British Journal of Dermatology

Velasco, P.; Lange‐Asschenfeldt, B.

doi: 10.1046/j.1365-2133.2002.05073.xpmid: 12410692

Summary Neovascularization is vital for the growth of tumours, providing a lifeline for sustenance and waste disposal. Tumour vessels can grow by sprouting, intussusception or by incorporating bone marrow‐derived endothelial precursor cells into growing vessels. Recent advances in vascular biology have identified some key factors that control vascular growth, and have led to the hypothesis that in normal tissues vascular quiescence is maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. In contrast, increased secretion of angiogenic factors and the down‐regulation of endogenous angiogenesis inhibitors induce tumour angiogenesis. Vascular quiescence in the skin seems to be primarily maintained by a balance between the endogenous angiogenesis inhibitors thrombospondin 1 and thrombospondin 2 and the potent proangiogenic factor vascular endothelial growth factor A. Inhibiting tumour growth by controlling angiogenesis is an intriguing approach with great potential for the treatment of vascular tumours such as haemangioma, Kaposi's sarcoma and solid cutaneous tumours such as squamous cell carcinoma, melanoma and basal cell carcinoma. In this review, the role of angiogenesis and more recent topics such as lymphangiogenesis in cutaneous tumour growth, invasion and metastasis will be discussed.

Oguchi, M.; Sagara, J.; Matsumoto, K.; Saida, T.; Taniguchi, S.

doi: 10.1046/j.1365-2133.2002.04948.xpmid: 12410693

Summary  Background It has been suggested that A‐ and B‐type lamins, proteins of the nuclear lamina, play important roles in the morphogenesis of the nucleus and cellular differentiation.Objectives To investigate the expression of these nuclear proteins in normal skin and some keratinocytic tumours of the skin.Methods We examined by means of immunohistochemistry the expression of lamins in normal skin and some keratinocytic tumours of the skin, such as squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Bowen's disease, solar keratosis, keratoacanthoma and seborrhoeic keratosis.Results In normal skin, A‐type lamin was expressed in all epidermal cells, but the expression level of B‐type lamins diminished from basal cells to granular cells. In keratinocytic tumours, the expression of A‐type lamin was reduced, especially in BCCs, Bowen's disease and poorly differentiated SCCs. B‐type lamins were reduced and exhibited heterogeneous expression patterns in most well‐differentiated SCCs and keratoacanthomas. Antibodies against B‐type lamins stained only peripheral cells of the lobules in keratoacanthomas, while no regular staining patterns were seen in well‐differentiated SCCs.Conclusions Lamin expression depends on the differentiation and transformation of the human skin. This finding should be useful for the diagnosis of keratinocytic tumours.

Oishi, Y.; Fu, Z.W.; Ohnuki, Y.; Kato, H.; Noguchi, T.

doi: 10.1046/j.1365-2133.2002.04949.xpmid: 12410694

Summary  Background Glucocorticoids are widely used for the treatment of various diseases, despite known side‐effects such as skin atrophy. Many studies have shown that the status of collagen fibres in the skin is affected by glucocorticoid treatment. However, the molecular mechanism underlying the alteration of collagen metabolism in the skin by glucocorticoid treatment remains unknown.Objectives To characterize the molecular mechanisms related to the deterioration of the dermis in response to glucocorticoids, the status of two major types of collagen, collagenase, and tissue inhibitors of metalloproteinases (TIMPs) in the dorsal skin of rats was studied at the protein and mRNA levels.Methods Samples of rat dorsal skin were obtained after daily (1 mg kg−1) subcutaneous injections of dexamethasone (DEX) for 8 days. mRNA levels of two types of collagen and of TIMPs were measured by a lysate RNase protection assay. mRNA levels of collagenase were measured by a quantitative polymerase chain reaction. Protein levels of collagen and collagenase were measured by an immunoblot analysis.Results Levels of type I tropocollagen and type III tropocollagen were drastically reduced in response to DEX. The effects of DEX treatment were more severe on type III than type I collagen: it also produced a significant decrease in fibril collagen of type III collagen. DEX treatment was found to decrease both active and latent forms of collagenase as well as its mRNA levels. Among TIMPs, mRNA levels of TIMP‐1 and TIMP‐2 were decreased in response to DEX treatment, whereas those of TIMP‐3 were not affected.Conclusions These results suggest that DEX treatment strongly interferes with both the synthesis and degradation of type I collagen and, more drastically, type III collagen, the molecule that is known to play a major role in the initiation of wound healing. The present study may provide a molecular basis for the deterioration of skin function, impaired wound healing, and skin atrophy caused by glucocorticoid treatment.

Downie, M.M.T.; Sanders, D.A.; Kealey, T.

doi: 10.1046/j.1365-2133.2002.04946.xpmid: 12410695

Summary  Background Acne lesions spontaneously remit, but the mechanism of this remission has not been elaborated. It is known, however, that the remission is associated with a de‐differentiation of sebocytes, causing a cessation of sebum secretion specific to that particular pilosebaceous unit. We have previously described the cytokines that will promote in vitro the lesions of acne.Objectives To show that those same cytokines may also promote a de‐differentiation of sebocytes analogous to that seen during remission of some lesions.Methods Human chest sebaceous glands were maintained in vitro as whole organs. We then chronicled the effects of the appropriate cytokines and growth factors on the glandular rates of (i) lipogenesis and (ii) DNA synthesis, as well as on (iii) glandular morphology, (iv) the expression patterns of the proliferation marker Ki‐67, (v) keratinocyte‐specific markers, and (vi) the sebocyte marker epithelial membrane antigen.Results We have shown that the same cytokines that promote comedogenesis (interleukin‐1α), expression of infundibular intercellular adhesion molecule‐1 and human leucocyte‐associated antigen‐DR (tumour necrosis factor‐α and interferon‐γ), and infundibular disruption (epidermal growth factor/transforming growth factor‐α) in human infundibula in vitro, will also inhibit sebaceous lipogenesis in vitro and will also induce, histologically, a de‐differentiation of human sebocytes into a keratinocyte‐like phenotype.Conclusions These results confirm our hypothesis that the cytokines that induce the infundibular changes in acne may also inhibit the secretion of lipid from the sebaceous gland and thus, on diffusing down to the gland, contribute to the remission of the individual lesions. These findings help to explain the known natural history of the disease.

Akiyama, H.; Huh, W‐K.; Yamasaki, O.; Oono, T.; Iwatsuki, K.

doi: 10.1046/j.1365-2133.2002.04962.xpmid: 12410696

Summary  Background Bacteria that adhere to damaged tissues encase themselves in a hydrated matrix of polysaccharides, forming a slimy layer known as a biofilm. This is the first report of detection of glycocalyx production by Staphylococcus aureus using confocal laser scanning microscopy (CLSM) on damaged skin tissues.Objectives To analyse glycocalyx production by S. aureus cells on damaged skin tissues and the influence of polymorphonuclear leucocytes (PMNs) and various antimicrobial agents on its production using CLSM in cyclophosphamide (Cy)‐treated (neutropenic) or non‐Cy‐treated (normal) mice.Methods  S. aureus cells were inoculated on damaged skin tissues in neutropenic or normal mice with or without topical application of antimicrobial agents. S. aureus cells were stained with safranine, and positive staining with fluorescein isothiocyanate‐conjugated concanavalin A was considered to indicate the presence of glycocalyx.Results All S. aureus cells tested on damaged skin tissues formed microcolonies encircled by glycocalyx. The colony counts of S. aureus cells on croton oil dermatitis in normal mice treated with 2% fusidic acid ointment were about 100 times lower than those in neutropenic mice (control).Conclusions As S. aureus cells can generally produce a biofilm on damaged skin tissues, antimicrobial agents may not eradicate S. aureus cells without the help of PMNs. S. aureus glycocalyx may play a crucial role in colonization and adherence to damaged skin tissues.

Moulin, V.; Plamondon, M.

doi: 10.1046/j.1365-2133.2002.04975.xpmid: 12410697

Summary  Background Fetal skin wound healing is characterized by an absence of contraction and scar formation, two important observations associated with adult healing often leading to pathological problems.Objectives We have studied the capacity of adult and fetal human skin fibroblasts to contract collagen gels, collagen being the major structural component of dermal matrix.Methods In parallel with collagen gel contraction studies, we have used fluorescence‐activated cell sorter analysis to study the levels of collagen receptors expressed at the surface of fibroblasts derived from fetal or adult skin samples.Results Strong differences were detected between freshly isolated fetal and adult fibroblasts. Fetal fibroblasts had a very low capacity to contract collagen gel, whereas adult cells significantly contracted gels in the same conditions. The expression of α1, α2 and α3 integrin subunits was also significantly different depending of the donor age: α1 and α3 integrin subunit expression was lower in fetal cells compared with adult cells, whereas α2 integrin subunit expression was higher. When grown in monolayers, adult cells showed rapid changes in their contractile capacity and integrin expression while fetal cells were only affected after several passages.Conclusions These observations indicate that intrinsic differences between fetal and adult fibroblasts can strongly influence the quality of wound repair.

Olsson, M.J.; Juhlin, L.

doi: 10.1046/j.1365-2133.2002.04837.xpmid: 12410698

Summary  Background In vitiligo and piebaldism the lack of melanin in the epidermis is due to the fact that melanocytes are missing. The patients suffer psychologically and the white areas have lost the part of the skin barrier protection normally provided by the melanocytes. Medical treatments are ineffective in many of the patients, and surgical methods have therefore been developed.Objectives It is important to investigate the long‐term results and factors that might influence the outcome of melanocyte transplantations in order to form a basis for guidance in the selection of patients who will benefit most from the treatments.Methods A follow‐up of 132 patients who had been treated by transplantation on 176 occasions in total, 1–7 years previously, was carried out by questionnaires and clinical examinations. We investigated the responses in five types of leucoderma to three different transplantation methods: autologous cultured melanocytes, ultrathin epidermal sheets and basal layer cell suspension.Results Stable types of leucoderma, i.e. segmental vitiligo and piebaldism, responded in most cases with 100% repigmentation, regardless of the surgical method used. For these types of leucoderma surgery seems to be the method of choice. The largest group, vitiligo vulgaris, was thoroughly scrutinized and three statistical models were used to analyse the data. The ultrathin epidermal sheet method gave somewhat better overall results, but was the method that gave the worst outcome in knee and elbow areas, emphasizing the importance of the right choice of method depending on the anatomical location to be treated. Irrespective of the method, fingers and elbows were the most difficult areas to repigment. The trunk and the arms and legs (not including elbows and knees) responded best. Patients with increasing and/or extensive vitiligo vulgaris more often showed incomplete repigmentation. They also had a lower chance of retaining their repigmentation compared with those with less extensive vitiligo. Patients in whom untreated white lesions had increased in recent years tended to respond less well to transplantation compared with patients with unchanged or decreased lesions. Within the vitiligo vulgaris group, patients with short disease duration or with small total vitiligo area responded best to transplantation. The subgroup of vitiligo vulgaris patients with hypothyroidism tend to respond less well to the transplantation and they were generally older at vitiligo onset. This information is of great importance for the selection of patients and when informing about the chances of improvement after transplantation. Slight hyperpigmentation was common, especially when ultrathin epidermal sheets had been used. No scars or indurations were seen in treated areas.Conclusions Transplantations are the methods of choice in stable types of leucoderma. Progressive, widespread vitiligo vulgaris should never be selected for transplantation.

Chen, K‐R.; Toyohara, A.; Suzuki, A.; Miyakawa, S.

doi: 10.1046/j.1365-2133.2002.04933.xpmid: 12410699

Summary  Background Cutaneous manifestations are the most frequent, and often the initial feature of extra‐articular involvement in patients with rheumatoid vasculitis.Objectives The purpose of the study was to evaluate the clinical and histological spectrum of cutaneous vasculitis and the associated systemic involvement in patients with rheumatoid vasculitis.Methods Among 525 patients with rheumatoid arthritis, 20 tissue specimens with histologically proven cutaneous necrotizing vasculitis from 11 patients were investigated by studying the types and levels of affected vessels and related clinical features.Results Small‐vessel vasculitis identified as dermal necrotizing venulitis was found in 10 patients, clinically characterized by palpable purpura, maculopapular erythema, erythema elevatum diutinum and haemorrhagic blisters. Arteritis histologically resembling cutaneous polyarteritis nodosa, clinically characterized by subcutaneous nodules, livedo reticularis, atrophie blanche and deep ulcers was identified in four patients all with systemic complications. Coexistence of venulitis and arteritis was identified in three patients. Different cutaneous vasculitic manifestations often coexisted and recurred in the same patient. Three patients with systemic complications of mononeuritis multiplex (two of three), interstitial pulmonary fibrosis (two of three) and abdominal microaneurysms (one of three) died within 1 year of onset of the cutaneous vasculitis. Immunofluorescence demonstrated vessel wall deposition of IgM and/or complement in six of the seven patients examined.Conclusions Features of cutaneous rheumatoid vasculitis overlapping both the characteristics of cutaneous necrotizing venulitis and cutaneous polyarteritis nodosa together with coexistence of these different type of vasculitis in the same or different lesional skin account for the associated diverse cutaneous vasculitic manifestations. Although dermal venulitis (leucocytoclastic vasculitis) was the most common presentation, the presence of leucocytoclastic vasculitis in rheumatoid patients did not necessarily indicate a favourable prognosis. Associations with mononeuritis multiplex and bowel involvement had a fatal prognosis, while patients with superficial dermal venulitis without other extra‐articular involvement may follow a favourable prognosis.

Gutgesell, C.; Heise, S.; Seubert, A.; Stichtenoth, D.O.; Frölich, J.C.; Neumann, C.

doi: 10.1046/j.1365-2133.2002.04938.xpmid: 12410700

Summary  Background Several laboratory markers have been described to correlate positively with disease activity of atopic dermatitis (AD). These include soluble adhesion molecules and eosinophil granular proteins. Although the correlation of these parameters with the severity and extent of skin involvement has been repeatedly studied in the past, no systematic investigation has been performed over a lengthy period of time. In addition, no subjective disease parameters recorded by the patient have been included in studies dealing with disease activity.Objectives To assess the validity of different objective and subjective parameters [soluble E‐selectin (sE‐selectin), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), eosinophil cationic protein (ECP), urinary nitrate excretion (reflecting endogenous nitric oxide formation) and the patients' impressions of pruritus, sleeplessness and skin status] as markers of AD disease activity.Methods Twenty patients were examined for 1 year and their skin status was evaluated by an established score (SCORAD). sE‐selectin, sVCAM‐1 and ECP were analysed by commercial test kits. Urinary nitrate concentration was measured by gas chromatography‐mass spectrometry. The subjective parameters, pruritus, sleeplessness and impression of skin status, were recorded by the patients on a visual analogue scale.Results In this long‐term trial, only sE‐selectin and the subjective parameters showed a statistically significant correlation with the SCORAD score.Conclusions Our data indicate that basic clinical scoring remains a most effective and relevant method of recording skin disease activity in AD.

Ben‐Gashir, M.A.; Seed, P.T.; Hay, R.J.

doi: 10.1046/j.1365-2133.2002.04965.xpmid: 12410701

Summary  Background The prevalence of atopic dermatitis (AD) has been shown to be higher in London‐born black Caribbean children than in their white counterparts, but little is known about the severity of the disease.Objectives To carry out a longitudinal survey to investigate potential risk factors for AD severity in children. We report our findings in relation to differences in disease severity between white and black children and the effect of inclusion and exclusion of erythema scores on this comparison.Methods The recruited children were identified by their general practitioners (GPs) as having presented with AD, and the U.K. diagnostic criteria for AD were used to verify the diagnosis. Interview and clinical examination of children took place up to four times, 6 months apart. Each time, the same observer assessed AD severity using the SCORAD (SCORe Atopic Dermatitis) index. Potential risk factors and confounders were evaluated with a five‐page questionnaire. Non‐parametric tests were used for statistical analysis and the study participant remained the unit of the analysis.Results In total, 137 children (82 urban and 55 rural) were recruited, and each seen up to four times. This gave 380 observations (69% of an expected 548). The urban population contained 42 (51%) white children, 26 (32%) black children and 14 (17%) from other races. The rural population was entirely white. The 14 children from other races were completely excluded from the statistical analysis. The black children were all born in the U.K. On crude analysis, children with black skin showed a non‐significantly lower risk of severe disease when compared with white children (odds ratio, OR 0·84; 95% confidence interval, CI 0·4–1·76; P = 0·65), while a highly significantly increased risk was found after adjusting for erythema score (OR 5·93; 95% CI 1·94–18·12; P = 0·002). The difference remained significant even after controlling for other potential confounders.Conclusions Black children with AD are about six times more at risk of having severe AD than their white counterparts. GPs and dermatologists should note that erythema can be a misleading indicator of severity in black children. Difficulties of assessment due to skin pigmentation might mean that severe cases are not being detected and appropriately treated.