[A 39-year-old patient with maculopapular rash, recurrent fever, and arthralgia]. / 39-Jährige mit makulopapulösem Exanthem, Fieberschüben und Arthralgien.

Adult-onset Still's disease is a rare disorder of unknown etiology. We report the case of a 39-year-old patient who showed the characteristic symptoms: recurrent attacks of fever, arthralgia, maculopapular rash, sore throat, and lymphadenopathy. After the possibility of an infectious or paraneoplastic process was excluded and the laboratory findings were evaluated (increased C-reactive protein, liver values, and ferritin level), the diagnosis was established according to the criteria of Yamaguchi. Therapy with steroids and nonsteroidal anti-inflammatory drugs was started successfully.

The novel protein PTPIP51 is expressed in human keratinocyte carcinomas and their surrounding stroma.

BACKGROUND: The novel protein PTPIP51 (SwissProt accession code Q96SD6) is known to interact with two non-transmembrane protein-tyrosine phosphatases, PTP1B and TCPTP in vitro. Overexpression of the full-length protein induces apoptosis in HeLa and HEK293T cells (Lv et al. 2006). PTPIP51 shows a tissue-specific expression pattern and is associated with cellular differentiation and apoptosis in some mammalian tissues, especially in human follicular and interfollicular epidermis. PTPIP51 protein is expressed in all suprabasal layers of normal epidermis, whereas the basal layer contains PTPIP51 mRNA only but lacks the protein. OBJECTIVES: The expression of PTPIP51 was investigated in keratinocyte carcinomas, that is human basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) as well as Bowen's disease (BD) and keratoacanthomas (KAs) on a transcriptional (mRNA) and translational (immunohistochemical) level. METHODS: Formalin-fixed, paraffin-embedded sections of BCCs, SCCs, KAs and BD, respectively, were analysed by RT-PCR, as well as immunohistochemistry and subsequent fluorescence microscopy. PTPIP51-positive cells of the tumour and the surrounding stroma were identified on the basis of specific morphological features by means of H & E staining. To obtain further information about a putative function of PTPIP51, a possible association of PTPIP51 with apoptotic cells, as well as an assumed negative correlation with proliferating cells was investigated by means of an in-situ TUNEL assay and Ki67/MIB-1 antigen staining, respectively. Co-immunostainings with PTPIP51 were performed for the following antigens: TCPTP, PTP1B and beta-catenin. RESULTS: PTPIP51-expression was detected in BCCs and SCCs of the skin, as well as in KAs and BD. Both types of keratinocyte carcinoma revealed a specific localization pattern of PTPIP51 in malignant keratinocytes. Whereas PTPIP51-positive cells of BCC were found to form two cluster types with a different subcellular localization of the protein, i.e. cytoplasmic and nuclear or predominantly membranous, investigation of SCC revealed a meshwork-like appearance of PTPIP51-positive malignant keratinocytes, created by a mainly membranous localization. BD and KA resembled the findings of PTPIP51-expression in SCC. Furthermore, we observed a partial co-localization of PTP1B and PTPIP51 in BCC. SCC and BCC showed a co-expression and partial co-localization of PTPIP51 with beta-catenin. Some PTPIP51-positive cells were found to undergo apoptosis. PTPIP51 was also expressed in cells comprising the surrounding stromal microenvironment. This was particularly noticed for endothelial cells lining peritumoural vessels as well as for infiltrating cells of both, the innate and the adaptive immune system. CONCLUSIONS: The results showed a distinct mainly membranous expression pattern of PTPIP51 in BCCs and SCCs. Since PTPIP51 was also detected in the peritumoural tissue, the protein may play a crucial role in ke

Reduced expression of nicotinic alpha subunits 3, 7, 9 and 10 in lesional and nonlesional atopic dermatitis skin but enhanced expression of alpha subunits 3 and 5 in mast cells.

BACKGROUND: The skin cholinergic signalling system is modulated in atopic dermatitis (AD). OBJECTIVES: To investigate of the role of nicotinic acetylcholine receptors (nAChRs) in the pathogenesis of AD. METHODS: We investigated the expression and localization of nAChR alpha subunits in AD by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry of biopsies from lesional and nonlesional areas of AD skin and of skin biopsies from healthy control persons. RESULTS: Our data demonstrate the presence of mRNA and protein of the nAChR alpha subunits 3, 5, 7, 9 and 10 in keratinocytes and mast cells in healthy and AD skin. Expression of the alpha subunits 3, 7, 9 and 10 was generally reduced in the skin of patients with AD whereas mast cells in AD but not in healthy skin showed alpha3 and alpha5 subunit immunoreactivity. Differences in the subunit mRNA levels between lesional and nonlesional skin were obtained for the alpha subunits 3, 9 and 10 with higher levels of alpha3 but lower levels of alpha10 subunit mRNA in lesional areas. No differences in the expression of the alpha subunits was found between the groups of extrinsic, intrinsic or mixed AD types, between genders and between smokers and nonsmokers. CONCLUSIONS: This supports the idea that the cholinergic system is dysregulated independently from inflammation in AD and that inflammation further modulates individual nAChR subunits.

[Malassezia yeasts and their significance in dermatology]. / Malassezia-Hefen und ihre Bedeutung in der Dermatologie.

Yeasts of the genus Malassezia belong to the normal microflora of the human skin. In addition they are known to cause a variety of skin diseases; the most frequent of which is pityriasis versicolor. Malassezia yeasts are also thought to be associated with seborrheic dermatitis, dandruff and Malassezia folliculitis. Recently the significance of Malassezia yeasts as a trigger factor for atopic dermatitis of the head and neck region has been pointed out. The role of the Malassezia yeasts in these different diseases has been controversial in the past and remains an issue because of difficulties in isolation, culture and differentiation of the organism. Thanks to molecular techniques, 10 species can actually be differentiated. The article presents the different Malassezia-associated diseases, their clinical picture, diagnosis and appropriate therapy. In addition the speciation of Malassezia is reviewed.

Case report. Cutaneous phaeohyphomycosis due to Alternaria alternata.

A case of cutaneous alternariosis with a well-delimited lesion of traumatic origin is described in a renal transplant recipient. On the basis of histopathology the case was first thought to be cryptococcosis, but Alternaria alternata was identified after culturing by means of morphological and molecular examination. Surgical treatment, accompanied by prophylactic application of itraconazole (200 mg day(-1) for 4 weeks), resulted in complete cure.

LcrG-LcrV interaction is required for control of Yops secretion in Yersinia pestis.

Yersinia pestis expresses a set of plasmid-encoded virulence proteins called Yops and LcrV that are secreted and translocated into eukaryotic cells by a type III secretion system. LcrV is a multifunctional protein with antihost and positive regulatory effects on Yops secretion that forms a stable complex with a negative regulatory protein, LcrG. LcrG has been proposed to block the secretion apparatus (Ysc) from the cytoplasmic face of the inner membrane under nonpermissive conditions for Yops secretion, when levels of LcrV in the cell are low. A model has been proposed to describe secretion control based on the relative levels of LcrG and LcrV in the bacterial cytoplasm. This model proposes that under secretion-permissive conditions, levels of LcrV are increased relative to levels of LcrG, so that the excess LcrV titrates LcrG away from the Ysc, allowing secretion of Yops to occur. To further test this model, a mutant LcrG protein that could no longer interact with LcrV was created. Expression of this LcrG variant blocked secretion of Yops and LcrV under secretion permissive conditions in vitro and in a tissue culture model. These results agree with the previously described secretion-blocking activity of LcrG and demonstrate that the interaction of LcrV with LcrG is necessary for controlling Yops secretion.

Virulence role of V antigen of Yersinia pestis at the bacterial surface.

Yersinia pestis, the etiologic agent of plague, secretes a set of environmentally regulated, plasmid pCD1-encoded virulence proteins termed Yops and V antigen (LcrV) by a type III secretion mechanism (Ysc). LcrV is a multifunctional protein that has been shown to act at the level of secretion control by binding the Ysc inner-gate protein LcrG and to modulate the host immune response by altering cytokine production. LcrV also is essential for the unidirectional targeting of Yops to the cytosol of infected eukaryotic cells. In this study, we constructed an in-frame deletion within lcrG (DeltalcrG3) to further analyze the requirement of LcrV in Yop targeting. We confirmed the essentiality of LcrV and found that LcrG may have a facilitative role, perhaps by promoting efficient secretion of LcrV. We also constructed mutants of lcrV expressing LcrV truncated at the N or C terminus. Both the N and C termini of LcrV were required for the secretion of LcrV into the medium and targeting of Yops. LcrV was detected in punctate zones on the surface of fixed Y. pestis by laser-scanning confocal microscopy, and this localization required a functional Ysc. However, the truncated LcrV proteins were not found on the bacterial surface. Finally, we tested the ability of LcrV-specific Fab antibody fragments or full-length antibody to interfere with Yop targeting and found no interference, even though this antibody protects mice against plague. These results indicate that LcrV may function in Yop targeting at the extracellular surface of yersiniae and that the protective efficacy of LcrV-specific antibodies can be manifested without blocking Yop targeting.

The V antigen of Yersinia pestis regulates Yop vectorial targeting as well as Yop secretion through effects on YopB and LcrG.

Yersinia pestis expresses a set of secreted proteins called Yops and the bifunctional LcrV, which has both regulatory and antihost functions. Yops and LcrV expression and the activity of the type III mechanism for their secretion are coordinately regulated by environmental signals such as Ca2+ concentration and eukaryotic cell contact. In vitro, Yops and LcrV are secreted into the culture medium in the absence of Ca2+ as part of the low-Ca2+ response (LCR). The LCR is induced in a tissue culture model by contact with eukaryotic cells that results in Yop translocation into cells and subsequent cytotoxicity. The secretion mechanism is believed to indirectly regulate expression of lcrV and yop operons by controlling the intracellular concentration of a secreted negative regulator. LcrG, a secretion-regulatory protein, is thought to block secretion of Yops and LcrV, possibly at the inner face of the inner membrane. A recent model proposes that when the LCR is induced, the increased expression of LcrV yields an excess of LcrV relative to LcrG, and this is sufficient for LcrV to bind LcrG and unblock secretion. To test this LcrG titration model, LcrG and LcrV were expressed alone or together in a newly constructed lcrG deletion strain, a delta lcrG2 mutant, of Y. pestis that produces low levels of LcrV and constitutively expresses and secretes Yops. Overexpression of LcrG in this mutant background was able to block secretion and depress expression of Yops in the presence of Ca2+ and to dramatically decrease Yop expression and secretion in growth medium lacking Ca2+. Overexpression of both LcrG and LcrV in the delta lcrG2 strain restored wild-type levels of Yop expression and Ca2+ control of Yop secretion. Surprisingly, when HeLa cells were infected with the delta lcrG2 strain, no cytotoxicity was apparent and translocation of Yops was abolished. This correlated with an altered distribution of YopB as measured by accessibility to trypsin. These effects were not due to the absence of LcrG, because they were alleviated by restoration of LcrV expression and secretion alone. LcrV itself was found to enter HeLa cells in a nonpolarized manner. These studies supported the LcrG titration model of LcrV's regulatory effect at the level of Yop secretion and revealed a further role of LcrV in the deployment of YopB, which in turn is essential for the vectorial translocation of Yops into eukaryotic cells.

Yersinia pestis LcrV forms a stable complex with LcrG and may have a secretion-related regulatory role in the low-Ca2+ response.

Yersinia pestis contains a virulence plasmid, pCD1, that encodes many virulence-associated traits, such as the Yops (Yersinia outer proteins) and the bifunctional LcrV, which has both regulatory and antihost functions. In addition to LcrV and the Yops, pCD1 encodes a type III secretion system that is responsible for Yop and LcrV secretion. The Yop-LcrV secretion mechanism is believed to regulate transcription of lcrV and yop operons indirectly by controlling the intracellular concentration of a secreted repressor. The activity of the secretion mechanism and consequently the expression of LcrV and Yops are negatively regulated in response to environmental conditions such as Ca2+ concentration by LcrE and, additionally, by LcrG, both of which have been proposed to block the secretion mechanism. This block is removed by the absence of Ca2+ or by contact with eukaryotic cells, and some Yops are then translocated into the cells. Regulation of LcrV and Yop expression also is positively affected by LcrV. Previously, LcrG was shown to be secreted from bacterial cells when the growth medium lacks added Ca2+, although most of the LcrG remains cell associated. In the present study, we showed that the cell-associated LcrG is cytoplasmically localized. We demonstrated that LcrG interacts with LcrV to form a heterodimeric complex by using chemical cross-linking and copurification of LcrG and LcrV. Additionally, we found that small amounts of LcrV and YopE can be detected in periplasmic fractions isolated by cold osmotic shock and spheroplast formation, indicating that their secretion pathway is accessible to the periplasm or to these procedures for obtaining periplasmic fractions. We propose that the cytoplasmically localized LcrG blocks the Yop secretion apparatus from the cytoplasmic side and that LcrV is required to remove the LcrG secretion block to yield full induction of Yop and LcrV secretion and expression.

[Epithelioid cell histiocytoma]. / Das epitheloidzellige Histiozytom.

We report on seven examples of this rare, only recently described benign tumor, which presented clinically as solitary elevated nodules on the lower (n = 5) and upper (n = 2) extremity, measuring between 0.6 and 1.1 cm in diameter. Histologically, all tumors were well-defined with a characteristic epidermal collarette. There were abundant (60-80%) epithelioid cells with prominent cytoplasm, a vesicular nucleus and inconspicuous nucleolus, as well as a number of dilated blood vessels. Immunohistologically, tumor cells did not react with monocyte/macrophage antibodies (KP1, MAC387). In addition, there was no evidence of myofibroblastic differentiation (alpha-smooth muscle actin and desmin negative). Thus, while immunohistological markers are helpful to exclude the diagnosis of other tumors, they do not shed light on the differentiation of epithelioid cell histiocytomas. The present cases are identical to those described originally. Recently similar lesions have been described in deeper parts of the corium as well as more cellular forms. Epithelioid cell histiocytoma represents a characteristic, poorly known variant within the spectrum of benign fibrous histiocytomas; it needs to be distinguished clinically and histopathologically especially from Spitz nevus.

[Solitary subcutaneous metastasis of a chondrosarcoma]. / Solitäre subkutane Metastase eines Chondrosarkoms.

We report on a rare case of a solitary subcutaneous metastasis from a chondrosarcoma. The metastasis occurred 7 years after excision of the primary neoplasm. Further investigations revealed no evidence of other metastases. Nevertheless, according to data in the literature, the prognosis has to be considered very poor.

Elastosis and cancer.

Recently we have shown that the autofluorescence within or just outside of a malignant tumor is rather small or large resp. in comparison to healthy tissue when excited at 365 nm. Studies with unfixed, unstained cryosections of skin with melanomas have revealed bulky fiber-like structures with a high fluorescence intensity just outside of a malignant tumor. Using polarized light, the structures could be identified as elastic fibers. This was also confirmed by studies on arterial walls.

Surface microscopy of naevi and melanomas--clues to melanoma.

In this present study, 260 histologically confirmed melanocytic skin tumours (188 benign naevi and 72 malignant melanomas; from 1989 to 1990) were investigated with regard to valid surface microscopical criteria of malignancy. The tumours were analysed using a system which assessed eight components. Most melanomas were characterized by the following pattern: asymmetrical pigment distribution, more than three colours, black pigment, peripheral stripes, and asymmetrical depigmentation. The results were evaluated statistically by contingency tables and logistic regression procedures. On the basis of the classification derived, the sensitivity and specificity were determined for lesions from 1991, and were 0.9 and 0.85, respectively. Many melanocytic naevi were not identified by the above criteria, or were found only occasionally. Pigment network was often absent in naevi and melanomas, and was not decisive for the diagnosis. The present investigation demonstrates that in vivo diagnosis of pigmented melanocytic lesions can be improved by surface microscopy.

Analytic morphology in clinical and experimental dermatology.

During the past several years, quantitative morphology has gained increasing attention in diagnostic pathology and in certain research applications. In the field of dermatopathology, quantitative morphology has been applied to numerous problems, ranging from the interactive measurement of nuclear contours to fully automated, high-resolution image analysis of ultrastructural micrographs. Dermatologic applications are reviewed, and potential developments in the future are briefly outlined.

[Fox-Fordyce disease (apocrine miliaria)]. / Morbus Fox-Fordyce (Apokrine Miliaria).

A 1-year follow-up in a 12 year old girl suffering from Fox-Fordyce disease is reported. Reddish papules were found in the typical locations in the regions with a high density of apocrine glands. A biopsy specimen showed keratin plugs in the infundibula of apocrine glands. Since hormone therapy could not yet be given, external therapy only was performed, with good results.

Spiradenomas in Brooke-Spiegler syndrome.

Brooke-Spiegler syndrome is an autosomal dominantly inherited disease characterized by the development of multiple trichoepitheliomas and cylindromas. Among other neoplasms that may also occur in Brooke-Spiegler syndrome are basal cell carcinomas and spiradenomas. Spiradenomas and cylindromas have so many features in common that they have been regarded as variants of the same neoplasm. This assumption was supported by the occurrence of both types of lesions in Brooke-Spiegler syndrome. We report a case of Brooke-Spiegler syndrome in which spiradenomas were found in the immediate vicinity of trichoepitheliomas and in continuity with follicles. Because of the embryonic relationship between follicles and apocrine glands, these features indicate that spiradenomas are apocrine neoplasms. We conclude that Brooke-Spiegler syndrome is an inherited disease that affects the folliculosebaceous apocrine unit.

[Atypical mycobacteriosis in immunosuppression]. / Atypische Mykobakteriose bei Immunsuppression.

We report on a 50-year-old patient with bluish swellings on the forearms and hands. These symptoms were accompanied by arthralgia. The patient treated himself with about 120 mg methylprednisolone daily, which initially resulted in only slight improvement. Microbiological investigations from cutaneous abscesses demonstrated an atypical mycobacterium (Mycobacterium chelonae). Occurrence of these bacteria is ubiquitous. In immunodeficient states infections are possible, which may be followed by dissemination of the mycobacteria in traumatic skin lesions. In the patient under discussion, dissemination was probably enhanced by the misuse of steroids. Despite chemotherapy, the patient died, perhaps as a consequence of dissemination.

Distribution of cytokeratin polypeptides in syringomas. An immunohistochemical study on paraffin-embedded material.

The distribution of cytokeratin (CK) polypeptides expressed in syringomas (12 cases) was compared with that in normal eccrine sweat ducts using immunohistochemical techniques on paraffin-embedded tissue. Intradermal and intraepidermal segments of the eccrine duct showed reactivity with an antibody to CK1/5/10/11 in all cell layers, whereas CK19 expression was restricted to the luminal cell layer. CK14 was expressed in all cells of the eccrine duct except for the peripheral cells of the intraepidermal duct. Expression of CK5/6 was seen in the basal cells of the dermal duct and of the lower intraepidermal duct (sweat duct ridge) exclusively. Reactivity with an antibody to CK1 was found in the intermediate cells of the uppermost part of the eccrine dermal duct. In addition, this antibody gave a strong staining of the peripheral cells of the intraepidermal duct, leaving basal cells of the sweat duct ridge and luminal cells unstained. In syringoma, CK distribution was essentially comparable with that found in the uppermost part of the dermal duct and in the sweat duct ridge. Namely, ductal luminal cells expressed CK1/5/10/11, CK19, and variably CK14. Intermediate cells of ductal structures and solid nests were homogeneously stained by antibodies to CK1 and CK1/5/10/11, whereas CK14 was expressed heterogeneously. The basal or outermost layer of ductal structures and solid nests was reactive with antibodies to CK1/5/10/11, CK5/6, and CK14. With regard to CK expression, the results indicate that syringoma represents a tumor differentiating toward both the uppermost part of the dermal duct and the lower intraepidermal duct (sweat duct ridge) of the eccrine sweat gland.