Beware of anal fissures: pemphigus vulgaris of the anal canal.

A case of anal pemphigus vulgaris in a 49-year-old female suffering from pemphigus vulgaris of the oral cavity is reported. The oral manifestations were in remission until she presented with episodes of anal pain and bleeding on defecation, initially mimicking anal fissures. Inspection revealed prominent painful erosions in the anal canal with external hemorrhoids and strands of sloughing skin and maceration in the anal verge. Histology and direct immunofluorescence test were consistent with pemphigus vulgaris. The disease was refractory to treatment and complete remission was only achieved with the combination of rituximab and corticosteroids. Anal involvement seems to be an uncommon or underreported manifestation of pemphigus vulgaris. Gastroenterologists should be aware of this entity, especially in areas with a high incidence of the disease, for appropriate diagnosis and management.

Multiple cutaneous reticulohistiocytosis with T-cell large granular lymphocyte clonopathy.

A 63-year-old Caucasian man presented with a 4-month history of disseminated asymptomatic reddish-brown papulonodular lesions. A skin biopsy showed dermal infiltration with CD68+ histiocytes, predominantly with eosinophilic cytoplasm, some with a ground-glass cytoplasm, and a small number of giant cells. The diagnosis of multiple cutaneous reticulohistiocytosis was made. Bone marrow immunophenotyping due to peripheral blood lymphocytosis revealed the presence of a monoclonal population of CD3+ , CD8+ CD57+ large granular lymphocytes. The present case suggests the coexistence of multiple cutaneous reticulohistiocytosis with an underlying disorder.

Mycobacterium avium Auricular Infection in an Apparent Immunocompetent Patient: A Case Report.

INTRODUCTION: Soft tissue infections with Mycobacterium avium complex are more likely to appear in immunocompromised patients. However, they may rarely arise in non-immunosuppressed individuals. AIM: To present the case of an ear infection with Mycobacterium avium in the absence of demonstrable immunosuppression. CASE REPORT: Clinical case description, blood tests, routine histology and tissue cultures. DISCUSSION: A female, apparent immunocompetent patient presented with a 6-month reddish, oedematous and painless lesion with fine scaling in the right ear. Histology showed numerous granulomas, composed of epithelioid histiocytes without central necrosis. Cultures grew Mycobacterium avium. An unusual accidental ear injury was the portal of microbial entry. The patient's lesion fully regressed after a 9-month course of antibiotics. CONCLUSION: Although M. avium infections are rare in immunocompetent patients, the possibility of such infections should be considered even in these subjects, when relevant clinical features and exposure to risk factors are present.

Prehistological evaluation of benign and malignant pigmented skin lesions with optical computed tomography.

Discrimination of benign and malignant melanocytic lesions is a major issue in clinical dermatology. Assessment of the thickness of melanoma is critical for prognosis and treatment selection. We aimed to evaluate a novel optical computed tomography (optical-CT) system as a tool for three-dimensional (3-D) imaging of melanocytic lesions and its ability to discriminate benign from malignant melanocytic lesions while simultaneously determining the thickness of invasive melanoma. Seventeen melanocytic lesions, one hemangioma, and normal skin were assessed immediately after their excision by optical-CT and subsequently underwent histopathological examination. Tomographic reconstructions were performed with a back-propagation algorithm calculating a 3-D map of the total attenuation coefficient (AC). There was a statistically significant difference between melanomas, dysplastic nevi, and non-dysplastic nevi, as indicated by Kruskal-Wallis test. Median AC values were higher for melanomas compared with dysplastic and non-dysplastic nevi. No statistically significant difference was observed when thickness values obtained by optical-CT were compared with histological thickness using a Wilcoxon sighed rank test. Our results suggest that optical-CT can be important for the immediate prehistological evaluation of biopsies, assisting the physician for a rapid assessment of malignancy and of the thickness of a melanocytic lesion.

Successful treatment of cutaneous leishmaniasis with intralesional aminolevulinic acid photodynamic therapy.

Leishmaniasis is a protozoan infectious disease that often affects the skin and may acquire a chronic and difficult to treat course. Topical photodynamic therapy (PDT) is a novel treatment which involves the selective uptake of a photosensitizing agent. Exposure to an appropriate light source in the presence of oxygen leads to formation of reactive oxygen species and destruction of the target cells. We report on the successful treatment of a 69-year-old patient with a relapse of long-standing cutaneous leishmaniasis using intralesional aminolevulinic acid-PDT.

Opposite regulation of the human apolipoprotein M gene by hepatocyte nuclear factor 1 and Jun transcription factors.

HDL is a negative risk factor for atherosclerosis because of its multiple atheroprotective functions. Inflammation converts HDL particles from anti-atherogenic to pro-atherogenic, and this transformation is associated with changes in HDL structure and composition. Apolipoprotein M (apoM) has been recently shown to play a role in the maturation of HDL in plasma and to protect from atherosclerosis. ApoM gene is expressed primarily in the liver and kidney and is down-regulated by pro-inflammatory signals. We now show that the human apoM promoter harbors a dual specificity regulatory element in the proximal region that binds hepatocyte nuclear factor 1 (HNF-1) and members of the AP-1 family of pro-inflammatory transcription factors (c-Jun and JunB). Overexpression of c-Jun or JunB repressed both the basal and the HNF-1-mediated transactivation of the human apoM promoter. Treatment of HepG2 cells with potent inflammation-inducing phorbol esters or overexpression of PKCα was associated with a marked inhibition of apoM gene expression in a c-Jun/JunB-dependent manner. We provide evidence for a novel mechanism of inflammation-induced transcriptional repression that is based on the competition between HNF-1 and Jun proteins for binding to the same regulatory region. A similar mechanism accounts for the down-regulation of the liver-specific apolipoprotein A-II gene by Jun factors. Our studies provide novel insights on the mechanisms that control the expression of liver-specific apolipoprotein genes during inflammation and could affect the maturation and the functionality of HDL particles.

Identification of the M541L sequence variation of the transmembrane KIT domain in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive KIT-positive cutaneous tumor. KIT mutations are considered to play a key role in the pathogenesis of various neoplasms, but have not been found so far in MCC. The aim of the present study was therefore to investigate the presence of KIT mutations in MCC. MATERIALS AND METHODS: The entire coding region of KIT in the MCC cell line MCC-1 was sequenced. KIT exon 10 was amplified from archival paraffin-embedded MCC specimens by PCR and sequenced. RESULTS: Exon 10 M541L KIT sequence variation, which confers increased sensitivity to KIT ligand stem cell factor, was detected in the MCC-1 cell line. Sequencing of KIT exon 10 in six archival MCC specimens revealed the wild-type sequence. CONCLUSION: The presence of the M541L KIT variation in MCC warrants further studies for its role in the pathogenesis of this tumor.

KIT receptor activation by autocrine and paracrine stem cell factor stimulates growth of merkel cell carcinoma in vitro.

The co-expression of KIT receptor and its ligand stem cell factor (SCF) has been reported in biopsy specimens of Merkel cell carcinoma (MCC). However, the functional role of SCF/KIT in the pathogenesis of this aggressive tumor has not been elucidated. The present study reports expression and effects of SCF and KIT in the Merkel cell carcinoma cell line MCC-1 in vitro. SCF and KIT were endogenously co-expressed in MCC-1 cells. Exogenous soluble SCF modulated KIT receptor mRNA and protein expression, stimulated growth of MCC-1 cells, upregulated endogenous activation of KIT, AKT, and of extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. On the contrary, an inhibitory antibody that neutralized the KIT ligand binding site, reduced growth of MCC-1 cells, as did high doses of the KIT kinase inhibitors imatinib and nilotinib. Also, inhibitors of KIT downstream effectors, U0126 that blocks MEK1/2 as well as wortmannin and LY294002 that inhibit phosphatidylinositol 3-kinase-dependent AKT phosphorylation, inhibited the proliferation of MCC-1 cells. These data support the hypothesis that KIT is activatable by paracrine or autocrine tumor cell-derived SCF and stimulates growth of Merkel cell carcinoma in vitro. Blockade of KIT and the downstream signaling cascade at various levels results in inhibition of Merkel cell carcinoma growth in vitro, suggesting targets for therapy of this cancer.

Analysis of epidemiology, clinical features and management of erysipelas.

BACKGROUND: Erysipelas is a superficial form of cellulitis affecting the upper dermis and superficial lymphatics. The widespread use of antibiotics may affect clinical findings and response to therapy of infectious disorders. The purpose of the study was to investigate the epidemiological, clinical, and laboratory features of erysipelas and to compare the results of treatment with penicillin vs. other antibiotic regimens. METHODS: All charts of erysipelas patients treated at the University Hospital of Heraklion, Crete, Greece from 1994 to 2002 were retrospectively studied. RESULTS: Median age of the 99 patients was 54.5 years; 59% were females. The most frequent site involved was the lower extremity (76%), followed by the face (17%) and upper extremity (6%). In 61 patients (62%), a possible entry portal was identified. The most common manifestation of erysipelas was local symptoms and signs (pain, erythema, and swelling) in all patients, together with elevated erythrocyte sedimentation rate (ESR) (60%). Fever was present in 25% of patients. The most commonly used antibiotic was intravenous penicillin G (64%). In the penicillin group, mean duration of fever after treatment initiation was shorter than in the nonpenicillin group (1.7 vs. 4.5 days, P = 0.002). Both treatment failures and recurrences were the same between the two groups. DISCUSSION: The diagnosis of erysipelas can be based on careful examination for local signs and symptoms. The role of ESR in primary diagnosis needs further investigation. Penicillin seems to preserve its fundamental role in the treatment of disease.

Co-expression of KIT receptor and its ligand stem cell factor in Merkel cell carcinoma.

BACKGROUND/AIMS: KIT receptor has been implicated in the pathogenesis of cancer, either by mutation or autocrine activation. Merkel cell carcinoma (MCC) is a rare KIT-positive cutaneous tumor. We investigated the co-expression of KIT and its ligand stem cell factor (SCF) in MCC. METHODS: Sixteen specimens from 13 MCC patients of various tumor stages were examined by immunohistochemistry for SCF, KIT, Ki67/MIB-1 and cleaved caspase 3 expression, and for apoptosis by TUNEL. RESULTS: KIT was expressed in 13 of 16 tumors, and SCF in 15 of 16 specimens. Co-expression of KIT and SCF was detected in 12 of 16 tumors. KIT and SCF immunoreactivity scores were independent of tumor stage. Ki67/MIB-1 proliferation rates were high, whereas apoptosis rates were low, and did not depend on KIT or SCF expression. CONCLUSION: Co-expression of KIT and SCF in a high percentage of MCC tumors hints to an autocrine mechanism. KIT and SCF expression in primary tumors and in metastases suggests an early event in Merkel cell transformation.

Interferon-alpha inhibits proliferation and induces apoptosis of merkel cell carcinoma in vitro.

Merkel cell carcinoma is a tumor with aggressive biological behavior and limited response to chemotherapy. The present study investigated the effect of interferon (IFN)-alpha on growth and apoptosis of Merkel carcinoma cells in vitro. Proliferation of MCC-1 cell line was reduced dose-dependently by IFN-alpha and diminished when higher IFN-alpha concentrations were used. Additionally, IFN-alpha potently decreased DNA-synthesis and Ki67/MIB-1 proliferation index of MCC-1 cultures. Furthermore, IFN-alpha induced dose-dependently apoptosis of MCC-1 cells as shown by caspase-3 activation, and detection of apoptotic DNA strand breaks and fragmented nuclei. These findings suggest that IFN-alpha may have antitumor activity against Merkel cell carcinoma.

Exposure of normal human melanocytes to a tumor promoting phorbol ester reverses growth suppression by transforming growth factor beta.

Transforming growth factor-beta (TGF-beta), a potent inhibitor of normal melanocyte growth, does not significantly suppress growth of melanoma cells. The mechanism of melanocyte desensitization to TGF-beta in the transformation process remains largerly unknown. We investigated whether the tumor promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) may induce melanocyte resistance to TGF-beta. Cell proliferation and DNA synthesis of normal human melanocytes were strongly inhibited by TGF-beta, whereas in the presence of TPA remained largerly unaffected. The inactive phorbol ester 4alpha-phorbol 12,13 didecanoate did not modify the TGF-beta antiproliferative effect, whereas the diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol counteracted TGF-beta effects. Protein kinase C (PKC) is the major cellular receptor of tumor promoting phorbol esters. PKC-alpha expression and phosphorylation were almost completely downregulated under combined treatment with TGF-beta + TPA at 24 and 72 h, as shown by immunoblots. Confocal microscopy demonstrated that TGF-beta-induced nuclear accumulation of PKC-alpha was abolished in the presence of TPA at the same time points. The selective PKC inhibitor Ro-31-8220 weakened the TGF-beta antiproliferative effect. Smads are central mediators for TGF-beta signal transduction. Smad-dependent transcriptional activity was suppressed in TGF-beta-treated melanocytes in the presence of TPA, as well as in ALK5 (constitutively active type I TGF-beta receptor)- or Smad3 + Smad4-transfected melanocytes in the presence of Ro-31-8220. In addition, an antisense oligodeoxynucleotide against PKC-alpha abolished TGF-beta-driven Smad-mediated transcription. These findings show that tumor promoting phorbol esters induce melanocyte resistance to TGF-beta, associated with downregulation of PKC-alpha and suppression of Smad-dependent transcription. This may represent an important mechanism for expansion of melanocytes exposed to PKC-targeting tumor promoters.

Invasive cutaneous infection with Geotrichum candidum: sequential treatment with amphotericin B and voriconazole.

A rare case of an invasive cutaneous infection by Geotrichum candidum in an 80-year-old male patient with diabetes mellitus is reported. The primary site of infection manifested after trauma as an ulcerative lesion on the distal phalanx of the midfinger and extended throughout the right hand. Histological examination showed fungal invasion in the deep dermis without vascular involvement and G. candidum was grown in cultures from the biopsy material. Angiography revealed severe obstructive disease of the right brachial artery and its branches. Treatment, after susceptibility testing of the isolated strain, consisted of sequential administration of intravenous liposomal amphotericin B with oral voriconazole followed by liposomal amphotericin B, resulting in substantial improvement of the infection.

Primary care and pattern of skin diseases in a Mediterranean island.

BACKGROUND: In Greece where primary health care services are not fully developed, patients with simple or minor conditions have to attend to hospitals to be treated. We analysed the data of patients with cutaneous disorders attending the tertiary referral hospital on the Island of Crete, with the aim to identify the most common conditions that patients complain of, in order to define the areas where the education of General Practitioners in Dermatology must focus. METHODS: All patients attending the Dermatology ambulatory office in the Emergency Department of the University General Hospital of Heraklion from January 2003 to December 2003 were included in this retrospective analysis. The medical records of the patients (history, physical examination and laboratory investigations) were analysed to ascertain the diagnosis and the management of cases. All patients were evaluated by qualified dermatologists. RESULTS: A total of 3715 patients attended the Dermatology Clinic. Most patients were young adults in the age group 21-40 years (38.4%), and the male to female ratio was 1 to 1.2. Allergic skin diseases, mostly dermatitis and urticaria (35.7%) were the most common for attendance, followed by infectious diseases (26.1%) and insect bites (10.2%). Inflammatory and autoimmune disorders accounted for 7.9% of the cases. Pruritus of unknown origin was diagnosed in 6.3% of patients. Skin tumors were detected in 2.7%. The management of the vast majority of cases (85.0%) consisted of advice with or without a prescription, while only 4.8% of patients required admission. CONCLUSION: Allergic and infectious skin diseases were the most common cutaneous diseases in patients attending this tertiary University hospital, while the management of most patients did not require specialised care. On the basis of the present data, the training of primary health care providers in Dermatology should emphasize these common conditions, with the aim of improving primary care and alleviating the burden on hospital care.

Bullous erysipelas: clinical presentation, staphylococcal involvement and methicillin resistance.

BACKGROUND: Erysipelas is a bacterial infection of the dermis and hypodermis, mostly of streptococcal origin. Bullous erysipelas represents a severe form of the disease. OBJECTIVE: To evaluate the clinical and microbiological characteristics and treatment of bullous erysipelas. METHODS: Patients with a diagnosis of bullous erysipelas who were treated at the Department of Dermatology, University Hospital of Heraklion, Crete, Greece, between the years 1996 and 2001 were retrospectively studied. RESULTS: Fourteen patients (11 women, 3 men) with bullous erysipelas were evaluated. The lesions were located on the legs and face in 9 and 4 patients, respectively. The median duration of disease before hospital admission was 4 days. Eight patients had fever at presentation. Local trauma and various lesions were common causes for pathogen entry. The initial empirical antibiotic treatment included intravenous beta-lactams and was modified according to the sensitivities of the isolated strains. Staphylococcus aureus was isolated from 7 (50%), while S. warneri, Streptococcus pyogenes and Escherichia coli grew from the lesions of 3 other patients. Six out of 7 S. aureus strains were methicillin resistant (MRSA) but susceptible to several other non-beta-lactam antibiotics such as quinolones, vancomycin, rifampicin and trimethoprim/sulfamethoxazole. CONCLUSION: Our findings suggest that S. aureus is frequently involved in and probably contributes in synergy with beta-hemolytic streptococci to the complicated course of bullous erysipelas. The frequency of MRSA isolation suggests that beta-lactam antibiotics may not be sufficient for the treatment of bullous erysipelas anymore, at least in areas with a high incidence of MRSA strains. The role of other classes of antibiotics providing adequate coverage for MRSA has to be evaluated in prospective clinical trials.

Scleredema adultorum of Buschke presenting as periorbital edema: a diagnostic challenge.

Scleredema adultorum is a rare sclerotic disorder characterized by diffuse swelling and nonpitting induration of the skin. Its occurrence has been documented in association with infections, diabetes mellitus, paraproteinemia, multiple myeloma, and monoclonal gammopathy. We report an unusual case of a 48-year-old man with an asymptomatic bilateral eyelid edema of sudden onset. During a period of 6 months, the condition slowly progressed to extensive nonpitting edematous swelling restricted to the periorbital sites. The presumptive diagnosis of scleredema adultorum was confirmed by the presence of typical histologic findings. This case is unique in that the periorbital swelling remained as the sole clinical manifestation of scleredema during the 5-year follow-up and was complicated with partial vision blockage.

Proliferation of human melanoma cells is under tight control of protein kinase C alpha.

Exponential proliferation of human melanoma cells has been associated with low levels of protein kinase C (PKC)-alpha. The aim of the present study was to investigate the functional relationship between PKC-alpha and melanoma cell proliferation. Treatment of human melanoma cells with the selective PKC inhibitor Ro-31-8220 resulted in a significant increase of cell proliferation as measured by (3)H-thymidine incorporation and a fluorometric microassay. In addition, phosphorothioate antisense-oligodeoxynucleotides (ODNs) to PKC-alpha enhanced DNA-synthesis of human melanoma cells. Furthermore, microinjection and transient transfection of melanoma cells with PKC-alpha decreased their proliferation, as shown by the reduction of nuclear staining with the proliferation marker Ki-67. The presented data demonstrate a cause-effect relationship between PKC-alpha and melanoma cell growth, whereby PKC-alpha reversely influences the rate of cell proliferation.