Cationic Lipid Is Not Required for Uptake and Selective Inhibitory Activity of ICAM-1 Phosphorothioate Antisense Oligonucleotides in Keratinocytes

Keratinocyte intercellular adhesion molecule-1 (ICAM-1) is important in mediating retention of T cells within the epidermal compartment. To determine if antisense oligonucleotides designed to hybridize to various ICAM-1 mRNA regions could selectively influence cultured keratinocyte ICAM-1 expression following gamma interferon (IFN-γ), cells were exposed to several antisense compounds, in the absence and presence of cationic lipid (lipofectin). Keratinocytes rapidly internalized sense and antisense compounds (within 30-60 min), even in the absence of lipofectin with approximately 30% of the cell possessing positive nuclei. Such nuclear accumulation was not observed in the absence of lipofectin in cultured fibroblasts, smooth muscle cells, or endothelial cells, even though total cellular uptake within the cytoplasm was significantly increased in all these cell types. Using flow cytometry, IFN-γ-inducible ICAM-1 expression was reduced 50% by antisense compounds with lipofectin, and by 30% without lipofectin. This inhibition was specific as no change was observed for HLA-DR or tumor necrosis factor-α receptor expression. Northern blot hybridization studies confirmed that ICAM-1 antisense oligonucleotides selectively and significantly inhibited ICAM-1 expression. These results suggest that such antisense compounds interact with keratinocytes differently than other cell types, and provide the in vitro basis for clinical trials in which reduction (or elimination) of ICAM-1 expression by epidermal keratinocytes could be selectively accomplished without necessarily influencing dermal cell types such as fibroblasts, endothelial cells, or smooth muscle cells

Spontaneous Development of Psoriasis in a New Animal Model Shows an Essential Role for Resident T Cells and Tumor Necrosis Factor-α

Psoriasis is a common T cell–mediated autoimmune disorder where primary onset of skin lesions is followed by chronic relapses. Progress in defining the mechanism for initiation of pathological events has been hampered by the lack of a relevant experimental model in which psoriasis develops spontaneously. We present a new animal model in which skin lesions spontaneously developed when symptomless prepsoriatic human skin was engrafted onto AGR129 mice, deficient in type I and type II interferon receptors and for the recombination activating gene 2. Upon engraftment, resident human T cells in prepsoriatic skin underwent local proliferation. T cell proliferation was crucial for development of a psoriatic phenotype because blocking of T cells led to inhibition of psoriasis development. Tumor necrosis factor-α was a key regulator of local T cell proliferation and subsequent disease development. Our observations highlight the importance of resident T cells in the context of lesional tumor necrosis factor-α production during development of a psoriatic lesion. These findings underline the importance of resident immune cells in psoriasis and will have implications for new therapeutic strategies for psoriasis and other T cell–mediated diseases

Lesbian and bisexual women's experiences of sexuality-based discrimination and their appearance concerns

Lesbian and bisexual women frequently experience sexuality-based discrimination, which is often based on others' judgements about their appearance. This short article aims to explore whether there is a relationship between lesbian and bisexual women's experiences of sexuality-based discrimination and their satisfaction with the way that they look. Findings from an online survey suggest that discrimination is negatively related to appearance satisfaction for lesbian women, but not for bisexual women. It is argued that this difference exists because lesbian appearance norms are more recognisable and distinctive than bisexual women's appearance norms

Screening Breakdown on the Route toward the Metal-Insulator Transition in Modulation Doped Si/SiGe Quantum Wells

Exploiting the spin resonance of two-dimensional (2D) electrons in SiGe/Si quantum wells we determine the carrier-density-dependence of the magnetic susceptibility. Assuming weak interaction we evaluate the density of states at the Fermi level D(E_F), and the screening wave vector, q_TF. Both are constant at higher carrier densities n, as for an ideal 2D carrier gas. For n < 3e11 cm-2, they decrease and extrapolate to zero at n = 7e10 cm-2. Calculating the mobility from q_TF yields good agreement with experimental values justifying the approach. The decrease in D(E_F) is explained by potential fluctuations which lead to tail states that make screening less efficient and - in a positive feedback - cause an increase of the potential fluctuations. Even in our high mobility samples the fluctuations exceed the electron-electron interaction leading to the formation of puddles of mobile carriers with at least 1 micrometer diameter.Comment: 4 pages, 3 figure

Elevated expression of the chemokine-scavenging receptor D6 is associated with impaired lesion development in psoriasis

D6 is a scavenging-receptor for inflammatory CC chemokines that are essential for resolution of inflammatory responses in mice. Here, we demonstrate that D6 plays a central role in controlling cutaneous inflammation, and that D6 deficiency is associated with development of a psoriasis-like pathology in response to varied inflammatory stimuli in mice. Examination of D6 expression in human psoriatic skin revealed markedly elevated expression in both the epidermis and lymphatic endothelium in "uninvolved" psoriatic skin (ie, skin that was more than 8 cm distant from psoriatic plaques). Notably, this increased D6 expression is associated with elevated inflammatory chemokine expression, but an absence of plaque development, in uninvolved skin. Along with our previous observations of the ability of epidermally expressed transgenic D6 to impair cutaneous inflammatory responses, our data support a role for elevated D6 levels in suppressing inflammatory chemokine action and lesion development in uninvolved psoriatic skin. D6 expression consistently dropped in perilesional and lesional skin, coincident with development of psoriatic plaques. D6 expression in uninvolved skin also was reduced after trauma, indicative of a role for trauma-mediated reduction in D6 expression in triggering lesion development. Importantly, D6 is also elevated in peripheral blood leukocytes in psoriatic patients, indicating that upregulation may be a general protective response to inflammation. Together our data demonstrate a novel role for D6 as a regulator of the transition from uninvolved to lesional skin in psoriasis

Length of migration and eating habits of Portuguese university students living in London, United Kingdom

Several studies have pointed adverse effects of long term migration on eating habits. Research is needed to understand if this effect occurs also with a short length of migration, as is the case of international students. Our aim was to evaluate the effect of short and long term migration on eating habits of Portuguese university students. Participants were 46 English and 55 Portuguese students from universities in London, United Kingdom. The findings from this study highlight the difficulties that Portuguese students faced in maintaining a traditional Mediterranean diet after moving to a Northern European environment

Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions

Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanisms are largely unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists increased inflammation. Similarly, AhR signaling via the endogenous ligand FICZ reduced the inflammatory response in the imiquimod-induced model of skin inflammation and AhR-deficient mice exhibited a substantial exacerbation of the disease, compared to AhR-sufficient controls. Nonhematopoietic cells, in particular keratinocytes, were responsible for this hyperinflammatory response, which involved upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders

A systematic policy approach to changing the food system and physical activity environments to prevent obesity

As obesity prevention becomes an increasing health priority in many countries, including Australia and New Zealand, the challenge that governments are now facing is how to adopt a systematic policy approach to increase healthy eating and regular physical activity. This article sets out a structure for systematically identifying areas for obesity prevention policy action across the food system and full range of physical activity environments. Areas amenable to policy intervention can be systematically identified by considering policy opportunities for each level of governance (local, state, national, international and organisational) in each sector of the food system (primary production, food processing, distribution, marketing, retail, catering and food service) and each sector that influences physical activity environments (infrastructure and planning, education, employment, transport, sport and recreation). Analysis grids are used to illustrate, in a structured fashion, the broad array of areas amenable to legal and regulatory intervention across all levels of governance and all relevant sectors. In the Australian context, potential regulatory policy intervention areas are widespread throughout the food system, e.g., land-use zoning (primary production within local government), food safety (food processing within state government), food labelling (retail within national government). Policy areas for influencing physical activity are predominantly local and state government responsibilities including, for example, walking and cycling environments (infrastructure and planning sector) and physical activity education in schools (education sector). The analysis structure presented in this article provides a tool to systematically identify policy gaps, barriers and opportunities for obesity prevention, as part of the process of developing and implementing a comprehensive obesity prevention strategy. It also serves to highlight the need for a coordinated approach to policy development and implementation across all levels of government in order to ensure complementary policy action