Eccrine porocarcinoma of the head: An important differential diagnosis in the elderly patient

Background: Eccrine porocarcinoma is a rare malignant tumor of the sweat gland, characterized by a broad spectrum of clinicopathologic presentations. Surprisingly, unlike its benign counterpart eccrine poroma, eccrine porocarcinoma is seldom found in areas with a high density of eccrine sweat glands, like the palms or soles. Instead, eccrine porocarcinoma frequently occurs on the lower extremities, trunk and abdomen, but also on the head, resembling various other skin tumors, as illustrated in the patients described herein. Observations: We report 5 cases of eccrine porocarcinoma of the head. All patients were initially diagnosed as having epidermal or melanocytic skin tumors. Only after histopathologic examination were they classified as eccrine porocarcinoma, showing features of epithelial tumors with abortive ductal differentiation. Characteristic clinical, histopathologic and immunohistochemical findings of eccrine porocarcinomas are illustrated. Conclusion: Eccrine porocarcinomas are potentially fatal adnexal malignancies, in which extensive metastatic dissemination may occur. Porocarcinomas are commonly overlooked, or misinterpreted as squamous or basal cell carcinomas as well as other common malignant and even benign skin tumors. Knowledge of the clinical pattern and histologic findings, therefore, is crucial for an early therapeutic intervention, which can reduce the risk of tumor recurrence and serious complications. Copyright (c) 2008 S. Karger AG, Basel

l-Arginine deprivation impairs Leishmania major-specific T-cell responses

The amino acid l-arginine plays a crucial role in the regulation of immune responses. We have recently shown that uncontrolled replication of Leishmania parasites at the site of pathology correlates with high levels of arginase activity in nonhealing leishmaniasis and that this elevated arginase activity causes local depletion of l-arginine. To further our understanding of the impact of l-arginine deprivation in experimental leishmaniasis, here we characterize in detail the effects of l-arginine deprivation on antigen-specific T cells and MΦ. The results of our study show that decrease of l-arginine levels in the extracellular milieu affects the biological activities of Leishmania major-specific T cells, both at the level of the magnitude and the quality of their responses. L. major-specific CD4+ T cells rendered hyporesponsive by l-arginine deprivation can be partially rescued by addition of exogenous l-arginine to produce IL-4 and IL-10, but not to produce IFN-γ. Furthermore, our results show that l-arginine deprivation also greatly impacts parasite growth in activated macrophages. In summary, our results suggest that l-arginine levels affect both Th cell responses and parasite replication

Humoral Autoimmune Responses to the Squamous Cell Carcinoma Antigen Protein Family in Psoriasis

Substantial evidence indicates that psoriasis is a T-lymphocyte-mediated autoimmune disease. However, longstanding data also indicate IgG and complement deposition in upper epidermis of psoriasis plaques. This led us to propose that autoantigen–autoantibody interactions in the skin may also be of pathogenic importance. Here, we have confirmed the presence of IgG in upper lesional epidermis and used high-resolution two-dimensional immunoblotting of extracts from this tissue, and laser desorption mass spectrometry of tryptic peptides, to define a series of epidermal proteins that bind IgG from psoriatic serum. The most prominent of these autoantigens are homologues of the serpin, squamous cell carcinoma antigen (SCCA), the other autoantigens identified including arginase 1, enolase 1, and keratin 10. Blood levels of IgG autoantibodies that bind to SCCA proteins were significantly higher in psoriasis than healthy controls (P=0.005), but were not detectable in sera from patients with active atopic dermatitis. To our knowledge, SCCA proteins have not previously been described as autoantigenic in animals or humans and form complexes with IgG that are associated with complement deposition. These findings expose potentially pathogenic humoral immunologic events and thus possible therapeutic targets in psoriasis

Chronic recurrent Gorham-Stout syndrome with cutaneous involvement

Type IV osteolysis or Gorham-Stout syndrome is a rare condition characterized by recurrent vascular tumors that disrupt normal anatomical architecture. Gorham-Stout syndrome is most commonly associated with the skeletal system with resulting replacement of bone with scar tissue following tumor regression. The loss of entire bones has given Gorham-Stout syndrome the moniker vanishing bone disease. Natural progression of Gorham-Stout syndrome is characterized by spontaneous disease resolution. However, rare variants of recurrent, progressive, and/or systemic disease have been reported. We present a patient with a history of recurrent Gorham- Stout disease refractory to all treatment options considered. In addition to skeletal disease, our patient had soft tissue and cutaneous involvement, thus reflecting the more aggressive disease variant. Previous surgical attempts to control disease had been ineffective and the patient was referred to us for radiation therapy. Treatment with external beam radiation therapy resulted in good local control and symptom palliation, but full disease resolution was never accomplished. In addition to presentation of this patient, a review of the literature on etiological hypotheses and past/future treatment options was conducted and is included

Chitosan nanoparticles for nitric oxide delivery in human skin

The use of nanoparticle-based transdermal delivery systems is a promising approach to efficiently carry and deliver therapeutic agents for dermal and systemic administration. Nitric oxide (NO) is a key molecule that plays important roles in human skin such as the control of skin homeostasis, skin defense, control of dermal blood flow, and wound healing. In addition, human skin contains stores of NO derivatives that can be mobilized and release free NO upon UV irradiation with beneficial cardiovascular effects, for instance the control of blood pressure. In this work, the NO donor precursor glutathione (GSH) was encapsulated (encapsulation efficiency of 99.60%) into ultra-small chitosan nanoparticles (CS NPs) (hydrodynamic size of 30.65 +/- 11.90 nm). GSH-CS NPs have a core-shell structure, as revealed by atomic force microscopy and X-ray photoelectron spectroscopy, in which GSH is protected in the nanoparticle core. Nitrosation of GSH by nitrous acid led to the formation of the NO donor S-nitrosogluthathione (GSNO) into CS NPs. The GSNO release from the CS NPs followed a Fickian diffusion described by the Higuchi mathematical model. Topical application of GSNO-CS NPs in intact human skin significantly increased the levels of NO and its derivatives in the epidermis, as assayed by confocal microscopy, and this effect was further enhanced by skin irradiation with UV light. Therefore, NO-releasing CS NPs are suitable materials for transdermal NO delivery to local and/or systemic therapies.FAPESP [2015/00393-8, 2016/10347-6]Brazilian Network on Nanotoxicology (MCTI/CNPq) [552120/2011-1]Laboratory of Nanostructure Synthesis and Biosystem InteractionsNANOBIOSS (MCTI) [402280-2013]Newton Advanced Fellowship (The Royal Society) [NA140046]Univ Fed Sao Paulo, Exact & Earth Sci Dept, Rua Sao Nicolau 210, BR-09913030 Diadema, SP, BrazilUniv Fed ABC, Ctr Nat & Human Sci, Av Estados 5001, BR-09210580 Santo Andre, SP, BrazilUniv Edinburgh, Queens Med Res Inst, MRC, Ctr Inflammat Res, 47 Little France Crescent, Edinburgh EH16 4TJ, Midlothian, ScotlandNatl Ctr Energy & Mat CNPEM, Natl Nanotechnol Lab LNNano, Rua Giuseppe Maximo Scolfaro 10-000, BR-13083970 Campinas, SP, BrazilUniv Fed Sao Paulo, Exact & Earth Sci Dept, Rua Sao Nicolau 210, BR-09913030 Diadema, SP, BrazilWeb of Scienc

IL-17A Synergizes with IFN-γ to Upregulate iNOS and NO Production and Inhibit Chlamydial Growth

IFN-γ-mediated inducible nitric oxide synthase (iNOS) expression is critical for controlling chlamydial infection through microbicidal nitric oxide (NO) production. Interleukin-17A (IL-17A), as a new proinflammatory cytokine, has been shown to play a protective role in host defense against Chlamydia muridarum (Cm) infection. To define the related mechanism, we investigated, in the present study, the effect of IL-17A on IFN-γ induced iNOS expression and NO production during Cm infection in vitro and in vivo. Our data showed that IL-17A significantly enhanced IFN-γ-induced iNOS expression and NO production and inhibited Cm growth in Cm-infected murine lung epithelial (TC-1) cells. The synergistic effect of IL-17A and IFN-γ on Chlamydia clearance from TC-1 cells correlated with iNOS induction. Since one of the main antimicrobial mechanisms of activated macrophages is the release of NO, we also examined the inhibitory effect of IL-17A and IFN-γ on Cm growth in peritoneal macrophages. IL-17A (10 ng/ml) synergizes with IFN-γ (200 U/ml) in macrophages to inhibit Cm growth. This effect was largely reversed by aminoguanidine (AG), an iNOS inhibitor. Finally, neutralization of IL-17A in Cm infected mice resulted in reduced iNOS expression in the lung and higher Cm growth. Taken together, the results indicate that IL-17A and IFN-γ play a synergistic role in inhibiting chlamydial lung infection, at least partially through enhancing iNOS expression and NO production in epithelial cells and macrophages

Pathway Analysis for Genome-Wide Association Study of Basal Cell Carcinoma of the Skin

Recently, a pathway-based approach has been developed to evaluate the cumulative contribution of the functionally related genes for genome-wide association studies (GWASs), which may help utilize GWAS data to a greater extent.In this study, we applied this approach for the GWAS of basal cell carcinoma (BCC) of the skin. We first conducted the BCC GWAS among 1,797 BCC cases and 5,197 controls in Caucasians with 740,760 genotyped SNPs. 115,688 SNPs were grouped into gene transcripts within 20 kb in distance and then into 174 Kyoto Encyclopedia of Genes and Genomes pathways, 205 BioCarta pathways, as well as two positive control gene sets (pigmentation gene set and BCC risk gene set). The association of each pathway with BCC risk was evaluated using the weighted Kolmogorov-Smirnov test. One thousand permutations were conducted to assess the significance.Both of the positive control gene sets reached pathway p-values<0.05. Four other pathways were also significantly associated with BCC risk: the heparan sulfate biosynthesis pathway (p  =  0.007, false discovery rate, FDR  =  0.35), the mCalpain pathway (p  =  0.002, FDR  =  0.12), the Rho cell motility signaling pathway (p  =  0.011, FDR  =  0.30), and the nitric oxide pathway (p  =  0.022, FDR  =  0.42).We identified four pathways associated with BCC risk, which may offer new insights into the etiology of BCC upon further validation, and this approach may help identify potential biological pathways that might be missed by the standard GWAS approach