Biomedical subjects
Publications and source records attributed to H Degreef.
Two elderly female patients with fatal calciphylaxis, despite nearly normal renal functions, occurring during treatment for giant cell arteritis, are described. The possible mechanisms for this association are discussed.
The purpose of this retrospective study was to test whether the initial pattern of clinical presentation of shoe dermatitis could indicate the causative allergen(s) and to estimate the odds on foot dermatitis in patients with a positive patch test versus those with a negative patch-test result. Between 1990 and 2002, 8543 patients were patch tested with the standard series (and additional allergens, if appropriate). Of them, 1168 (14%) had been referred because of foot dermatitis and 474 of these patients (5.5% of the total group) presented a positive reaction to one or more substances related to shoes. We found that 6 standard allergens in the male group and 8 standard allergens in the female group were statistically significant for the shoe dermatitis group. The data showed a relationship between the distribution pattern of the foot lesions and most of the allergens. These results have clinical applications since the gender of the patients and the localization of the foot eruptions can, indeed, indicate what allergen is involved.
Dermatomycoses are among the most widespread and common superficial and cutaneous fungal infections in humans. These typically nonfatal conditions are difficult to treat, especially infections of the nail. Dermatomycoses are caused by filamentous fungi such as Trichophyton, Microsporum or Epidermophyton species. These filamentous fungi have a high affinity for keratin, an important component of hair, skin and nails, which are the primary areas of infection by dermatophytes. The antifungal agents currently marketed for dermatomycoses are mainly inhibitors of ergosterol biosynthesis, except for griseofulvin, which interferes with the cytoplasmic and nuclear microtubular system. Three different types of inhibitors of the ergosterol biosynthetic pathway have been proven to be effective in clinic: the azoles (e.g. topical miconazole and topical/oral ketoconazole, itraconazole and fluconazole), the allylamines (e.g. terbinafine) and morpholines (amorolfine). Even today more effective antifungal azoles with less adverse effects and short-term therapy are deemed necessary to treat dermatophytosis. A promising novel triazole compound in this respect is R126638, which showed potent in vitro and in vivo activity.
BACKGROUND: Discoid lupus erythematosus (DLE) and systemic lupus erythematosus (SLE) are chronic inflammatory diseases of unknown aetiology; the relationship of DLE with SLE has been a subject of debate for many years. OBJECTIVES; To find evidence for systemic immune activation in DLE by analysis of the immunophenotypic profiles of circulating lymphocytes, and to compare these changes with those in patients with SLE. METHODS: The immunophenotypic profile of peripheral blood lymphocyte subsets from 23 DLE patients without clinical or laboratory evidence of systemic disease, 25 SLE patients and 38 healthy donors was characterized by two-colour immunofluorescence flow cytometry analysis. None of the patients was receiving corticosteroid or immunosuppressive treatment. RESULTS: Patients with DLE had increased numbers of circulating HLA-DR+ CD3+ T cells and HLA-DR+ CD4+ T cells, indicating systemic T-cell activation, and an expansion of CD5+ CD19+ B cells. Decreased numbers of T-cell subsets expressing the differentiation markers CD11b and CD16/56, and of CD16/56+ natural killer cells were also found. In SLE, the changes were similar but more pronounced. In addition, a profound CD4+ T-cell lymphopenia and an increase of HLA-DR+ CD8+ T cells were found only in SLE. CONCLUSIONS: Our data provide evidence for systemic activation of the cellular immune system in patients with purely cutaneous DLE. Similarities in the lymphocyte immunophenotypic profiles in patients with DLE compared with SLE suggest that there are common immunopathological processes in these two conditions.
We describe two patients in whom chronic radiodermatitis with therapy-resistant ulceration of the right scapular region developed, following percutaneous coronary intervention with fluoroscopic imaging. Contrary to most reported cases in the literature, which involve numerous cardiac catheterization procedures, in both patients described here the total radiation dose was given during two successive procedures, involving difficult and prolonged coronary intervention with stent implantation. In both cases, local treatment of the ulcerative lesions was insufficient, necessitating excision of the radiodermatitis area and replacement with a skin graft, with good therapeutic result. The incidence of radiodermatitis after percutaneous coronary interventions is rising with the increasing number and complexity of these procedures. The main risk factor is a long duration of fluoroscopy using the same incidence. The skin lesions encompass a wide spectrum, ranging from erythema, telangiectasia, atrophy, hyperpigmentation and hypopigmentation to necrosis, chronic ulceration and squamous cell carcinoma. The lesions can appear from 15 days to 10 years after the procedure. To prevent radiation-induced injury, the radiation dose has to be limited and monitored. Also, careful inspection of the skin at the site of exposure is necessary and the radiographic beam has to be restricted to the smallest field size. A good clinical follow-up at regular intervals is important after long and complicated procedures.
Genital condylomata acuminata are nonmalignant human papillomavirus (HPV)-induced tumors in which HPV types 6 and 11 are most commonly found. Usual treatments for condylomata acuminata are nonspecific and are based on the destruction or removal of infected tissue. These procedures are often painful and are characterized by a high relapse rate. We report here what is to our knowledge the first double-blind, placebo-controlled study of the use of cidofovir, a nucleotide analogue, for the treatment of genital papillomavirus infections. Thirty patients were enrolled in the study; 19 received cidofovir, and 11 received placebo. The median number of warts and the median baseline wart area were comparable for both groups. Nine (47%) of 19 patients in the cidofovir group had a complete response (total healing), compared with 0 of the patients in the placebo group (P=.006). None of the patients in the cidofovir group experienced progression of the disease, compared with 5 (45%) of 11 patients in the placebo group. The side effects recorded for both groups were comparable.
Mutations in the ras gene are key events in the process of carcinogenesis; in particular, point mutations in codon 61 of exon 2 of the N-ras gene occur frequently in malignant melanoma (MM). We searched for point mutations in the N-ras gene in a large series of primary and metastatic MM from 81 different retrospectively selected patients using the very sensitive denaturing gradient gel electrophoresis technique, followed by sequencing. The classical codon 12 and codon 61 mutations were found in 21 and 17% of the cases, respectively. No codon 13 mutation was found. A novel mutation at codon 18 of exon 1, consisting of a substitution of alanine (GCA) by threonine (ACA), was found in 15% of the primary MMs but in none of the metastatic MMs. All of the other cases were free of mutations. Using microdissected cells from distinctive MM growth phases as source of DNA for mutation analysis, this particular N-ras exon 1 mutation at codon 18 was already present in the radial growth phase and preserved throughout the successive growth phases; it was also found in a dysplastic nevi in continuity with a MM, indicating a clonal relationship between both lesions. Our findings also illustrate the clonal relationship between the distinctive growth phases in MM and suggest the codon 18 mutation to occur early in MM development. The MM in patients with this mutation were significantly thinner than those without a codon 18 mutation (P = 0.0257). Statistical analysis, comparing the group of codon 18 patients with the group of patients with the classical mutations and without mutations, revealed a highly significant difference in overall outcome. The cumulative probability of developing metastasis was significantly lower for the group patients with a codon 18 mutation (P = 0.0130). We can thus conclude that this codon 18 mutation identifies a group of patients with better prognosis than patients with melanoma that harbor wild-type sequence or classical activating point mutations in codon 12 or 61. Preliminary nucleotide binding measurements could not detect a difference between wild-type Ras protein and the mutant Ras(A18T) protein. However, for a precise elucidation of the role of the N-Ras(A18T) mutant in melanoma, additional studies aimed to measure the affinity to guanine nucleotide exchange factors and GTPase-activating proteins are needed.
Immunocompromised patients may have severe forms of infections. Since there is an increasing number of patients maintained under immunosuppressive therapy, we will be confronted with increasing frequency with these infectious problems. Effective treatments will be of great value. The case is described of a renal transplant with a giant orf lesion, which continued growing instead of regressing spontaneously as is observed usually. The treatment options in such patients are limited. It was decided to treat the patient with the antiviral drug cidofovir (HPMPC, Vistide. Topical cidofovir treatment resulted in complete regression of the lesion. This case is discussed in the context of the known literature on orf (ecthyma contagiosum).
Endothelins (ETs) exert several functions in human melanocytes, including proliferation, dendrite formation, and melanin synthesis. Among the ET receptors, the non-selective endothelin-B (ETB) receptor is the major receptor in melanocytes and malignant melanoma (MM) cells. In spite of the important role of ETs and their receptors in the growth and differentiation of melanocytes, the distribution and expression levels of ETB receptors in tissue sections of benign and malignant pigment cell lesions is still unknown. We combined immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) to study ETB receptor expression in benign and malignant pigment cell lesions and in normal skin. Immunohistochemistry on paraffin-embedded tissue sections of 159 cases revealed a significant increase in intensity of ETB receptor expression from common nevi over dysplastic nevi and primary MM to metastatic MM. Quantitative PCR using realtime detection on 75 samples confirmed the immunohistochemical results. These data add the ETB receptor to the growing list of tumor progression markers in MM and suggest that ETs play a role in the progression of MM in the skin.
Mutations in the ras genes are key events in the process of carcinogenesis; in particular, point mutations in codon 61 of exon 2 of the N-ras gene occur frequently in cutaneous melanoma. To investigate whether these mutations occur in early or late tumor progression phases, we searched for point mutations in the N- and K-ras genes in 69 primary cutaneous melanoma, 35 metastases, and seven nevocellular nevi in association with cutaneous melanoma. Lesions were microdissected in order to procure pure tumor samples from the distinctive growth phases of the cutaneous melanoma; the very sensitive denaturing gradient gel electrophoresis technique was used to visualize the mutations, and was followed by sequencing. Point mutations in the N-ras gene but not in the K-ras gene were detected on denaturing gradient gel electrophoresis. Twenty-three primary (33%) and nine metastatic (26%) melanomas showed bandshifts for N-ras. In the majority of cases, mutations occurring in early growth phases (i.e., the "intraepidermal" radial growth phase), were preserved in later growth phases (i.e., the invasive radial growth phase, vertical growth phase, and metastatic phase), which proves the clonal relationship between the successive growth phases. In three cases, however, the mutations differed between the distinctive growth phases within the same cutaneous melanoma, due to the occurrence of an additional mutation (especially in codon 61) in a later tumor progression phase. Our approach also permitted us to analyze the mutational status of nevi, associated with cutaneous melanoma. Six out of seven associated nevi carried the same sequence (mutated or wild-type) as the primary cutaneous melanoma, whereas in one case the sequence for N-ras differed between the primary melanoma and the associated nevus. In conclusion, this approach allowed us to demonstrate the clonal relationship between subsequent growth phases of melanoma and associated nevi; our results suggest that N-ras exon 1 mutations preferentially occur during early stages of tumor progression and hence may be involved in melanoma initiation, whereas those in N-ras exon 2 are found preferentially during later stages and hence are more probably involved in metastatic spread of cutaneous melanoma.
A 76-year-old woman, with a history of thymoma, presented with a painful extensive stomatitis, painful paronychia, lichenoid papules on the hands and superficial erosions on the neck and the trunk. Histological examination showed lichenoid changes, acantholytic blister formation and apoptotic keratinocytes. Direct immunofluorescence was positive for IgG both in the epidermal intercellular spaces and along the basement membrane zone. Indirect immunofluorescence was similarly positive in a pemphigus vulgaris pattern. There was only a partial response to intravenous corticoids. These findings allowed the diagnosis of paraneoplastic pemphigus. The diagnostic characteristics, histopathology and the differential diagnosis of this disease are discussed.
Oral contraceptives (OCs) can reduce acne by lowering the production of adrenal and ovarian androgens, by inhibiting 5-alpha-reductase, which in turn, reduces the levels of dihydrotestosterone, and by stimulating sex hormone binding globulin (SHBG), thus reducing the levels of free testosterone. In newer OCs, such as Tricyclen and Diane-35, the progestin component is minimally androgenic and anti-androgenic respectively, thereby enhancing the favorable profile of these products in the treatment of hyperandrogenic disorders, including acne. The efficacy of these agents and their long-term safety profile supports their use in various grades of acne in females: * As adjunctive therapy to topical agents for women with mild non-scarring acne desiring oral contraception * As primary therapy for patients with moderate non-scarring acne in combination with topical therapy and systemic antibiotics * As one of two preferred methods of contraception in patients with scarring and severe inflammatory acne being treated with systemic isotretinoin.
To improve our understanding of the cutaneous vitamin D system, we studied vitamin D receptor (VDR) gene regulation in cultured human keratinocytes. Because VDR and its ligand 1 alpha,25-dihydroxyvitamin D(3) have been implicated in epidermal growth control, we investigated VDR expression as related to cellular proliferation by using different cell cycle synchronization protocols. Keratinocytes, deprived of growth factors, were forced into quiescence and a concomitant loss of VDR expression was observed. Mitogenic stimulation of these G(0) cells however quickly upregulated VDR levels several hours ahead the G(1)-S transition point. Growth arrest at the G(1)-S border by mimosine treatment or at the metaphase by nocodazole also downregulated VDR levels but a restoration of VDR expression was again quickly achieved after reentering the cell cycle. These findings indicate that VDR expression in keratinocytes is restricted to actively cycling cells, but not limited to one particular phase of the cell cycle.
Apigenin, a flavonoid with chemopreventive properties, induces cellular growth arrest, with concomitant inhibition of intracellular signaling cascades and decreased proto-oncogene expression. We report that apigenin potently inhibited vitamin D receptor (VDR) mRNA and protein expression in human keratinocytes without changes in VDR mRNA half-life. Concurrently, downregulation of retinoid X receptor alpha, a dramatic loss of c-myc mRNA, and upregulation of p21(WAF1) took place. Furthermore, a nearly complete suppression of vitamin D responsiveness was observed as estimated by induction of 24-hydroxylase mRNA. The apigenin effect on VDR expression was shared by some other (quercetine and fisetine) but not all tested flavonoids. Interestingly, the apigenin-mediated VDR suppression was counteracted by the NFkappaB inhibitors sodium salicylate and caffeic acid phenethyl ester. The presented results propose suppression of nuclear receptor levels as a novel mechanism whereby flavonoids exert their pleiotropic effects. This study may also contribute to the understanding of the regulation of VDR expression in epidermal keratinocytes.
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To gain more insight in the role of the vitamin D system in epidermal differentiation, we studied the expression of the vitamin D receptor and its heterodimeric partner retinoid X receptor alpha in cultured normal human keratinocytes during squamous differentiation, as triggered by different approaches. Northern and western blot analysis allowed us to investigate mRNA and protein levels of these nuclear receptors and of markers for growth control (c-myc, cyclin D1, p21WAF1) and differentiation (keratinocyte transglutaminase, small proline rich proteins). Growing cells to postconfluence was a potent stimulus for growth arrest and differentiation with concomitant suppression of vitamin D receptor and induction of retinoid X receptor alpha, at both the mRNA and the protein level. These changes could be prevented by concomitant treatment with epidermal growth factor or keratinocyte growth factor. Subjecting the cells to a calcium switch leading to stratification and differentiation lowered vitamin D receptor protein levels without affecting vitamin D receptor mRNA and induced both retinoid X receptor alpha mRNA and protein. Interferon-gamma and the phorbolester 12-O-tetradecanoyl phorbol 13-acetate, two well-known inducers of keratinocyte differentiation, both inhibited vitamin D receptor expression but only interferon-gamma induced retinoid X receptor alpha. The decreased vitamin D receptor expression was accompanied by reduced vitamin D responsiveness (as assessed by 24-hydroxylase mRNA induction) in postconfluent, high calcium, and 12-O-tetradecanoyl phorbol 13-acetate treated keratinocytes but not with interferon-gamma treatment. Taken together, our results associate vitamin D receptor expression with undifferentiated, proliferating keratinocytes, whereas retinoid X receptor alpha expression appears to be related to the differentiated phenotype. Therefore, proliferating and differentiating keratinocytes may be differentially targeted by active vitamin D metabolites.
One to two per cent of primary cutaneous melanomas share clinical features with benign melanocytic and non-melanocytic skin lesions, and even at histology recognition of their malignant nature is problematic, mainly due to the lack of an intraepithelial component, their nodular aspect and the monotonous cell population throughout the lesion. These tumours were termed minimal deviation melanomas (MDMs) by Reed et al. and later naevoid melanomas by Schmoeckel et al. The name MDM suggests the concept of a more favourable outcome for these melanomas that do not (yet) show the typical features of fully evolved lesions able to metastasize, although naevoid melanomas seem to behave like 'common' melanomas. In a retrospective analysis of nine cases of MDM collected from our database and followed for a median duration of 112 months, we faced similar clinical and histological pitfalls and observed local recurrence following marginal resection. Wide excision, even of local recurrence, and therapeutic node dissection could nevertheless provide survival comparable at least to that predicted by mathematical models for patients who initially had optimal treatment.
This review addresses the current concepts about dandruff. The nature, origin and treatments of such skin conditions are scrutinized. The role of Malassezia spp. and other triggering factors is highlighted.