Livedoid vasculopathy: does hyperhomocysteinaemia play an aetiological role?

BACKGROUND: Livedoid vasculopathy (LV) has been shown to be associated with hypercoagulability. However, relevant genetic and exogenous thrombophilic factors are not fully determined. OBJECTIVES: To evaluate the frequency of hyperhomocysteinaemia (HHCE) and genotypes of hypercoagulative factors in LV patients. MATERIAL AND METHODS: Plasma homocysteine level was measured in 42 LV patients. Polymorphism of MTHFR (677C > T and 1298A > C), PAI1 (-675 5G/4G and -844A > G), and F2 (20210G > A), and the F5 Leiden mutation, as well as biochemical parameters for hypercoagulability, were analysed. RESULTS: Of the LV patients, 62% revealed mild HHCE. Polymorphisms of MTHFR were observed in 75% and 56% and the PAI1 -675 5G/4G polymorphism in 100% and 83% of patients with and without HHCE, respectively. All LV patients with renal failure had mild HHCE. A high level of comorbidity of hypertension (99%) and diabetes type 2 (44%) were noted. CONCLUSION: HHCE seems to play a major pathogenetic role in LV. A high prevalence of further procoagulative factors might support the view that LV is a "complex disease".

Aberrant Promoter Hypermethylation of RASSF Family Members in Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is one of the most aggressive cancers of the skin. RASSFs are a family of tumor suppressors that are frequently inactivated by promoter hypermethylation in various cancers. We studied CpG island promoter hypermethylation in MCC of RASSF2, RASSF5A, RASSF5C and RASSF10 by combined bisulfite restriction analysis (COBRA) in MCC samples and control tissue. We found RASSF2 to be methylated in three out of 43 (7%), RASSF5A in 17 out of 39 (44%, but also 43% in normal tissue), RASSF5C in two out of 26 (8%) and RASSF10 in 19 out of 84 (23%) of the cancer samples. No correlation between the methylation status of the analyzed RASSFs or between RASSF methylation and MCC characteristics (primary versus metastatic, Merkel cell polyoma virus infection, age, sex) was found. Our results show that RASSF2, RASSF5C and RASSF10 are aberrantly hypermethylated in MCC to a varying degree and this might contribute to Merkel cell carcinogenesis.

Radiogenic lymphangiogenesis in the skin.

The time course of microvascular changes in the environment of irradiated tumors was studied in a standardized human protocol. Eighty skin biopsies from 40 patients with previously treated primary breast cancer were taken from irradiated skin and corresponding contralateral unirradiated control areas 2 to 8 weeks, 11 to 14 months, or 17+ months after radiotherapy (skin equivalent dose 30 to 40 Gy). Twenty-two biopsies of 11 melanoma patients who had undergone lymph node dissection were used for unirradiated control. We found an increase of total podoplanin(+) lymphatic microvessel density resulting mainly from a duplication of the density of smallest lymphatic vessels (diameter <10 microm) in the samples taken 1 year after radiation. Our findings implicate radiogenic lymphangiogenesis during the 1st year after therapy. The numbers of CD68(+) and vascular endothelial growth factor-C(+) cells were highly elevated in irradiated skin in the samples taken 2 to 8 weeks after radiotherapy. Thus, our results indicate that vascular endothelial growth factor-C expression by invading macrophages could be a pathogenetic route of induction of radiogenic lymphangiogenesis.

Persistent erythema and edema of the midthird and upper aspect of the face (morbus morbihan): evidence of hidden immunologic contact urticaria and impaired lymphatic drainage.

BACKGROUND: A persistent erythema and edema of the midthird and upper aspect of the face, which bears some resemblance to Melkersson-Rosenthal syndrome and rosaceous lymphedema, has been characterized as morbus morbihan (MM) by French dermatologists. The disease of yet unknown cause starts with recurrent facial edema of short duration, which ultimately leads to persistent swelling after a period of weeks or months. METHODS: We recruited 6 patients with MM and acquired their history, routine blood tests, and individual UV light tolerability. To check for contact allergies the allergen patch test and the open epicutaneous patch test were performed. To objectify the skin conditions laser Doppler flowmetry and 20-MHz ultrasound were used. Five patients with similar symptoms, but with definitely transient facial erythema and edema caused by proven contact urticaria on cosmetics served as a comparison group. RESULTS: In all patients, routine blood tests and UVA/UVB light tests showed no pathologic results. Observations of 6 patients with MM revealed the common feature of a clinically relevant immunologic contact urticaria caused by various cosmetic ingredients, which could be diagnosed in all of them. Delayed resorption of the acute edema and prolonged inflammation were shown by laser Doppler flowmetry and 20-MHz ultrasound in the affected skin areas in patients with MM after induction of immunologic contact urticaria by a cosmetic ingredient. Strict avoidance of cosmetics yielded a remarkable clinical benefit in the follow-up examinations. CONCLUSIONS: We conclude that recurrent and possibly subclinical inflammation caused by immunologic contact urticaria in conjunction with a locally pre-existing lowered lymphatic drainage plays a crucial role in the evolution of MM.

The influence of L-arginine on the regulation of epidermal arginase.

Topical preparations containing urea are firmly established in dermatological therapy and nursing care therapy. In addition, urea is frequently used as an inactive ingredient with disinfecting, keratoplastic and penetration-promoting action in topical preparations. Despite good tolerance and ensured action, particularly the irritating effect on erosive, exudative or strongly inflammatory skin restricts its application. Endogenic urea is synthesised from L-arginine by an extra-hepatic arginase in keratinocytes. This enzymatic reaction is subject to regulation by manganese ions and the intracellular L-arginine concentration. L-Arginine is predominantly transported into the cell by a membrane transport system that is dependent on the membrane potential. By incubating keratinocyte cultures in different concentrations of L-arginine and manganese chloride, it could be shown that the keratinocytic urea synthesis can be increased. In relevant concentrations, L-arginine and manganese chloride do not exhibit any proliferation-inhibiting action, do not trigger any apoptosis or necrosis, and are stable. An increase in the expression of arginase cannot be detected using L-arginine. The application of L-arginine alone or in combination with manganese chloride increases the endogenous intrakeratinocytic urea synthesis and thus offers an option for topical therapeutic application in cases of dry skin conditions.