Fifteen-minute consultation: Approach to the adolescent presenting with hirsutism.

Hirsutism, unwanted terminal hair growth in androgen-dependent areas, is a common presentation to general paediatricians, dermatologists and endocrinologists. Polycystic ovarian syndrome is the most common cause but can be challenging to diagnose in young people due to the significant overlap of features with the healthy adolescent population. There are other rare, but important, causes to consider such as non-classic congenital adrenal hyperplasia and androgen-secreting tumours. Hirsutism carries a significant psychological burden for those living with it. This 15 min consultation piece describes the causes of hirsutism, introduces a novel assessment tool and suggests an approach to investigations and management, including signposting to psychological support.

Diagnostic utility of PELP1 and GATA3 in primary and metastatic triple negative breast cancer / Utilidad diagnóstica de PELP1 y GATA3 en cáncer de mama triple negativo primario y metastásico

Introduction: Metastasis from Triple-negative breast cancer (TNBC) is a significant cause of morbidity and death and also presents a diagnostic challenge. There are significant therapeutic implications for making a correct and timely diagnosis of metastatic TNBC because the tumors may respond to chemotherapy. PELP1 expression has been reported recently in BC but is poorly studied in the diagnosis of primary and metastasis of TNBC.ObjectivesThe aim of the present study is to assess the diagnostic utility of PELP1and compare it with GATA3, the most commonly used in our practice for breast cancer.MethodsPELP1 and GATA3 were assessed by immunohistochemistry in formalin fixed paraffin embedded tissue blocks of 30 cases of primary TNBC and 15 cases of metastatic TNBC at the Pathology department, Zagazig University, Egypt.ResultsThe immunohistochemical expression of PELP1 revealed a higher frequency of expression than GATA3 in both primary and metastatic TNBC. PELP1 revealed a (96.67%) positive expression rate in primary TNBC and a (86.67%) positive in metastatic TNBC. In comparison to GATA3, revealed (53.33%) positive expression rate in primary TNBC and (60%) positive in metastatic TNBC. Furthermore, the majority of the PELP1 positive cases showed diffuse strong staining, making observation of the staining easy and suggested that PELP1 may be a molecular target for TNBC therapy. We predict that this analysis will shed light on PELP1's significance in TNBC.ConclusionIn comparison to GATA3, PELP1 protein expression is substantially higher in diagnosis of primary and metastatic TNBC. (AU)

Introducción: La metástasis del cáncer de mama triple negativo (TNBC) es una causa importante de morbilidad y muerte y también presenta un desafío diagnóstico. Existen importantes implicaciones terapéuticas para hacer un diagnóstico correcto y oportuno de TNBC metastásico porque los tumores pueden responder a la quimioterapia. La expresión de PELP1 se ha informado recientemente en BC, pero está poco estudiada en el diagnóstico de metástasis primaria y de TNBC.ObjetivosEl objetivo del presente estudio es evaluar la utilidad diagnóstica de PELP1 y compararlo con GATA3, el más utilizado en nuestra práctica para el cáncer de mama.MétodosPELP1 y GATA3 se evaluaron mediante inmunohistoquímica en bloques de tejido embebidos en parafina fijados con formalina de 30 casos de TNBC primario y 15 casos de TNBC metastásico en el departamento de Patología de la Universidad de Zagazig, Egipto.ResultadosLa expresión inmunohistoquímica de PELP1 reveló una mayor frecuencia de expresión que GATA3 en TNBC tanto primaria como metastásica. PELP1 reveló una tasa de expresión positiva (96,67%) en TNBC primario y un (86,67%) positivo en TNBC metastásico. En comparación con GATA3, reveló (53,33%) tasa de expresión positiva en TNBC primaria y (60%) positiva en TNBC metastásica. Además, la mayoría de los casos positivos de PELP1 mostraron una tinción fuerte difusa, lo que facilitó la observación de la tinción y sugirió que PELP1 puede ser un objetivo molecular para la terapia de TNBC. Predecimos que este análisis arrojará luz sobre la importancia de PELP1 en TNBC.ConclusiónEn comparación con GATA3, la expresión de la proteína PELP1 es sustancialmente mayor en TNBC primaria y metastásica. (AU)

Patch testing is a useful investigation in children with eczema.

BACKGROUND: Allergic contact dermatitis in children is less recognized than in adults. However, recently, allergic contact dermatitis has started to attract more interest as a cause of or contributor to eczema in children, and patch testing has been gaining in recognition as a useful diagnostic tool in this group. OBJECTIVES: The aim of this analysis was to investigate the results of patch testing of selected children with eczema of various types (mostly atopic dermatitis) attending the Sheffield Children's Hospital, and to assess potential allergens that might elicit allergic contact dermatitis. PATIENTS AND METHODS: We analysed retrospectively the patch test results in 110 children aged between 2 and 18 years, referred to a contact dermatitis clinic between April 2002 and December 2008. We looked at the percentages of relevant positive reactions in boys and girls, by age groups, and recorded the outcome of treatment following patch testing. RESULTS: One or more positive allergic reactions of current or past relevance was found in 48/110 children (44%; 29 females and 19 males). There were 94 allergy-positive patch test reactions in 110 patients: 81 had a reaction of current or past relevance, 12 had a reaction of unknown relevance, and 1 had reaction that was a cross-reaction. The commonest allergens with present or past relevance were medicaments, plant allergens, house dust mite, nickel, Amerchol® L101 (a lanolin derivative), and 2-bromo-2-nitropropane-1,3-diol. However, finding a positive allergen was not associated with a better clinical outcome. CONCLUSIONS: We have shown that patch testing can identify relevant allergens in 44% of children with eczema. The commonest relevant allergens were medicament allergens, plant allergens, house dust mite, nickel, Amerchol® L101, and 2-bromo-2-nitropropane-1,3-diol. Patch testing can be performed in children as young as 2 years with the proper preparation.

Epidermal barrier dysfunction in atopic dermatitis.

Atopic dermatitis (AD) is a multifactorial, heterogenous disease that arises as a result of the interaction between both environmental and genetic factors. Changes in at least three groups of genes encoding structural proteins, epidermal proteases, and protease inhibitors predispose to a defective epidermal barrier and increase the risk of developing AD. Loss-of-function mutations found within the FLG gene encoding the structural protein, filaggrin, represent the most significant genetic factor predisposing to AD identified to date. Enhanced protease activity and decreased synthesis of the lipid lamellae lead to exacerbated breakdown of the epidermal barrier. Environmental factors, including the use of soap and detergents, exacerbate epidermal barrier breakdown, attributed to the elevation of stratum corneum pH. A sustained increase in pH enhances the activity of degradatory proteases and decreases the activity of the lipid synthesis enzymes. The strong association between both genetic barrier defects and environmental insults to the barrier with AD suggests that epidermal barrier dysfunction is a primary event in the development of this disease. Our understanding of gene-environment interactions should lead to a better use of some topical products, avoidance of others, and the increased use and development of products that can repair the skin barrier.

Randomized, controlled, single-blind study on use of autologous keratinocytes on a transfer dressing to treat nonhealing diabetic ulcers.

AIM: To compare the rate of healing of diabetic neuropathic ulcers using cultured autologous keratinocytes delivered on chemically defined transfer discs (Myskin) (active treatment) versus healing obtained with cell-free discs (placebo). MATERIALS AND METHODS: After a 4-week lead-in period patients (randomly assigned) received active or placebo treatments weekly for 6 weeks. All patients then received active treatments for a maximum of 12 treatments where required. Altogether, 16 patients with a total of 21 ulcers resistant to conventional therapy were recruited from four specialist diabetic centers in three cities. RESULTS: All 21 ulcers were treated and of these ten healed and eight improved, with two failing to respond (one ulcer was lost due to autoamputation). For analysis according to the study criteria, however, only the 12 patients with 12 index ulcers who completed treatment protocols were eligible - five in the placebo group and seven in the active group. Of these, five ulcers healed completely and seven were reduced by more than 50%. Complete healing took a median of ten active applications. CONCLUSIONS: Repeated regular applications of the patient's keratinocytes, delivered on the carrier dressing, initiated wound healing in ulcers resistant to conventional therapy, with 18 out of 21 ulcers responding. The healing observed did not appear attributable to patient recruitment or the cell-free carrier dressing but to the delivery of the cultured cells.

New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions.

Atopic dermatitis (AD) is a multifactorial, chronic inflammatory skin disorder in which genetic mutations and cutaneous hyperreactivity to environmental stimuli play a causative role. Genetic mutations alone might not be enough to cause clinical manifestations of AD, and this review will propose a new perspective on the importance of epidermal barrier dysfunction in genetically predisposed individuals, predisposing them to the harmful effects of environmental agents. The skin barrier is known to be damaged in patients with AD, both in acute eczematous lesions and also in clinically unaffected skin. Skin barrier function can be impaired first by a genetic predisposition to produce increased levels of stratum corneum chymotryptic enzyme. This protease enzyme causes premature breakdown of corneodesmosomes, leading to impairment of the epidermal barrier. The addition of environmental interactions, such as washing with soap and detergents, or long-term application of topical corticosteroids can further increase production of stratum corneum chymotryptic enzyme and impair epidermal barrier function. The epidermal barrier can also be damaged by exogenous proteases from house dust mites and Staphylococcus aureus. One or more of these factors in combination might lead to a defective barrier, thereby increasing the risk of allergen penetration and succeeding inflammatory reaction, thus contributing to exacerbations of this disease.

Predisposition to sensitive skin and atopic eczema.

Genes that control the thickness of our skin and its vulnerability to chemicals in the environment play a role in the development of contact dermatitis and atopic eczema. Sensitive skin manifests itself as a burning, stinging or itching sensation following the application of topical products such as soap, bubble baths and cosmetics. The skin may become red and dry after repeated application of these products. New insights into the skin barrier can help us improve treatment of the skin and prevent problems associated with atopic eczema and sensitive skin

Dopa oxidase activity in the hair, skin and ocular melanocytes is increased in the presence of stressed fibroblasts.

We previously reported that mesenchymal cells (dermal fibroblasts and dermal papilla cells) can stimulate dopa oxidase activity in the skin melanocytes. This study extends the investigation of the influence of the fibroblast in a comparative study of melanogenesis in melanocytes from the hair, the skin and the eye. Culture of melanocytes with normal proliferative dermal fibroblasts slightly increased dopa oxidase activity of the hair, skin and ocular melanocytes (by 17, 11 and 28%, respectively), but co-culture with fibroblasts recovering from storage in liquid nitrogen or growth-arrested by means of gamma radiation showed much greater effects. Most dramatic results were obtained with fibroblasts, which had been both gamma-irradiated and then frozen in liquid nitrogen, where increases in dopa oxidase activity of 125, 227 and 185% for melanocytes of the hair, the skin and the eye, respectively, were seen. Experiments by using transwell cultures of melanocytes and fibroblasts and by using fibroblast-conditioned medium showed that a large proportion of this fibroblast influence could be mediated by diffusible factors, of which a good proportion was attributable to basic Fibroblast Growth Factor (bFGF). The addition of bFGF significantly increased dopa oxidase activity of the skin melanocytes, when fibroblasts were present, but not in their absence. These data show that fibroblasts in vitro, particularly when deliberately stressed, have the ability to increase dopa oxidase activity in melanocytes of the hair, the skin and the eye and further suggest that this effect is mediated by bFGF acting in combination with some other fibroblast-derived factors.

Inhibition of tumor necrosis factor-alpha stimulated NFkappaB/p65 in human keratinocytes by alpha-melanocyte stimulating hormone and adrenocorticotropic hormone peptides.

Alpha-melanocyte stimulating hormone (alpha-MSH) has pigmentary, anti-inflammatory, antipyretic, and general immunomodulatory roles. It can oppose several cytokines including tumor necrosis factor-alpha in a number of tissues, including skin. We have previously shown that alpha-MSH can inhibit tumor necrosis factor-alpha stimulated intercellular adhesion molecule 1 upregulation and nuclear factor kappaB (NFkappaB) transcription factor activation in melanocyte and melanoma cells. It is thought, however, that this MSH biology may also extend to other cells of the skin and in this study we extend our work to keratinocytes. We have investigated in detail the ability of three alpha-MSH peptides to inhibit tumor necrosis factor alpha stimulated NFkappaB activation in nonpigmentary HaCaT keratinocytes (alpha-MSH, L-Lys-L-Pro-L-Val, and L-Lys-L-Pro-D-Val) and two adrenocorticotropic hormone (ACTH) peptides (1-17 and 1-39), reported to be present in skin tissue. NFkappaB/p65 activation was analyzed by electrophoretic mobility shift assay and immunofluorescent microscopy. alpha-MSH, L-Lys-L-Pro-L-Val, and L-Lys-L-Pro-D-Val all significantly inhibited tumor necrosis factor alpha stimulated NFkappaB activation, whereas ACTH 1-17 and 1-39 did not, in the HaCaT keratinocytes. MSH peptides and ACTH 1-39 were effective, however, at inhibiting NFkappaB activation in normal human keratinocytes. Immunolabeling of inhibitor kappaBalpha of NFkappaB (IkappaBalpha) revealed an abnormal localization to the nucleus of HaCaT cells, which was unaffected by MSH/ACTH peptides. In contrast, normal human keratinocytes showed a normal IkappaBalpha distribution that responded to MSH/ACTH with nuclear translocation. Our data support previous work on the role of MSH/ACTH peptides as immunomodulatory/anti-inflammatory regulators, and extend this work to keratinocytes identifying a novel IkappaBalpha mechanism and extends findings to ACTH peptides, identifying an abnormal IkappaBalpha mechanism in the immortal HaCaT versus normal keratinocyte.