[Verrucous squamous cell carcinoma complicating hypertrophic lichen planus. Three case reports and review of the literature]. / Verruköses spinozelluläres Karzinom auf Lichen ruber hypertrophicus. Drei Fallberichte mit Literaturüberblick.

Lichen planus is a chronic mucocutaneous T-cell-mediated disease, whose cause is still unknown. The first case of lichen planus that transformed into squamous cell carcinoma was reported in 1903. We present three patients in whom squamous cell carcinomas were identified in chronic lichen planus. The world literature includes at least 91 cases, including our three cases. In an epidemiological study, no significant risk of transformation of cutaneous lichen planus into squamous cell carcinomas was found. In contrast, there is a significantly higher risk of malignant transformation in mucosal lichen planus, so that the WHO had graded mucosal lichen planus as a premalignant condition.

[Ulcers following therapy with hydroxyurea. Three case reports and review of the literature]. / Ulzerationen unter Therapie mit Hydroxyharnstoff. Drei Fallberichte mit Literaturüberblick.

Hydroxyurea is frequently used for therapy of myeloproliferative disorders. One cutaneous side-effect is painful, therapy-resistant ulcers which have bizarre configurations and occur at atypical sites for venous ulcers. Improvement or healing often first occurs when hydroxyurea is discontinued. We report on one patient with essential thrombocythemia and two with polycythemia vera, who developed such ulcers during hydroxyurea therapy. In one case, the ulcers developed shortly after hydroxyurea was started. In addition we give a short overview of the current literature.

[Diagnostic pitfall: basal cell carcinoma arising in a therapy-resistant chronic venous ulcer of the lower leg]. / Diagnostische Falle: ein Basalzellkarzinom unter dem Bild eines therapieresistenten Ulcus cruris.

HISTORY: A 96-year-old woman attended our department with an ulcer on the lower leg. It looked typical of an ulcer due to chronic venous insufficiency an had been resistant to treatment for 20 years. INVESTIGATIONS: On the left lower leg there was a 5 x 5 cm ulcer with a sharply demarkated border. Because of its chronicity and its resistance to treatment several biopsies were taken from its borders. DIAGNOSIS, TREATMENT AND CLINICAL COURSE: Histopathologically examination revealed a basal cell carcinoma. The ulcer was excised with a wide margin and the wound closed with a mesh-graft. CONCLUSION: This case demonstrates the need of re-evaluating the pathology of chronic ulcers due to venous stasis in the leg to exclude malignancy.

[Cathelicidin LL-37. A central factor in the pathogenesis of inflammatory dermatoses?]. / Cathelicidin LL-37. Ein zentraler Faktor in der Pathogenese entzündlicher Dermatosen?

Keratinocytes produce and secrete antimicrobial peptides which function as endogenous antibiotics and as signaling molecules within the cutaneous innate immune system. Recent studies demonstrate that the antimicrobial peptide cathelicidin LL-37 plays an important role in the pathogenesis of atopic eczema, rosacea and psoriasis. Whereas skin in atopic eczema shows decreased cathelicidin expression which leads to increased susceptibility to superinfection in those patients, overabundant expression of cathelicidin peptide fragments causes inflammation in rosacea. Finally, in psoriasis cathelicidin peptide binds to self DNA which triggers an autoimmune response. These studies demonstrate the role of cathelicidin as a central factor in the pathogenesis of cutaneous inflammation. Therapies targeting cathelicidin expression and function could lead to new treatments for these diseases.

[Topical treatment of persistent cutaneous leishmaniasis with paromomycin]. / Topische Therapie einer persistierenden kutanen Leishmaniase mit Paromomycin.

Cutaneous leishmaniasis is an infectious disease with increasing prevalence in Germany. Diagnosis and therapy may be difficult due to the variability of the clinical and histomorphological picture and resistance to therapy. In this case study we report on a female patient with a persistent cutaneous leishmaniasis successfully treated with topical administration of paromomycin.

NF-kappaB and AP-1 are responsible for inducibility of the IL-6 promoter by ionizing radiation in HeLa cells.

PURPOSE: To investigate the mechanisms leading to initiation by ionizing radiation of IL-6 transcription in HeLa cells. MATERIALS AND METHODS: HeLa cells were irradiated with X-rays at a dose rate of approximately 1 Gy/min or treated with TPA (100 ng/ml). Transient transfection analysis with truncated IL-6 promoter CAT constructs was used to identify the radiation-sensitive region within the IL-6 promoter/enhancer. RESULTS: For basal expression of the IL-6 gene in unirradiated control cells the presence of the binding site for the nuclear factor kappa B (NF-kappaB) and the multiple response elements (MRE) were necessary. After deletion of either the activator protein (AP)-1 or the MRE site, radiation-induced IL-6 promoter CAT activity was significantly reduced, whereas after deletion of the NF-kappaB site it was completely abolished. Maximal radiation-induced IL-6 promoter CAT activity was observed when the AP-1, NF-kappaB and MRE motifs were present. In electrophoretic mobility shift analyses (EMSA), X-ray-inducible activity was found for NF-kappaB and AP-1 at the MRE constitutive, but no inducible activities were detectable. The nuclear factor IL-6 (NF-IL6) element showed no specific radiation-responsive activity. CONCLUSIONS: These results demonstrate that NF-kappaB plays a major role in X-ray-inducible IL-6 expression in HeLa cells. The fact that IL-6 promoter activity was dramatically enhanced in the presence of the MRE and distal AP-1 binding motif is indicative of a cooperative mode of transcriptional activation involving all three transcription factor systems. These data provide new insights into the prodromal events of radiation-induced inflammation of epithelial cells and putatively the cutaneous radiation syndrome.

[Erythema palmare hereditarium ("red palms")]. / Erythema palmare hereditarium ("red palms").

We report a woman with erythema palmare hereditarium, an anomaly not documented so far in the German literature. It is characterized by a bright erythema of the palms, usually persistent since birth. It is transmitted in an autosomal-recessive mode and has a benign course. In our patient it was possible to trace the palmar erythema over three generations.

Lupus erythematosus tumidus and chronic discoid lupus erythematosus in carriers of X-linked chronic granulomatous disease.

Two Caucasian carriers for chronic granulomatous disease (CGD) developed cutaneous lupus erythematosus (LE) with clinically and morphologically characteristic appearance for chronic discoid lupus erythematosus (DLE) and lupus erythematosus tumidus (LET). Direct immunofluorescent examinations and ANA titers were positive in both young women. No systemic involvement due to the ACR criteria was evident. Their sons suffered from X-linked cytochrome-b negative CGD. The diagnosis of CGD was based on measurement of oxidative burst activity by nitroblue tetrazolium (NBT) slide test and by flow cytometry using dihydrorhodamine 123 (DHR). The absence of cytochrome b558 in neutrophilic granulocytes was confirmed photometrically and by flow cytometry using the 7D5 monoclonal antibody against cytochrome b. We report for the first time the association of the photosensitive LE subtype LET and the X-linked CGD carrier state. Tissue damage by UV radiation and a reduced antimicrobial capacity may lead to recurrent immune stimulation and may together with genetic predisposition explain the occurrence of cutaneous LE in female carriers of CGD.

Structural analysis, expression, and chromosomal localization of the mouse ikba gene.

The pleiotropic transcription factor NF-kappaB is localized in the cytoplasm bound to its inhibitory subunit IkappaB. The predominant form of NF-kappaB is a p50/p65 heterodimer which can be released from IkappaB-alpha and migrate to the nucleus. Previous studies have shown that IkappaB-alpha-/- mice die 8 to 10 days postnatally, showing runting and a severe dermatitis. However, the organ distribution of mouse IkappaB-alpha, the exon-intron structure, and the chromosomal localization of ikba have not been determined so far. A mouse Sv129 genomic DNA library was screened with a human IkappaB-alpha/MAD-3 cDNA probe. One clone (P1) was isolated, spanning the complete ikba gene and the promoter/enhancer region. We show that the exon-intron structure between mouse and pig ikba is completely conserved. In contrast to human ikba, the ankyrin repeat 5 is not interrupted by an intron. Furthermore, the mouse ikba promoter contains 6 putative NF-kappaB binding sequences, which are conserved in mouse, pig, and human, underlining the importance of NF-kappaB as a key regulator of ikba transcription. The deduced amino acid sequence shows >90% similarity between mouse, pig, and human ikba. Chromosome mapping localized the mouse ikba gene to chromosome 12. Northern blot analysis demonstrated predominant expression in lymphoid tissue (lymph node and thymus). However, IkappaB-alpha mRNA was detected as well in liver tissue, the gastrointestinal tract, and the reproductive tract. The cloning and determination of the structure are a prerequisite for the construction of vectors for conditional gene targeting experiments.

Isolation of a hypoxia-induced cDNA with homology to the mammalian growth-related protein p23.

Hypoxia leads to a cellular stress reaction and can induce transcription of immediate early genes, such as c-fos. We have generated a differential cDNA cloning strategy to isolate further hypoxia-induced genes. We report on the identification and characterization of a novel transcript (cDNA clone pSH16), which is inducible 12-fold in HeLa cells after 50 min of exposure to hypoxia. Sequence analysis revealed a hybrid transcript with high homology to the mammalian growth-related protein p23 mRNA fused to mitochondrial 16S rRNA. Complete homology was found for the coding region, whereas the 3'-untranslated part of the hypoxia-induced p23 sequence was elongated and carried an ATTTA box and a second consensus poly(A) signal in addition. The functional integrity of the pSH16 mRNA was verified by cell-free translation. Hypoxia induced the expression of both fusion partners, p23 and 16S rRNA, separately. In contrast to the hypoxia-induced expression in HeLa cells, we found constitutive high-level expression in breast and cervix tissue. No further upregulation of p23 transcripts was detectable in primary tumors of the breast and cervix. These data provide first evidence for a hypoxia-induced upregulation of the mammalian growth-related protein p23, which might be relevant for understanding of the physiology of hypoxic conditions in tumors.

Hypoxia induces c-fos transcription via a mitogen-activated protein kinase-dependent pathway.

Hypoxia is a pathophysiological condition that occurs during injury, ischemia, and stroke. It is characterized by a decrease of reactive oxygen intermediates and a change of the intracellular redox level. In tumors hypoxia is regarded as a trigger for enhanced growth and metastasis. Here we report that in HeLa cells, hypoxic conditions induce the transcriptional activation of c-fos transcription via the serum response element. Mutations in the binding site for the ternary complex factor Elk-1 and the serum response factor abolished this induction, indicating that a ternary complex at the serum response element is necessary for the induction of the c-fos gene under hypoxia. The transcription factor Elk-1 was covalently modified by phosphorylation in response to hypoxia. Furthermore this hyperphosphorylation of Elk-1, the activation of mitogen-activated protein kinase (MAPK), and the induction of c-fos transcripts were blocked by PD98059, a specific inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase kinase 1. An in vitro kinase assay with Elk-1 as substrate showed that MAPK is activated under hypoxia. The activation of MAPK corresponds temporally with the phosphorylation and activation of Elk-1. Thus, a decrease of the intracellular reactive oxygen intermediate level by hypoxia induces c-fos via the MAPK pathway. These results suggest that the intracellular redox levels may be directly coupled to tumor growth, invasion, and metastasis via Elk-1-dependent induction of c-Fos controlled genes.

Study of gene regulation by NF-kappa B and AP-1 in response to reactive oxygen intermediates.

Reactive oxygen intermediates (ROIs), such as hydrogen peroxide or superoxide, are an evolutionarily ancient threat to all organisms. Exposure of bacteria to ROIs initiates a genetic program that coordinates the production of novel proteins with protective functions. This genetic response is mediated by regulatory proteins that have the potential to initiate transcription of genes when the levels of the ROIs increase. In plant cells, a variety of viral pathogens increase hydrogen peroxide production, which is required to mount a defensive genetic response. It was suggested that in this case H2O2 is used as a secondary messenger and an immediate-early pathogen signal. In higher vertebrates, two transcription factors, nuclear factor kappa B and activator protein 1, were found to respond to ROIs. Both are well studied: they are induced by a great variety of seemingly unrelated conditions and serve important roles in immune, inflammatory, and other pathogen-related genetic responses. In this article we discuss how the ROI responsiveness of transcription factors can be experimentally studied and summarize evidence to suggest that ROIs have been conserved during evolution as messengers of a general pathogen response.

Antioxidants as well as oxidants activate c-fos via Ras-dependent activation of extracellular-signal-regulated kinase 2 and Elk-1.

Intracellular reactive oxygen intermediate (ROI) levels play an important role in numerous physiological and pathophysiological conditions. Apart from causing oxidative stress and damage, ROI changes differentially activate gene expression. However the proto-oncogene encoding the AP-1 transcription factor subunit c-Fos is induced by both prooxidants and antioxidants. Here, the transcription factor Elk-1 is identified as being responsible for c-fos serum response element (SRE) induction in response to changes in the cellular redox status induced by treatment with either the oxidant H2O2 or various structurally unrelated antioxidants. A temporal correlation is observed between changes in the phosphorylation status of Elk-1 and the activation of the mitogen-activated protein kinase 2 (ERK2) in response to cellular redox changes. Correspondingly, the transcriptional response of the SRE to redox fluctuations is attenuated upon mutation of critical ERK2 target residues within the Elk-1 transactivation domain to alanine. Signals elicited by antagonistic intracellular redox changes converge at or above the level of Ras or an effector of Ras, leading to similar activation of c-fos transcription, since an [N17]Ras mutant interfered with redox signaling. Hence components of signaling pathways are revealed to be shared by mitogenic and redox-dependent stimuli.

Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha.

The transcription factor NF-kappa B regulates genes participating in immune and inflammatory responses. In T lymphocytes, NF-kappa B is sequestered in the cytosol by the inhibitor I kappa B-alpha and released after serine phosphorylation of I kappa B-alpha that regulates its ubiquitin-dependent degradation. We report an alternative mechanism of NF-kappa B activation. Stimulation of Jurkat T cells with the protein tyrosine phosphatase inhibitor and T cell activator pervanadate led to NF-kappa B activation through tyrosine phosphorylation but not degradation of I kappa B-alpha. Pervanadate-induced I kappa B-alpha phosphorylation and NF-kappa B activation required expression of the T cell tyrosine kinase p56ick. Reoxygenation of hypoxic cells appeared as a physiological effector of I kappa B-alpha tyrosine phosphorylation. Tyrosine phosphorylation of I kappa B-alpha represents a proteolysis-independent mechanism of NF-kappa B activation that directly couples NF-kappa B to cellular tyrosine kinase.

Cutaneous manifestations of congenital afibrinogenaemia.

Skin problems from coagulation disorders have rarely been described in the dermatological literature. Here we report a patient with a complete congenital absence of fibrinogen which led to leg ulceration, necrosis of the toes and a life-threatening haemorrhage following skin biopsy. This patient shows that leg ulcers may have a complex aetiology and can reflect serious underlying disease.