A narrative review of the literature about people with intellectual disability who identify as lesbian, gay, bisexual, transgender, intersex or questioning.

This narrative review of the research literature presents a summary about the key issues facing people with intellectual disability (ID) who identify as lesbian, gay, bisexual, transgender, intersex or questioning (LGBTIQ). The aim of this review was to consolidate research of the topic; to identify whether any pilot studies reporting social/sexual/educational interventions had been published; and to offer some perspective on the type of future research required to better inform policy, practice and theory that may lead to better outcomes for people with ID who identify as LGBTIQ. Almost all of the research literature on the topic is either exploratory or descriptive which serves to outline the range of issues faced by people with ID who identify as LGBTIQ. Urgently needed as the next step, however, is a concerted effort to conduct a range of innovative educational and social interventions with collection of targeted and appropriate outcomes data.

Transforming growth factor alpha (TGFalpha)-stimulated secretion of HSP90alpha: using the receptor LRP-1/CD91 to promote human skin cell migration against a TGFbeta-rich environment during wound healing.

Jump-starting and subsequently maintaining epidermal and dermal cell migration are essential processes for skin wound healing. These events are often disrupted in nonhealing wounds, causing patient morbidity and even fatality. Currently available treatments are unsatisfactory. To identify novel wound-healing targets, we investigated secreted molecules from transforming growth factor alpha (TGFalpha)-stimulated human keratinoytes, which contained strong motogenic, but not mitogenic, activity. Protein purification allowed us to identify the heat shock protein 90alpha (hsp90alpha) as the factor fully responsible for the motogenic activity in keratinocyte secretion. TGFalpha causes rapid membrane translocation and subsequent secretion of hsp90alpha via the unconventional exosome pathway in the cells. Secreted hsp90alpha promotes both epidermal and dermal cell migration through the surface receptor LRP-1 (LDL receptor-related protein 1)/CD91. The promotility activity resides in the middle domain plus the charged sequence of hsp90alpha but is independent of the ATPase activity. Neutralizing the extracellular function of hsp90alpha blocks TGFalpha-induced keratinicyte migration. Most intriguingly, unlike the effects of canonical growth factors, the hsp90alpha signaling overrides the inhibition of TGFbeta, an abundant inhibitor of dermal cell migration in skin wounds. This finding provides a long-sought answer to the question of how dermal cells migrate into the wound environment to build new connective tissues and blood vessels. Thus, secreted hsp90alpha is potentially a new agent for wound healing.

Extracellular heat shock protein-90alpha: linking hypoxia to skin cell motility and wound healing.

Hypoxia is a microenvironmental stress in wounded skin, where it supports wound healing by promoting cell motility. The mechanism of the hypoxia action remained speculative. Here, we provide evidence that hypoxia promotes human dermal fibroblast (HDF) migration by inducing secretion of heat shock protein-90alpha (hsp90alpha) into the extracellular environment through hypoxia-inducible factor-1alpha (HIF-1alpha). The secreted hsp90alpha in turn executes hypoxia's pro-motility effect. Expression of an activated HIF-1alpha mimicked, whereas expression of an inactive HIF-1alpha or suppression of endogenous HIF-1alpha blocked, hypoxia-induced hsp90alpha secretion and HDF migration. Interestingly, the hypoxia-HIF-1 pathway-induced hsp90alpha secretion required neither changes in the steady-state mRNA level nor in the promoter activity of hsp90alpha. Recombinant hsp90alpha fully duplicated the hypoxia effect on HDFs. Inhibition of extracellular hsp90alpha function completely blocked the hypoxia-HIF-1 pathway-stimulated HDF migration. More intriguingly, topical application of hsp90alpha accelerated wound healing in mice. This study has demonstrated a novel mechanism of hypoxia>HIF-1>hsp90alpha secretion>skin cell migration>wound healing, and identified extracellular hsp90alpha as a potential therapeutic agent for skin wounds.