Human Skin Lesions Research Articles

TG-interacting factor mediates arsenic-induced malignant transformation of keratinocytes via c-Src/EGFR/AKT/FOXO3A and redox signalings.

Inorganic arsenic is well known as a carcinogen in human beings. Chronic exposure to inorganic arsenic increases risks of developing some cancers and non-carcinogenic diseases, such as skin lesions in humans. However, the modes of action are not well elucidated. In the present study, HaCaT cells, an immortalized non-tumorigenic human keratinocyte, were continuously exposed to low-dose trivalent arsenic (arsenic trioxide, 0.1 and 0.2 μM) for at least 4 weeks. We proved that low-dose arsenic could stimulate malignant transformation of HaCaT cells, including increase of cellular proliferation, epithelial-to-mesenchymal transition markers alteration, matrix metalloproteinases activation, invadopodia formation, migration/invasion activities, and anchorage-independent growth. Surprisingly, low-dose arsenic could also transcriptionally increase TG-interacting factor (TGIF) expression via c-Src/EGFR/AKT/FOXO3A signaling involving superoxide production from NADPH oxidase. Moreover, stable overexpression of TGIF could also induce malignant transformation of HaCaT cells. Knockdown of TGIF with its specific shRNA abolished the arsenic-induced effects. Taken together, we suggest that TGIF plays an important role in low-dose arsenic-induced malignant transformation of HaCaT cells, which is regulated by c-Src/EGFR/AKT/FOXO3A pathway and redox signaling.

CXCR7 expression correlates with tumor depth in cutaneous squamous cell carcinoma skin lesions and promotes tumor cell survival through ERK activation.

The chemokine receptor CXCR7 has been demonstrated to be involved in the development of certain cancers, but its role in cutaneous squamous cell carcinoma (SCC) has not been previously investigated. We seek to determine whether CXCR7 is expressed in human cutaneous SCC skin lesions and SCC cell lines. In addition, we evaluate whether CXCR7 plays a role in SCC cell proliferation, survival and migration and which signalling pathways are involved. Using quantitative RT-PCR to analyse the mRNA expression of 19 different chemokine receptors, we found that CXCR7 was much more highly expressed compared to other chemokine receptors in cutaneous SCC cell lines (HSC-1 and HSC-5). On immunohistochemical staining, CXCR7 was found to be expressed in 70% (28 of 40) of human cutaneous SCC tissue specimens, and its expression correlated with tumor depth >4mm and cancer stage ≥II. CXCR7 but not CXCR4 protein was expressed on the surface of HSC-1 and HSC-5 cells by flow cytometry. Activation of the CXCR7 receptor by CXCL12 promoted survival of HSC-1 and HSC-5 cells through the ERK pathway, but had no significant effect on cell proliferation or migration. In summary, our findings indicate that CXCR7 is frequently expressed in cutaneous SCC skin lesions and its expression correlates with tumor depth and cancer stage. CXCR7 is the predominant chemokine receptor expressed in SCC cell lines, and activation of CXCR7 by CXCL12 promotes survival of SCC cells through the ERK pathway. These findings provide new insights into the significance of CXCR7 in the pathophysiology of SCC.

Video‐mosaicing of reflectance confocal images for examination of extended areas of skin in vivo

With cellular-level resolution comparable to histology, reflectance confocal microscopy (RCM) imaging is a promising approach both for diagnosis of skin cancer in vivo with high sensitivity and specificity1,2, and for pre- and intra-operative detection of cancer margins to guide treatment.3–5 However, RCM images are limited to a field of view (FOV) of 1 mm -by- 1 mm, much smaller than the typical size of skin lesions. Many diagnostic features cannot be reliably identified in such small FOVs. Moreover, clinicians rely heavily on visual context of the surrounding tissue to perform diagnoses. Thus, larger areas must be imaged to evaluate cellular and morphologic features with high accuracy and repeatability. To address this concern, mosaicing approaches, which increase the FOV by acquiring a matrix of adjacent images and stitching them together to display a large area, have been developed for confocal microscopy6. In standard mosaicing, images are acquired while mechanically translating the microscope lens relative to the skin along pre-determined linear (straight-line) trajectories. This approach was implemented in the RCM scanner used in the cited studies1–5, and, in fact, is now routinely used on patients. However, the mechanics of translation limit speed and coverage to pre-selected small rectangular-shaped areas, currently up to 8 mm-by-8 mm, imaged in ~4.5 minutes. Coverage and speed could be increased, of course, with larger and faster mechanical translation systems, but would add significant size and cost to RCM scanners, and would certainly not be practical for routine use on patients. Miniaturized confocal endoscopes have been developed that allow the operator flexible control for imaging in vivo, without the constraints of mechanical translation7,8 Similar flexibility is now possible for imaging skin with the recent advent of smaller and miniaturized handheld confocal microscopes9,10,11. The operator manually moves the microscope along a desired curvilinear trajectory, with the lens gently pressed against the tissue, while acquiring a video sequence of images. Video microscopy enables the operator to choose the trajectory in real-time, allowing adaptive coverage of areas that can be selected in real-time during acquisition. Thus, an area with any shape and size may be rapidly imaged, without the previous constraints of straight-line trajectories and rectangular coverage. However, observing a video, by itself, merely as a time-sequence of small FOVs, does not readily provide the necessary visual context from the surrounding tissue. In this paper, we present results from an approach for computationally transforming such videos into mosaics that display the entire imaged area. Algorithms for video-mosaicing have been developed in the fields of computational photography and computer vision12, and their use has previously been reported for confocal endoscopic imaging7,8.We report here application of video-mosaicing to reflectance confocal images of human skin lesions and margins in vivo.

The role of ubiquitin and ubiquitin-like modification systems in papillomavirus biology.

Human papillomaviruses (HPVs) are small DNA viruses that are important etiological agents of a spectrum of human skin lesions from benign to malignant. Because of their limited genome coding capacity they express only a small number of proteins, only one of which has enzymatic activity. Additionally, the HPV productive life cycle is intimately tied to the epithelial differentiation program and they must replicate in what are normally non-replicative cells, thus, these viruses must reprogram the cellular environment to achieve viral reproduction. Because of these limitations and needs, the viral proteins have evolved to co-opt cellular processes primarily through protein-protein interactions with critical host proteins. The ubiquitin post-translational modification system and the related ubiquitin-like modifiers constitute a widespread cellular regulatory network that controls the levels and functions of thousands of proteins, making these systems an attractive target for viral manipulation. This review describes the interactions between HPVs and the ubiquitin family of modifiers, both to regulate the viral proteins themselves and to remodel the host cell to facilitate viral survival and reproduction.

Mechanisms of carcinogenesis in human skin against the background of papillomavirus infection.

The cells in the skin tumor developing under conditions of persisting papillomavirus infection are morphologically identical to blast cells in a blood smear from a leukemia patient. The cells filling the lesion focus are morphologically and immunohistochemically related to blood stem cells. A mechanism of epithelial layer modification under conditions of papillomavirus infection leading to carcinogenesis is proposed. The dynamics of structural changes in the skin is characterized by disturbed interactions between the epithelium and adjacent connective tissue, destruction of the basal membrane, disorders in the cambial keratinocyte differentiation, and absence of the spinous and granular layers. We conclude that detection of blast leukocytes in the human skin lesion can be explained by disorders in the cell-cell interactions in the epithelium-mesenchymal tissue system. High proliferative activity followed by death of cambial keratinocytes, migration of effector antigen-presenting CD68 cells to the adjacent connective tissue are the factors inducing migration of blast leukocytic forms to the focus. Not only keratinocyte restitution capacity, but also epithelium-dependent differentiation of young leukocytes disappeared. Undifferentiated cells are migrated from the blood to the epithelium alteration zone, but not in the reverse direction. The insufficiency or the absence of blood blast cell differentiation of the in the focus of epidermal injury and adjacent tissue triggers carcinogenesis. The authors suggest their model of carcinogenesis. The conclusions offer a new concept of cancer pathogenesis and suggest a new strategy in the search for methods for early diagnosis of carcinogenesis.

Inhibition of keratinocyte differentiation by the synergistic effect of IL-17A, IL-22, IL-1α, TNFα and oncostatin M.

Keratinocyte differentiation program leading to an organized epidermis plays a key role in maintaining the first line of defense of the skin. Epidermal integrity is regulated by a tight communication between keratinocytes and leucocytes, particularly under cytokine control. Imbalance of the cytokine network leads to inflammatory diseases such as psoriasis. Our attempt to model skin inflammation showed that the combination of IL-17A, IL-22, IL-1α, OSM and TNFα (Mix M5) synergistically increases chemokine and antimicrobial-peptide expression, recapitulating some features of psoriasis. Other characteristics of psoriasis are acanthosis and down-regulation of keratinocyte differentiation markers. Our aim was to characterize the specific roles of these cytokines on keratinocyte differentiation, and to compare with psoriatic lesion features. All cytokines decrease keratinocyte differentiation markers, but IL-22 and OSM were the most powerful, and the M5 strongly synergized the effects. In addition, IL-22 and OSM induced epidermal hyperplasia in vitro and M5 induced epidermal thickening and decreased differentiation marker expression in a mouse model, as observed in human psoriatic skin lesions. This study highlights the precise role of cytokines in the skin inflammatory response. IL-22 and OSM more specifically drive epidermal hyperplasia and differentiation loss while IL-1α, IL-17A and TNFα were more involved in the activation of innate immunity.

Skin manifestations of arthropod-borne infection in Latin America

Arthropods are a significant cause of human skin lesions and infections, especially in Latin America. This review summarizes recent articles on the cutaneous manifestations of arthropod-borne diseases, with an emphasis on those diseases causing direct skin damage but also considering those systemic diseases with cutaneous manifestations. Studies have shown a variety and increase of cutaneous manifestations caused by arthropod-borne infections, including petechiae, purpura, ulcers, nodules, atrophic, miliary and hyperpigmented lesions. Although unspecific, when considering other features they become a useful tool in the diagnostic approach. Unusual cutaneous presentation of these diseases has been found to be associated with development of immunity, virulent strain, drug resistance and immunosuppressive states. Also, because of globalization, climate change and large-scale migration, these manifestations have spread to new areas. Cutaneous manifestations of arthropod-borne infections are varied and nonspecific. Their atypical presentations are mainly related to immune impairment and strain virulence. When considering a patient with skin lesions, other clinical and laboratory features must be taken into account in order to make an accurate diagnostic approach.

Different detectability of cyclooxygenase-2 (COX-2) protein in standard paraffin sections and tissue microarrays of human melanomas and naevi – Comparative study

Cyclooxygenase-2 (COX-2), overexpressed in many types of human cancer, may be a valuable marker for human melanoma. However, there are discrepancies between expression levels detected by different groups. The majority of the studies were carried out using standard paraffin sections. Tissue microarrays (TMAs) might enable analysis of COX-2 expression in numerous lesions. Our study assesses to what extent reprocessing of tissue samples used for preparing TMAs may influence reproducibility of data obtained for standard sections.The study included TMAs and standard histopathologic sections. COX-2 was detected by immunohistochemistry with two primary antibodies targeting different epitopes.COX-2 expression levels detected with both antibodies in standard sections were similar as in our previous study. Surprisingly, results obtained in TMAs were significantly different. While one of the antibodies yielded for TMAs results similar to standard sections, COX-2 expression levels found with the second antibody were very low and expression patterns strikingly different from those observed for standard sections and for both TMAs studied with the first antibody.Good performance of the antibodies found in standard sections of human skin and melanocytic lesions does not guarantee similar results in TMAs. The finding discloses a new aspect of immunohistochemical assays involving TMAs.

Involvement of necroptosis in the development of imiquimod-induced psoriasis-like dermatitis (BA3P.135)

Abstract Necroptosis is a form of programed cell death, in which receptor-interacting protein (RIP)1 and subsequent RIP3 kinase activation is a central pathway for its development. Necroptotic cells induce inflammation through the release of various cytokines or necrotic danger-associated molecular patterns. Recent reports indicated that mice with keratinocyte-specific necroptotic cell death exhibit severe chronic skin inflammation, which suggests the involvement of necroptosis in the pathogenesis of chronic skin inflammatory diseases, such as psoriasis. In this study, we investigated the involvement of necroptosis in the pathogenesis of psoriasis using an imiquimod (IMQ)-induced mouse psoriasis model. Daily application of IMQ to skin caused skin inflammation with psoriariform scaly erythema with epidermal and dermal thickening. In the skin, we detected positive signals of TUNEL both in the epidermis and dermis, suggesting the induction of programmed cell death in skin by IMQ application. In addition, RIP3 expression was significantly upregulated both in mRNA and protein level in the skin lesions. Administration of necrostatin-1, a specific inhibitor of RIP1 kinase, significantly reduced the severity of IMQ-induced psoriasis-like dermatitis. Immunohistochemical analysis revealed positive signals for RIP3 in the human psoriasis skin lesion. These results indicate the involvement of necroptosis in mouse psoriasis model, and suggest it's involvement in the pathogenesis of psoriasis.

Basophils regulate the recruitment of eosinophils in a murine model of irritant contact dermatitis

Although eosinophils have been detected in several human skin diseases in the vicinity of basophils, how eosinophils infiltrate the skin and the role of eosinophils in the development of skin inflammation have yet to be examined. Using murine irritant contact dermatitis (ICD) as a model, we sought to clarify the roles of eosinophils in ICD andthe underlying mechanism of eosinophil infiltration of the skin. We induced croton oil-induced ICD in eosinophil-deficient ΔdblGATA mice with or without a reactive oxygen species (ROS) inhibitor. We performed cocultivation with fibroblasts and bone marrow-derived basophils and evaluated eosinophil migration using a chemotaxis assay. ICD responses were significantly attenuated in the absence of eosinophils or by treatment with the ROS inhibitor. ROS was produced abundantly by eosinophils, and both basophils and eosinophils were detected in human and murine ICD skin lesions. In coculture experiments, basophils attracted eosinophils, especially in the presence of fibroblasts. Moreover, basophils produced IL-4 and TNF-α in contact with fibroblasts and promoted the expression of eotaxin/CCL11 from fibroblasts invitro. Eosinophils mediated the development of murine ICD, possibly through ROS production. Recruitment of eosinophils into the skin was induced by basophils in cooperation with fibroblasts. Our findings introduce the novelconcept that basophils promote the recruitment of eosinophils into the skin through fibroblasts in the developmentof skin inflammation.

Inactivation of p15INK4b in chronic arsenic poisoning cases

Arsenic exposure from burning high arsenic-containing coal has been associated with human skin lesion and cancer. However, the mechanisms of arsenic-related carcinogenesis are not fully understood. Inactivation of critical tumor suppression genes by epigenetic regulation or genetic modification might contribute to arsenic-induced carcinogenicity. This study aims to clarify the correlation between arsenic pollution and functional defect of p15INK4b gene in arsenic exposure residents from a region of Guizhou Province, China. To this end, 103 arsenic exposure residents and 105 control subjects were recruited in this study. The results showed that the exposure group exhibited higher levels of urinary and hair arsenic compared with the control group (55.28 vs 28.87 μg/L, 5.16 vs 1.36 μg/g). Subjects with higher arsenic concentrations are more likely to have p15INK4b methylation and gene deletion (χ2 = 4.28, P = 0.04 and χ2 = 4.31, P = 0.04). We also found that the degree of p15INK4b hypermethylation and gene deletion occurred at higher incidence in the poisoning cases with skin cancer (3.7% and 14.81% in non-skin cancer group, 41.18% and 47.06 in skin cancer group), and were significantly associated with the stage of skin lesions (χ2 = 12.82, P < 0.01 and χ2 = 7.835, P = 0.005). These observations indicate that inactivation of p15INK4b through genetic alteration or epigenetic modification is a common event that is associated with arsenic exposure and the development of arsenicosis.

Expansion of natural killer cells in peripheral blood in a Japanese elderly with human T-cell lymphotropic virus type 1-related skin lesions.

Natural killer (NK) cells were proposed to play an important role in the pathogenesis of human T-cell lymphotropic virus type 1- (HTLV-1-) associated neurologic disease. Our patient was a 77-year-old Japanese man, who had been treated for infective dermatitis associated with HTLV-1 for nearly 10 years. When referred to us, he had facial eczema/edema as well as extensive dermatitis at the neck/upper chest and nuchal area/upper back regions. Dermal lesions had CD3+CD4+ cells, but no NK cells. Flow cytometry of his peripheral blood showed a phenotype of CD2+ (97%), CD3+ (17%), CD4+ (12%), CD7+ (94%), CD8+ (6%), CD11c+ (70%), CD16+ (82%), CD19+ (0%), CD20+ (0%), CD56+ (67%), HLA-DR+ (68%), and NKp46+ (36%). Absolute numbers of CD56+NK cells in the peripheral blood were in a range of 986/μL–1,270/μL. The expanded NK cells in the peripheral blood are considered to be reactive, to maintain the confinement of the HTLV-1-positive CD4+ cells in the skin, and to prevent the progression of the disease.

Comparative and retrospective molecular analysis of Parapoxvirus (PPV) isolates

Species members of the genus Parapoxvirus (PPV) within the family Poxviridae cause contagious pustular dermatitis in small ruminants (Orf virus, ORFV) and mostly mild localized inflammation in cattle (bovine papular stomatitis virus, BPSV and pseudocowpox virus, PCPV). All PPVs are known to be zoonotic, leading to circumscribed skin lesions in humans, historically known as milker's nodules. Human PPV isolates are often ill defined concerning their allocation to an animal origin.Here we present a comparative molecular analysis of a unique collection of 21 historic and recent human and animal PPV cell culture isolates (and two PPV DNA samples). Cell culture PPV propagation was restricted to primary ruminant fibroblasts and was strictly kept at low passages to avoid genomic changes by in vitro influences. For molecular arrangement of the isolate DNAs and their attribution to established PPV species DNA fragments of the PPVs were generated by two different discriminating PCR protocols, targeting the major part of the open reading frame (ORF) 011 (B2L gene) and the complete ORF 032. Multiple sequence alignments and phylogenetic analysis of both genes resulted in affiliation to the known PPV species. The sequences from the ORF 032 allowed discrimination of the isolate DNAs at a higher resolution. Human PPV isolates could be clearly assigned to the PPV species belonging to the reported or assumed animal host of transmission.For the first time, a whole PPV genome sequence comparison of a human biopsy derived virus (B029) and its ovine counterpart (B015) originating from a defined Orf outbreak in Germany is provided, revealing their well conserved relationship. Thus human PPVs can be molecularly retraced to the PPV species indicating the animal of transmission. After transmission to the human host, molecular conservation of the animal's virus peculiarities indicative for a PPV species became evident.

Prostaglandin E2 is critical for the development of niacin-deficiency-induced photosensitivity via ROS production

Pellagra is a photosensitivity syndrome characterized by three “D's”: diarrhea, dermatitis, and dementia as a result of niacin deficiency. However, the molecular mechanisms of photosensitivity dermatitis, the hallmark abnormality of this syndrome, remain unclear. We prepared niacin deficient mice in order to develop a murine model of pellagra. Niacin deficiency induced photosensitivity and severe diarrhea with weight loss. In addition, niacin deficient mice exhibited elevated expressions of COX-2 and PGE syntheses (Ptges) mRNA. Consistently, photosensitivity was alleviated by a COX inhibitor, deficiency of Ptges, or blockade of EP4 receptor signaling. Moreover, enhanced PGE2 production in niacin deficiency was mediated via ROS production in keratinocytes. In line with the above murine findings, human skin lesions of pellagra patients confirmed the enhanced expression of Ptges. Niacin deficiency-induced photosensitivity was mediated through EP4 signaling in response to increased PGE2 production via induction of ROS formation.

A new cultivation‐independent tool for fast and reliable detection ofMycobacterium marinum

The Mycobacterium marinum group (MMG) is a class of mycobacteria that includes M.marinum, the cause of chronic systemic infections in fish. This species occasionally causes granulomatous skin lesions in humans. Other members of MMG are mycolactone-producing mycobacteria (MPM; M.ulcerans, M.shottsii and M.pseudoshottsii). The cultivation-independent approach presented in this study brings a fast and reliable alternative to classically used cultivation methods. The developed triplex erp/IS2404 qPCR assay is based on a primary species-specific erp detection, which allows enumeration of MMG in analysed samples, and secondary IS2404 detection is suitable for the differentiation of M.marinum from MPM. The detection of M.marinum in clinical specimens and in artificially contaminated tissue samples has proven its applicability for diagnostic purposes.

Comprehensive Analysis of Varicella-Zoster Virus Proteins Using a New Monoclonal Antibody Collection

Varicella-zoster virus (VZV) is the etiological agent of chickenpox and shingles. Due to the virus's restricted host and cell type tropism and the lack of tools for VZV proteomics, it is one of the least-characterized human herpesviruses. We generated 251 monoclonal antibodies (MAbs) against 59 of the 71 (83%) currently known unique VZV proteins to characterize VZV protein expression in vitro and in situ. Using this new set of MAbs, 44 viral proteins were detected by Western blotting (WB) and indirect immunofluorescence (IF); 13 were detected by WB only, and 2 were detected by IF only. A large proportion of viral proteins was analyzed for the first time in the context of virus infection. Our study revealed the subcellular localization of 46 proteins, 14 of which were analyzed in detail by confocal microscopy. Seven viral proteins were analyzed in time course experiments and showed a cascade-like temporal gene expression pattern similar to those of other herpesviruses. Furthermore, selected MAbs tested positive on human skin lesions by using immunohistochemistry, demonstrating the wide applicability of the MAb collection. Finally, a significant portion of the VZV-specific antibodies reacted with orthologs of simian varicella virus (SVV), thus enabling the systematic analysis of varicella in a nonhuman primate model system. In summary, this study provides insight into the potential function of numerous VZV proteins and novel tools to systematically study VZV and SVV pathogenesis.

Spectral morphological analysis of skin lesions with a polarization multispectral dermoscope

Dermoscopy is the conventional technique used for the clinical inspection of human skin lesions. However, the identification of diagnostically relevant morphologies can become a complex task. We report on the development of a polarization multispectral dermoscope for the in vivo imaging of skin lesions. Linearly polarized illumination at three distinct spectral regions (470, 530 and 625 nm), is performed by high luminance LEDs. Processing of the acquired images, by means of spectral and polarization filtering, produces new contrast images, each one specific for melanin absorption, hemoglobin absorption, and single scattering. Analysis of such images could facilitate the identification of pathological morphologies.

CD44v6 expression in human skin keratinocytes as a possible mechanism for carcinogenesis associated with chronic arsenic exposure

Inorganic arsenic is a well-known human skin carcinogen. Chronic arsenic exposure results in various types of human skin lesions, including squamous cell carcinoma (SCC). To investigate whether mutant stem cells participate in arsenic-associated carcinogenesis, we repeatedly exposed the human spontaneously immortalized skin keratinocytes (HaCaT) cell line to an environmentally relevant level of arsenic (0.05 ppm) in vitrofor 18 weeks. Following sodium arsenite administration, cell cycle, colony-forming efficiency (CFE), cell tumorigenicity, and expression of CD44v6, NF-κB and p53, were analyzed at different time points (0, 5, 10, 15, 20, 25 and 30 passages). We found that a chronic exposure of HaCaT cells to a low level of arsenic induced a cancer stem-like phenotype. Furthermore, arsenictreated HaCaT cells also became tumorigenic in nude mice, their growth cycle was predominantly in G2/M and S phases. Relative to nontreated cells, they exhibited a higher growth rate and a significant increase in CFE. Western blot analysis found that arsenic was capable of increasing cell proliferation and sprouting of cancer stem-like phenotype. Additionally, immunohistochemical analysis demonstrated that CD44v6 expression was upregulated in HaCaT cells exposed to a low level of arsenic during early stages of induction. The expression of CD44v6 in arsenic-treated cells was positively correlated with their cloning efficiency in soft agar (r=0.949, P=0.01). Likewise, the expressions of activating transcription factor NF-κB and p53 genes in the arsenic-treated HaCaT cells were significantly higher than that in non-treated cells. Higher expressions of CD44v6, NF-κB and p53 were also observed in tumor tissues isolated from Balb/c nude mice. The present results suggest that CD44v6 may be a biomarker of arsenicinduced neoplastic transformation in human skin cells, and that arsenic promotes malignant transformation in human skin lesions through a NF-κB signaling pathway-stimulated expression of CD44v6.

Dimethyl Fumarate Modulation of Immune and Antioxidant Responses: Application to HIV Therapy

The persistence of chronic immune activation and oxidative stress in human immunodeficiency virus (HIV)-infected, antiretroviral drug-treated individuals are major obstacles to fully preventing HIV disease progression. The immune modulator and antioxidant dimethyl fumarate (DMF) is effective in treating immune-mediated diseases and it also has potential applications to limiting HIV disease progression. Among the relevant effects of DMF and its active metabolite monomethyl fumarate (MMF) are induction of a Th1 to Th2 lymphocyte shift, inhibition of pro-inflammatory cytokine signaling, inhibition of NF-κB nuclear translocation, inhibition of dendritic cell maturation, suppression of lymphocyte and endothelial cell adhesion molecule expression, and induction of the Nrf2-dependent antioxidant response element (ARE) and effector genes. Associated with these effects are reduced lymphocyte and monocyte infiltration into psoriatic skin lesions in humans and immune-mediated demyelinating brain lesions in rodents, which confirms potent systemic and central nervous system (CNS) effects. In addition, DMF and MMF limit HIV infection in macrophages in vitro, albeit by unknown mechanisms. Finally, DMF and MMF also suppress neurotoxin production from HIV-infected macrophages, which drives CNS neurodegeneration. Thus, DMF might protect against systemic and CNS complications in HIV infection through its effective suppression of immune activation, oxidative stress, HIV replication, and macrophage-associated neuronal injury.

Fish Tank Granuloma Caused byMycobacterium marinumin Two Aquarists: Two Case Reports

Mycobacterium marinum, the cause of chronic systemic infections in fish, occasionally causes granulomatous skin and soft tissue lesions in humans. Cutaneous mycobacterial infection in two patients owing to unusual circumstances is presented in this report. The first patient was infected through improper hygienic behavior, while infection in the second patient was previously misdiagnosed as rheumatoid arthritis and treated with methylprednisolone for a period of three months, which resulted in a rare systemic spread of M. marinum into the bones of the hand, testis, and epididymis. Simultaneously, screening for possible sources of M. marinum infection in patients' aquaria revealed positive fish harboring VNTR profiles identical to those obtained for clinical isolates from patients.