Large scale study of epidermal recovery after stratum corneum removal: dynamics of genomic response.

The stratum corneum (SC) is a superficial skin compartment that protects the body from the outside environment. Any disturbance of this function induces cascading steps of molecular and cellular repair in the whole epidermis. The aim of this study was to investigate epidermal gene expression following SC removal by tape stripping. Twenty-nine healthy male volunteers were included (27 +/- 4 years old). Tape stripping was processed on one inner forearm, the other unstripped forearm served as a control. Epidermis samples were collected at 2, 6, 19, 30 and 72 h after tape stripping. Trans-epidermal water loss measurements were performed at each step to monitor barrier restoration. Total RNA was extracted from collected epidermis samples and analysed by using DermArray cDNA microarrays. Among 4000 genes under investigation, we found that the expression of 370 genes varied significantly at least once during the time following stripping. Using an original clustering method, the modulated genes were gathered into eight groups. A functional characterization of the clusters enabled us to get a dynamic and global view of the main molecular processes taking place during epidermal recovery.

Analysis of alterations adjacent to invasive squamous cell carcinoma of the penis and their relationship with associated carcinoma.

BACKGROUND: In contrast to vulvar squamous cell carcinoma (SCC), the etiologic factors and precancerous lesions associated with penile carcinoma remain uncertain. OBJECTIVES: To describe the morphologic features of lesions adjacent to invasive penile SCC and their relationship with the associated carcinoma and to compare these associations with vulvar carcinoma. METHODS: This was a retrospective histologic analysis of 68 cases of penile SCC. Adjacent lesions were considered to be premalignant lesions. They were classified as penile intraepithelial neoplasia (PIN), squamous hyperplasia (SH), and lichen sclerosus (LS). PIN cases were divided into two subtypes depending on the extension of atypia throughout the epithelium and, by analogy, with the classification of the vulvar intraepithelial neoplasia (VIN). Thus they were designated as undifferentiated (or bowenoid) PIN, defined by full-thickness atypia throughout the epithelium, and differentiated PIN, characterized by atypia confined to the lower third of the epithelium. SCC subtypes were classified as usual, verrucous, warty (condylomatous), basaloid, and mixed. RESULTS: Undifferentiated PIN was observed in 22 cases; LS was observed in 26 cases. Differentiated PIN and SH (except for two cases) were associated with underlying LS. Undifferentiated PIN was always associated with warty (condylomatous) (4 cases), basaloid (16 cases) or mixed SCC (2 cases), and LS with usual (19 cases) or verrucous SCC (7 cases). LIMITATIONS: This was a retrospective analysis CONCLUSION: This study suggests that, similarly to vulvar carcinoma, penile SCC occurs in association with two types of penile lesions: undifferentiated (or bowenoid) PIN and LS-linked differentiated PIN and/or SH. It appears that the subtype of these carcinomas is related to these adjacent lesions.

Psoriasis: characterization of six different clinical phenotypes.

Until recently, psoriasis was considered as a single disease entity. However, the discovery of major differences between early- or late-onset psoriasis suggests the presence of distinct disease phenotypes which may differ in their pathophysiology and in their treatment responsiveness. The objective of this study was to use exploratory data analysis methods to identify potential clinical psoriasis phenotypes without a priori hypotheses. A prospective questionnaire-based survey collected comprehensive informations on the main clinical characteristics of 1484 psoriatic patients. Six statistically different clusters of clinical symptoms were observed, corresponding at least to six different clinical psoriasis phenotypes. Moreover, discriminant functions allow patients to be assigned to one or other of these phenotypes. Our findings open the way to focus genetic, pharmaco-genetic, pathophysiological and therapeutic studies on more homogenous group of patients.

Inhibition of IkappaB kinase subunit 2 in cutaneous T-cell lymphoma down-regulates nuclear factor-kappaB constitutive activation, induces cell death, and potentiates the apoptotic response to antineoplastic chemotherapeutic agents.

PURPOSE: A key molecular feature of cutaneous T-cell lymphomas (CTCL) is the constitutive activation of the nuclear factor-kappaB (NF-kappaB) transcription factor. We investigated in vitro the effects on CTCL survival and chemoresistance of a specific inhibition of IkappaB kinase subunit 2 (IKK2). EXPERIMENTAL DESIGN: Selective IKK2 inhibition was carried out by transfection of SeAx and MyLa CTCL lines with an inactive form of IKK2 and by exposing these lines and tumor cells from 10 patients with Sézary syndrome (SS) to AS602868, a new IKK2 inhibitor. The constitutive nuclear translocation of NF-kappaB was analyzed by electrophoretic mobility shift assay and confocal microscopy. Apoptosis was determined by Annexin V/propidium iodide-positive staining and mitochondrial transmembrane potential alterations as well as poly(ADP-ribose)polymerase cleavage. The expression of Bcl-2 family oncoproteins and survivin was studied by immunoblotting. RESULTS: Specific IKK2 inhibition resulting from transfection or from incubation with AS602868 allowed a down-regulation of NF-kappaB transcriptional activity. As shown by electrophoretic mobility shift assay and apoptosis assays, AS602868 down-regulated the nuclear translocation of NF-kappaB and induced a potent apoptotic response in CTCL lines and in tumor cells from patients with SS while preserving the viability of both peripheral blood lymphocytes from healthy donors and of nonmalignant T cells from SS patients. Moreover, CTCL death induction by conventional antineoplastic agents etoposide and vincristine was potentiated by AS602868. Finally, AS602868-induced apoptosis of CTCL cells was associated with an up-regulation of Bax dimers and a decrease of survivin. CONCLUSION: These results indicate that IKK2 inhibition represents a promising strategy for the treatment of advanced stages of CTCL.

Solar urticaria successfully treated with intravenous immunoglobulins.

BACKGROUND: Idiopathic solar urticaria (SU) is a rare type of physical urticaria, occurring immediately after exposure to visible or ultraviolet (UV) light. Treatment is based on sun avoidance and on high doses of antihistamines, but is sometimes inefficient. METHODS: We report on a 41-year-old patient with severe SU who was successfully treated with a single course of 2 g/kg of intravenous immunoglobulins (IVIG). RESULTS: A dramatic improvement in UVA and UVB tolerance was rapidly observed, with an increase of up to 10 times the UVA minimal urticarial dose on day 3. The treatment with terfenadine was continued. Healing of photosensitivity was persistent since 100 days after the single course of IVIG, no urticarian reaction was provoked with polychromatic irradiation rising above 8.3 J/cm(2) or after UVA doses rising above 15 J/cm(2). CONCLUSION: Use of IVIG in severe SU can be discussed when high-dose antihistamines are inefficient and quality of life is affected.

An unusual bipolar primary herpes simplex virus 1 infection.

We describe an atypical primary HSV 1 genital infection with bilateral palmar involvement. Two routes of dissemination of HSV are discussed, self-inoculation and blood dissemination. This case highlights the role of HSV 1 in extragenital pustules in the context of sexually transmitted diseases.

Comparative study of stress and quality of life in outpatients consulting for different dermatoses in 5 academic departments of dermatology.

In this study, perceived stress and quality of life were measured with PCV-Metra and SF-12 scales in outpatients consulting for different dermatoses in 5 academic dermatology departments for 5 consecutive days. 658 patients were enrolled in the study. Perceived stress was higher in women and the mental component of their quality of life was more altered. Perceived stress was higher in Paris than in other areas and was respectively 11.4, 10.4, 9.2 and 8.9 for psoriasis, acne, atopic dermatitis and pigmented tumours. Perceived stress was correlated to mental quality of life. Stress was more elevated in people with inflammatory dermatoses than in those with tumours. To our knowledge, this is the first comparative study of both stress and quality of life levels in different dermatoses. Stress levels were lower in people with pigmented tumours, suggesting that they can be used as controls in comparative studies because they can be considered as healthy subjects. On the contrary, patients with psoriasis had a very high level of perceived stress and a deeply altered quality of life.

Clinical value of combined determination of plasma L-DOPA/tyrosine ratio, S100B, MIA and LDH in melanoma.

AIM OF THE STUDY: L-DOPA/tyrosine ratio (an index of tyrosinase activity), melanoma antigens S100B and MIA, lactate deshydrogenase (LDH) and their combinations were evaluated for clinical value as tumour markers in melanoma. METHODS: Blood samples were obtained in 170 melanoma patients (stage I-II: n=57, III: n=54, IV: n=59) at inclusion and in a sub-group of 82 subjects during follow-up for up to 4 years. Laboratory analyses were performed by HPLC (L-DOPA, L-tyrosine), immunoassays (S100B, MIA) and colourimetry (LDH). RESULTS: All markers, except LDH, were elevated in stage IV versus other stages. S100B and MIA highly correlated, especially in stage IV (r(s): 0.849, p<0.001). The combination of L-DOPA/tyrosine ratio with S100B displayed the highest sensitivity/specificity (73/70%) to confirm stage III-IV or stage IV alone (69/75%) (ROC optimised cut-off). Only the L-DOPA/tyrosine ratio significantly increased (+36% over 5 months, p=0.001) during progression from stage I-III to higher stages. S100B, MIA and LDH, but not the L-DOPA/tyrosine ratio, responded to progression towards death in stage IV. All markers exhibited a prognostic value in deceased patients (n=44); S100B and MIA were the best predictors of survival time by Cox proportional-hazards regression. CONCLUSION: The combination of plasma L-DOPA/tyrosine ratio and S100B appears an attractive approach for the biological follow-up of melanoma patients.

Accuracy of standard dermoscopy for diagnosing scabies.

BACKGROUND: Scabies is a contagious skin infestation caused by the human mite Sarcoptes scabiei. The usual reference method for definitive diagnosis is ex vivo identification of the mite with microscopic examination of skin scrapings. We compared diagnostic accuracy of in vivo dermoscopic (DS) mite identification using a pocket handheld low-magnification DS with the reference method. METHODS: We conducted a prospective, nonrandomized, evaluator-blinded, noninferiority study to compare sensitivities (main outcome) and other diagnostic properties of DS and microscopic examination of skin scrapings. Among 756 patients with a presumptive diagnosis of scabies consulting in one center, 238 were sequentially submitted to the two diagnostic procedures. Three dermoscopists (one expert, two inexperienced) were involved. Diagnostic strategies using clinical skills only, DS results, and a combination of both were compared. RESULTS: Sensitivities were 91% (95% confidence interval: 86-96) for DS and 90% (95% confidence interval: 85-96) for microscopic examination of skin scrapings (P = .005 for noninferiority). Specificities were 86% (95% confidence interval: 80-92) for DS and 100% (by definition) for microscopic examination of skin scrapings. DS sensitivities were similar for the expert and inexperienced dermoscopists, whereas differences were observed in specificities. However, diagnostic accuracy of inexperienced dermoscopists steadily increased during the study. Compared with clinical-based, DS-based treatment decision rule minimized the number of false-positive and false-negative findings, whereas a treatment decision rule based on combination of clinical presumption and DS result drastically reduced the number of patients with scabies left untreated. LIMITATIONS: There is no definitive standard for ruling out the diagnosis of scabies. CONCLUSIONS: Standard DS with a handheld DS is a useful tool for diagnosing scabies, with high sensitivity, even in inexperienced hands. It greatly enhances clinical skills for making treatment decisions.

Expression, subcellular localization and cytokinic modulation of Toll-like receptors (TLRs) in normal human keratinocytes: TLR2 up-regulation in psoriatic skin.

The aim of the research described here was to investigate the expression of Toll-like receptors (TLRs) in normal human keratinocytes, to study its modulation by proinflammatory cytokines, and to characterize the function of the latter within the epidermis. Our results demonstrate that normal human keratinocytes may present an intra-cytoplasmic expression of TLR2, TLR3, and TLR4. Exposure of keratinocytes to IFN-gamma and TNF-alpha increased intra-cytoplasmic expression and led to partial translocation at the cell surface. Keratinocyte activation by TLR2, TLR3, and TLR4 ligands led to the nuclear translocation of NF-kappab and the release of proinflammatory cytokines TNF-alpha and IL-8. In immunochemistry analysis, psoriatic skin showed a strong over-expression of TLR2 in the epidermis compared with normal skin. Our results thus demonstrate large TLR expression in keratinocytes and the functionality of TLRs 2, 3, and 4. TLR2 over-expression in psoriatic skin provides new insights into TLR implication in the pathogenesis of psoriasis, through inappropriate stimulation by infectious or endogen ligands.

Once-daily rupatadine improves the symptoms of chronic idiopathic urticaria: a randomised, double-blind, placebo-controlled study.

This randomised, double-blind, placebo-controlled, parallel-group, international, dose-ranging study investigated the effect of treatment with rupatadine 5, 10 and 20 mg once daily for 4 weeks on symptoms and interference with daily activities and sleep in 12-65 years-old patients with moderate-to-severe chronic idiopathic urticaria (CIU). Rupatadine 10 and 20 mg significantly reduced pruritus severity by 62.05% and 71.87% respectively, from baseline, over a period of 4 weeks compared to reduction with placebo by 46.59% (p < 0.05). Linear trends were noted for reductions in mean number of wheals and interference with daily activities and sleep with rupatadine 10 and 20 mg over the 4-week treatment period. The two most frequently reported AEs were somnolence (2.90% for placebo, 4.29% for 5 mg-, 5.41% for 10 mg- and 21.43% for 20 mg-rupatadine-treated group) and headache (4.35% for placebo, 2.86% for 5 mg-, 4.05% for 10 mg- and 4.29% for 20 mg-rupatadine-treated group). These findings suggest that rupatadine 10 and 20 mg is a fast-acting, efficacious and safe treatment for the management of patients with moderate-to-severe CIU. Rupatadine decreased pruritus severity, in a dose- and time-dependent manner.

MC1R and PTCH gene polymorphism in French patients with basal cell carcinomas.

In this study, we assessed the role of melanocortin 1 receptor (MC1R) variants and of two patched (PTCH) polymorphisms (c.3944C>T (P1315L), insertion 18 bp IVS1-83) as risk factors for basal cell carcinoma (BCC) in the French population. The population investigated comprised 126 BCC patients who were enrolled on the basis of specific criteria (multiple and/or familial BCC and/or onset before the age of 40 years and/or association with another tumor)--and 151 controls matched for ethnicity, age, and sex. MC1R variants appeared as a moderate risk factor for BCC (odds ratio (OR) for one and two variants, 2.17 [1.28-3.68] and 7.72 [3.42-17.38], respectively), independently of pigmentation characteristics (OR = 2.53 [1.34-4.8]). Interestingly, in addition to the predictable red hair color (RHC) alleles, two non-RHC alleles (V60L and V92M) were also closely associated with BCC risk (OR 3.21 [1.91-5.38] and 2.87 [1.5-5.48], respectively), which differs from the situation in the Celtic population. In addition, the PTCH c.3944C/C genotype was also associated with BCC risk (OR 1.94 [1.2-3.1]), especially in the subgroup of patients with multiple tumors (OR 2.16 [1.3-3.6]). Thus, our data show that MC1R and PTCH variants are associated with BCC risk in the French population. We further suggest that assessing MC1R and PTCH status could be useful, combined with the assessment of clinical risk factors, in identifying high-risk patients to be targeted for prevention or more rigorous surveillance.

A prospective study of upper aerodigestive tract manifestations of mucous membrane pemphigoid.

We conducted a prospective study between 1995 and 2002 to investigate nose and throat (NT) manifestations of mucous membrane pemphigoid (MMP). One hundred ten consecutive patients with clinical, histologic, and immunologic criteria of MMP were seen in 2 referral centers for bullous diseases. They were systematically asked about the existence of persistent NT symptoms. Patients who had any were examined with a flexible nasopharyngolaryngoscope by the same otorhinolaryngologist. When possible, NT mucous membrane (MM) biopsies were taken for direct immunofluorescence (IF) assays to determine lesion specificity. Thirty-eight (35%) patients (23 F/15 M; mean age, 58.5 yr) had the following NT symptoms: 35 (92%) nasal, 19 (50%) pharyngeal, and 10 (26%) laryngeal. Five (13%) had acute dyspnea. Thirty-three (87%) of the 38 symptomatic patients had lesions at physical examination: 30 (79%) nasal, 6 (16%) pharyngeal, and 19 (50%) laryngeal. Laryngeal involvement was asymptomatic in 11 patients. Lesions were mainly atrophic rhinitis and oropharyngeal and epiglottal erosions. Nasal valves, choanae, pharynx, and/or larynx were severely scarred in 7 (18%) patients, causing the death of 3. Direct IF showed malpighian epithelium associated with linear immune deposits (IgG, IgA, or C3) along the chorioepithelial junction in all 18 biopsies performed, including those of 4 symptomatic patients without lesions at physical examination. The presence of severe ophthalmologic lesions (p = 0.02) and > or =3 sites involved other than NT (p = 0.02) were predictive of laryngeal involvement. In contrast, laryngeal symptoms, disease duration, HLA DQB1*0301, and smoking were not significantly associated with laryngeal lesions. In conclusion, at least 35% of MMP patients had NT involvement. Atrophic rhinitis was the most frequent lesion. The most severe were the laryngeal lesions that were significantly associated with severe ocular involvement and disseminated disease, and could be fatal. Our results highlight the necessity of a multidisciplinary approach to MMP management to assure early diagnosis of NT involvement, to guide therapeutic choices, and to improve patient survival and functional outcomes.

Skin lightening and its complications among African people living in Paris.

BACKGROUND: Complications caused by skin lightening practices have not been systematically studied in Europe. OBJECTIVE: Our aim was to assess the complications of skin lightening among people of African descent living in Paris. METHODS: This was a descriptive study. All patients presenting with complications from skin lightening procedures underwent a complete clinical examination and were questioned about their practice. RESULTS: Forty-six patients from various African countries (39 women, 7 men) presented with skin changes suggestive of side effects from skin lightening practices. The complications seemed mainly related to the use of clobetasol and hydroquinone. LIMITATIONS: The selection bias does not allow assessment of uncomplicated skin lightening. CONCLUSION: Complications arising from skin lightening practices represent a significant health problem for people of African descent living in Paris.

[Psoriasis: evolution and revolution]. / Le psoriasis: évolution et révolution.

Psoriasis is a model disease in dermatology. It is a common disease that affects at least 2 to 3 % of the population. It is an illness characterized by an excessive reaction of the skin, in term of proinflammatory cytokines release, to no specific attacks: these attacks can be immunological, mechanical, metabolic, drug-induced or psychological. This excessive reaction is characterized by epidermal proliferation combined with incomplete terminal differentiation, as well as an inflammatory response responsible for the chronic nature of the lesions. The way to understand psoriasis is therefore to reach a better appreciation of the messages that enable the skin cells to initiate an inflammatory response, and by better understanding the way in which the inflammatory cells responsible for innate and acquired immune responses are capable of bringing about proliferation and abnormal epidermal differentiation. Taking an interest in psoriasis is therefore taking an interest in all facets of skin physiology and in all the ways the skin reacts to attacks from the environment. Every year for more than thirty years, more than 300 publications have endeavoured to explore one aspect or another of psoriasis from a clinical, epidemiological, physiopathological or therapeutic point of view. There is no new technique for observing the skin that has not been immediately applied to the study of psoriasis - which is privileged to enjoy the reflected progress made in dermatology. Nor has psoriasis remained untouched by whims of fashion, all manner of scenarios having been suggested to explain it, right from a scarring disease to an autoimmune illness through a genetic or psychosomatic disorder. Psoriasis is at the origin of a medical revolution mounted to supplement and enhance the effectiveness of evidence-based medicine ; it is the "patient-centred medicine". Psoriasis only exceptionally jeopardizes life. Conversely, it is a disease that does affect quality of life. The patient alone must be the judge of his or her quality of life, and it is therefore up to the patient, not the doctor, to gauge the severity of psoriasis and hence decide on reasonable therapeutic indications. Psoriasis, then, cannot be treated without placing the patient, not the illness, at the centre of therapeutic negotiations. The 20th century has seen the disease targeted by boundless efforts ; the 21st century will see the development of medical techniques that allow the patient, in all its complexity, to be positioned at the centre of therapeutic efforts. This revolution began in dermatology, centring around psoriasis, and is spreading progressively to all chronic disorders and all disciplines. New quite interesting therapeutic weapons are available from a few months making possible to better adjust the therapeutic strategies of psoriasis to the patients needs but they are expensive opening again the debates on the limit of the social solidarity.

Genodermatoses care in the Mediterranean region: a new initiative.

This article looks at a regional initiative to improve the quality of medical and social care for patients with severe skin diseases. The programme called "Genodermatoses and the Mediterranean--Together for a better care" aims to use shared international experience to alleviate the painful aspects of this condition and the methods used to facilitate this.

[Atopic dermatitis in adults]. / Eczéma atopique de l'adulte "lorsque l'EBM n'existe pas encore".

Eczema atopic is rare in adult. It is either a relapse caused by a modification of the environment (stress, cutaneous irritation, contact allergy), or the persistence since the early childhood of an atopic eczema usually severe and worsened by the use of a discontinuous topical steroids. The therapeutic effectiveness is based on the 'patient based medicine' approach, on the daily use of gradually diluted topical steroids, on the judicious use of topical immunosuppressive drugs like Protopic, and sometimes on the temporary or prolonged use of systemic drugs like ciclosporine, methotrexate, or mycophenolate mofetil.

Differential molecular profiling between skin carcinomas reveals four newly reported genes potentially implicated in squamous cell carcinoma development.

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are skin tumors with different invasive potential. In this work, we analysed mRNA differential expression between seven BCC and five SCC and their normal skin counterparts using 1176 cDNA macroarrays and verification by RT-PCR to identify genes modulated in each tumor type. We identified 37 genes commonly modulated in both tumors and four genes specifically modulated in SCC. Among these latter RhoC and EMMPRIN genes seem to be of particular interest and could participate in SCC aggressivity.

ESHAP for primary cutaneous T-cell lymphomas: efficacy and tolerance in 11 patients.

Systemic multiagent hemotherapy has been used to treat aggressive forms of primary cutaneous T-cell lymphomas (CTCL) with controversial results. Our objective was to retrospectively assess efficacy and toxicity of ESHAP (etoposide, cisplatin, high-dose aracytine, methylprednisolone) in patients with advanced CTCL. A total of 11 patients with aggressive primary CTCL, treated with the ESHAP protocol between 1995 and 2002, were studied. Two patients achieved complete remissions lasting 30+ and 6+ months, seven had partial remissions of short duration, one had stable disease and one experienced disease progression. ESHAP was poorly tolerated because of prolonged myelosuppression (91%) and infectious complications (82%). Our results suggest that ESHAP has a poor risk/benefit ratio in advanced CTCL because of the low number of complete remissions, the short duration of partial remissions and its high-grade toxicity.