Topical retinoic acid changes the epidermal cell surface glycosylation pattern towards that of a mucosal epithelium

Topical all-trims retinoic acid (RA) produces a number of epidermal changes which are indistinguishable from those observed following treatment with a local irritant, namely sodium lauryl sulphate (SI. S). This observation has led to criticism that the efficacy of RA in disorders such as photoageing. Is merely a result of irritancy. In stratified epithelia, the cellular differentiation process is characterized by a stepwise synthesis of cell surface carbohydrates, and each type of stratified epithelium has its own specific pattern of carbohydrate expression. Glycosyltransferases, which are responsible for carbohydrate synthesis, are influenced by retinoids. Thus, we investigated whether epidermal cell surface glycosylation is altered in skin treated with topical RA, and contrasted it with changes induced by topical SLS Skin biopsies were obtained from seven normal volunteers who had been treated, on three separate areas of buttock skin, with single applications of 0 1 RA. 2 SLS, or vehicle creams, followed by 4-day occlusion. Biopsies were assessed immunohistologically using highly specific monoclonal antibodies to cell surface carbohydrates (types 1, 2 and 3 chain structures), previously demonstrated in the epidermis and in oral mucosal epithelium. Although type 1 chain structures were not demonstrated in any of the samples, the distribution of type 2 and 3 chain structures in RA-treated epidermis was altered towards that seen in a mucosal epithelium. T antigen, a mucin-type cell surface carbohydrate structure normally expressed throughout the epidermis, was only observed in the granular layer of RA-treated epidermis-a feature of mucosal epithelia. Le y , normally only seen in non-keratinized buccal epithelium, was strongly expressed in RA-treated epidermis. In contrast, the glycosylation pattern of the SLS-treated epidermis was not significantly different from that observed after vehicle treatment. Thus, RA treatment converts normal stratified epithelium towards the phenotype of mucosal epithelium with a decrease in T antigen and a concomitant increase in Le y . These changes the not observed following treatment with SLS and identify an important difference between RA effects and irritancy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72220/1/j.1365-2133.1996.27762.x.pd

The ICAM-3/LFA-1 interaction is critical for epidermal Langerhans cell alloantigen presentation to CD4 + T cells

Intercellular adhesion molecule (ICAM)-3 is a recently described member of the immunoglobulin superfamily and, as such, is closely related to ICAM-1 and ICAM-2. All three ICAMS are cognate for the counter-receptor lymphocyte function associated antigen-1 (LFA-L CD11a/CD18). Unlike ICAM-1 and ICAM-2. ICAM-3 is constitutively expressed at high levels on resting leucocytes. We investigated the expression and function of ICAM-3 in normal skin ( n = 5), as well as its expression in psoriasis ( n = 4). atopic eczema ( n = 4), allergic (rhus) contact dermatitis ( n =3). and cutaneous T-cell lymphoma (CTCL. n =2). Five-micrometre cryostat sections of skin were stained using monoclonal antibodies to ICAM-3 and A well characterized immunoperoxidase technique. In normal skin. ICAM-3 was expressed by all cutaneous leucocytes hut most striking was the strong expression of ICAM-3 by Langerhans cells within both epidermis and dermis. This observation was confirmed by double-labelling with CD1a and negative staining with an IgG1 isotype control. In psoriasis, atopic eczema, allergic contact dermatitis, and CTCL. ICAM-3 was co-expressed on all CD1a + cells, although, in psoriasis, the intensity of ICAM-3 expression was reduced. Functional blocking experiments were performed to determine whether the observed ICAM-3 expression on Langerhans cells was functionally important in antigen presentation. CD4 + T cells were prepared from peripheral blood and 10 5 CD4 + T cells combined with 10 5 epidermal cells harvested from keratome biopsies of normal skin of an individual allogeneic to the T-cell donor. Addition of 50 Μg anti-ICAM-3 to the co-culture resulted in a consistent (50%) reduction in degree of alloantigen presentation by Langerhans cells to T cells. Inhibition was 77% of that produced by the addition of anti-LFA-1. These data indicate that ICAM-3 is constitutively expressed by Langerhans cells and is a major ligand for LFA-1 on CD4 + T cells during their response to Langerhans cells. Because fresh Langerhans ceils constitutively express little ICAM-1. whereas ICAM-3 is constitutively expressed at high levels, it would appear that 1CAM-3 is the dominant functional ICAM on in situ Langerhans cells in the normal epidermis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73969/1/j.1365-2133.1995.tb06911.x.pd

Immunological mechanisms involved in psoriasis

The past decade has borne witness to tremendous advances in our knowledge of the pathogenesis of psoriasis and the weight of evidence is now on the side of the T cell as being an integral mediator of this process. Advances in molecular technology have enabled direct in vivo measurement of cytokines and, although no animal model exists for the study of psoriasis, the use of cyclosporine has served as an excellent investigatory tool. The utilization of therapeutics to study psoriatic mechanisms is an unusual approach in that one must derive conclusions from disappearance of measurable factors such as cytokines and assume that these same factors are vital to the initiation and maintenance of a psoriatic plaque. Studying disease evolution using the Koebner phenomenon or relapse following treatment would supply a more accurate picture of initiating events. Based on the immune hypothesis, therapeutic modalities which are now entering the arena include T cell vaccination, particularly if psoriasis-specific T cell receptor V β -restricted clones can be isolated from psoriatic plaques.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46935/1/281_2004_Article_BF00200540.pd

Embedding effective depression care: using theory for primary care organisational and systems change

Background: depression and related disorders represent a significant part of general practitioners (GPs) daily work. Implementing the evidence about what works for depression care into routine practice presents a challenge for researchers and service designers. The emerging consensus is that the transfer of efficacious interventions into routine practice is strongly linked to how well the interventions are based upon theory and take into account the contextual factors of the setting into which they are to be transferred. We set out to develop a conceptual framework to guide change and the implementation of best practice depression care in the primary care setting.Methods: we used a mixed method, observational approach to gather data about routine depression care in a range of primary care settings via: audit of electronic health records; observation of routine clinical care; and structured, facilitated whole of organisation meetings. Audit data were summarised using simple descriptive statistics. Observational data were collected using field notes. Organisational meetings were audio taped and transcribed. All the data sets were grouped, by organisation, and considered as a whole case. Normalisation Process Theory (NPT) was identified as an analytical theory to guide the conceptual framework development.Results: five privately owned primary care organisations (general practices) and one community health centre took part over the course of 18 months. We successfully developed a conceptual framework for implementing an effective model of depression care based on the four constructs of NPT: coherence, which proposes that depression work requires the conceptualisation of boundaries of who is depressed and who is not depressed and techniques for dealing with diffuseness; cognitive participation, which proposes that depression work requires engagement with a shared set of techniques that deal with depression as a health problem; collective action, which proposes that agreement is reached about how care is organised; and reflexive monitoring, which proposes that depression work requires agreement about how depression work will be monitored at the patient and practice level. We describe how these constructs can be used to guide the design and implementation of effective depression care in a way that can take account of contextual differences.Conclusions: ideas about what is required for an effective model and system of depression care in primary care need to be accompanied by theoretically informed frameworks that consider how these can be implemented. The conceptual framework we have presented can be used to guide organisational and system change to develop common language around each construct between policy makers, service users, professionals, and researchers. This shared understanding across groups is fundamental to the effective implementation of change in primary care for depressio

Numerical approach to the Schrodinger equation in momentum space

The treatment of the time-independent Schrodinger equation in real-space is an indispensable part of introductory quantum mechanics. In contrast, the Schrodinger equation in momentum space is an integral equation that is not readily amenable to an analytical solution and is rarely taught. We present a numerical approach to the Schrodinger equation in momentum space. After a suitable discretization process, we obtain the Hamiltonian matrix and diagonalize it numerically. By considering a few examples, we show that this approach is ideal for exploring bound-states in a localized potential and complements the traditional (analytical or numerical) treatment of the Schrodinger equation in real-space.Comment: 14 pages, 4 figures, several changes and one figure correctio

Menopause induces changes to the stratum corneum ceramide profile, which are prevented by hormone replacement therapy

Abstract The menopause can lead to epidermal changes that are alleviated by hormone replacement therapy (HRT). We hypothesise that these changes could relate to altered ceramide production, and that oestrogen may have a role in keratinocyte ceramide metabolism. White Caucasian women were recruited into three groups: pre-menopausal (n = 7), post-menopausal (n = 11) and post-menopausal taking HRT (n = 10). Blood samples were assessed for hormone levels, transepidermal water loss was measured to assess skin barrier function, and stratum corneum lipids were sampled from photoprotected buttock skin. Ceramides and sphingomyelins were analysed by ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry. Post-menopausal stratum corneum contained lower levels of ceramides, with shorter average length; changes that were not evident in the HRT group. Serum oestradiol correlated with ceramide abundance and length. Ceramides had shorter sphingoid bases, indicating altered de novo ceramide biosynthesis. Additionally, post-menopausal women had higher sphingomyelin levels, suggesting a possible effect on the hydrolysis pathway. Treatment of primary human keratinocytes with oestradiol (10 nM) increased production of CER[NS] and CER[NDS] ceramides, confirming an effect of oestrogen on cutaneous ceramide metabolism. Taken together, these data show perturbed stratum corneum lipids post-menopause, and a role for oestrogen in ceramide production

Concurrent application of tretinoin (retinoic acid) partially protects against corticosteroid-induced epidermal atrophy

Cutaneous atrophy arising from prolonged use of potent topical corticosteroids has long been a concern. Thus, it would be advantageous to find an agent which protects against atrophy produced by corticosteroids but at the same time does not impair their anti-inflammatory effects. Recent work shows that topical all- trans retinoic acid (tretinoin) prevents skin atrophy in mice treated with topical corticosteroids, but such studies have not been performed in humans. We performed an 8-week clinical, histological and biochemical study to test the ability of tretinoin to enhance efficacy and inhibit atrophogenicity of topical corticosteroids, when used in the treatment of psoriasis. In each of 20 psoriasis patients, one plaque, and its perilesional skin, was treated once daily with betamethasone dipropionate and tretinoin 0 1 , and one plaque, and its perilesional skin, treated with once daily betamethasone dipropionate and tretinoin vehicle. There was no difference in the speed or degree of improvement in plaques treated with either the topical corticosteroid tretinoin combination or with corticosteroid alone. Light microscopy revealed a 19 reduction in epidermal thickness, in corticosteroid-treated perilesional skin, as compared with a slight (1 ) increase in corticosteroid tretinoin-treated perilesional areas (P 0.067). Western blot analysis showed a 55 reduction in procollagen I aminopropeptide in perilesional skin treated with corticosteroid alone, as compared with a 45 reduction in corticosteroid tretinoin-treated perilesional skin. These data indicate that the addition of tretinoin does not impair the efficacy of a topical corticosteroid, in the treatment of psoriasis, and partially ameliorates epidermal atrophy produced by the topical corticosteroid.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75727/1/j.1365-2133.1996.d01-933.x.pd