research pertained over the last few years suggests that epigenetic regulatory mechanisms play a pivotal role in the regulation of skin regeneration and control an execution of reparative gene expression programs in both skin epithelium and mesenchyme. Critical Issues: Epigenetic regulators appear to be inherently involved in the processes of skin repair, and are able to dynamically regulate keratinocyte proliferation, differentiation, and migration, together with influencing dermal regeneration and neoangiogenesis. This is achieved through a series of complex regulatory mechanisms that are able to both stimulate and repress gene activation to transiently alter cellular phenotype and behavior, and interact with growth factor activity. Future Directions: Understanding the molecular basis of epigenetic regulation is a priority as it represents potential therapeutic targets for the treatment of both acute and chronic skin conditions. Future research is, therefore, imperative to help distinguish epigenetic modulating drugs that can be used to improve wound healing.

No / Bone morphogenetic proteins (BMPs) and their receptors (BMPRs) play roles in embryonic development and postnatal remodelling of the skin. Many indications suggest that BMP signalling regulates keratinocyte proliferation and differentiation. Chronic wounds have been shown to exhibit high levels of BMP ligands; however, the effect of BMP pathway modulation on human skin healing remains undefined. A human ex vivo skin wound healing model was used to analyse the expression of BMP signalling pathway components during healing and to investigate the effects of BMPs and the BMP antagonist Noggin on skin repair. Additionally, the effects of BMP signalling on keratinocyte proliferation, apoptosis and migration were tested using in vitro flow cytometry and ‘scratch’ migration assays, respectively. BMP receptor-1B (BMPR-1B) and downstream signalling protein phosphorylated-Smad-1/5/8 were highly expressed in healing epidermis. Treatment of human skin with exogenous BMPs impaired wound closure by reducing keratinocyte proliferation and increasing apoptosis. The BMP antagonist Noggin negated the inhibitory effects of BMP ligands, and when used alone, Noggin reduced keratinocyte apoptosis in the wound bed. In vitro, BMP ligands suppressed keratinocyte proliferation whilst Noggin stimulated proliferation. Keratinocyte migration was slowed following BMP treatment; in contrast, migration was significantly accelerated due to inhibition of BMP activity by either Noggin or BMPR-1B silencing. BMP signalling is inherently involved in wound healing. BMPs slow skin repair by suppressing keratinocyte proliferation and migration. Thus, modulation of BMP signalling using BMP inhibitors such as Noggin may serve as a new approach to promote cutaneous wound repair. Level of evidence: Not ratable.

Yes / The cutaneous healing response has evolved to occur rapidly, in order to minimize infection and to re‐establish epithelial homeostasis. Rapid healing is achieved through complex coordination of multiple cell types, which importantly includes specific cell populations within the hair follicle (HF). Under physiological conditions, the epithelial compartments of HF and interfollicular epidermis remain discrete, with K15+ve bulge stem cells contributing progeny for HF reconstruction during the hair cycle and as a basis for hair shaft production during anagen. Only upon wounding do HF cells migrate from the follicle to contribute to the neo‐epidermis. However, the identity of the first‐responding cells, and in particular whether this process involves a direct contribution of K15+ve bulge cells to the early stage of epidermal wound repair remains unclear. Here we demonstrate that epidermal injury in murine skin does not induce bulge activation during early epidermal wound repair. Specifically, bulge cells of uninjured HFs neither proliferate nor appear to migrate out of the bulge niche upon epidermal wounding. In support of these observations, Diphtheria toxin‐mediated partial ablation of K15+ve bulge cells fails to delay wound healing. Our data suggest that bulge cells only respond to epidermal wounding during later stages of repair. We discuss that this response may have evolved as a protective safeguarding mechanism against bulge stem cell exhaust and tumorigenesis. / BBSRC.

No

No / Randomised, controlled trials are widely regarded as the gold standard by which the clinical effectiveness of healthcare products should be evaluated. Debate continues as to the value of this method of product assessment in a complex area such as wound care. Any method that is employed to define a product’s clinical value is, however, useless unless its ongoing effectiveness in a clinical area or with an individual patient is effectively monitored.

No / Wound healing remains a largely overlooked area despite the perceived large numbers of people with wounds and the high costs of treatment. The lack of visibility for wounds and wound healing may in part stem from the fragmented nature of the available data on wound occurrence often limited to descriptions of specific wound types within single care settings. A survey was undertaken across all care providers serving the population of Bradford, UK to identify the number of people with wounds, the characteristics of their wounds and the allocated interventions used to prevent and heal wounds. In March 2007, 1735 completed questionnaires were returned each marking the most severe wound experienced by a patient. The overall prevalence of wounds was 3.55 people with wounds per 1000 population (prevalence 0.355% 95% CI 0.33–0.37%). Almost one third (n = 556) of the people with wounds were located in acute care settings with the remainder spread across several community locations including residential and nursing homes. The most prevalent forms of wound were acute wounds (n = 826) followed by leg ulcers (n = 482) and pressure ulcers (n = 363). A previous survey with broadly similar methodology had shown a lower prevalence of wounds (0.279% 95% CI 0.26–0.29%) with this difference perhaps explained by different data collection methodologies within the nursing home sector that resulted in a 100% return compared with 50% in the earlier survey.

Yes / Dog bite injuries are a common cause of patient presentation to NHS emergency departments (EDs) and minor injuries units, and are generally associated with a low level of acuity, despite an inherent capacity for significant soft tissue damage to be inflicted by canine jaws capable of exerting terrific bite forces. Anatomical sites for injury correlate to victim age, with hand and wrist injuries predominating in the adult population. The most common complication is infection secondary to inoculation of oral flora, with the hands being particularly vulnerable due to their anatomy. Injuries to structures such as tendons can be discreet, and retained foreign bodies can easily be overlooked. Wound care has a propensity to attract a disproportionately high level of malpractice actions, and approaches to the management of dog bite injuries have largely been empirical, which may render the practitioner particularly exposed. In response to increasing pressures on healthcare systems, paramedics with extended scopes of practice, including wound care and suturing, are being utilised to assess, manage, treat, and either refer or discharge patients with apparently minor injuries, in strategies aimed at reducing hospital admissions. This article adopts a case study format to examine and evaluate treatment modalities and the current evidence base informing best practice in terms of dog bite injuries from the perspective of a paramedic practitioner, with critical reflection on the decision making process and complexities of such episodes of care in the pre-hospital setting.

Lai, Kwok Kin. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 229-251). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Tam, Chor Wing Jacqueline. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 322-359). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.