Epidermal Lesions Research Articles

Associations among plasma vitamin C, epidermal ceramide and clinical severity of atopic dermatitis.

BACKGROUND/OBJECTIVESAtopic dermatitis (AD), a chronic inflammatory skin disease, is accompanied by disruption of the epidermal lipid barrier, of which ceramide (Cer) is the major component. Recently it was reported that vitamin C is essential for de novo synthesis of Cer in the epidermis and that the level of vitamin C in plasma is decreased in AD. The objective of this study was to determine the associations among clinical severity, vitamin C in either plasma or epidermis, and Cer in the epidermis of patients with AD.SUBJECTS/METHODSA total of 17 patients (11 male and 6 female) aged 20-42 years were enrolled. The clinical severity of AD was assessed according to the SCORAD (SCORing Atopic Dermatitis) system. Levels of vitamin C were determined in plasma and biopsies of lesional epidermis. Levels of epidermal lipids, including Cer, were determined from tape-stripped lesional epidermis.RESULTSThe clinical severity of patients ranged between 0.1 and 45 (mild to severe AD) based on the SCORAD system. As the SCORAD score increased, the level of vitamin C in the plasma, but not in the epidermis, decreased, and levels of total Cer and Cer2, the major Cer species in the epidermis, also decreased. There was also a positive association between level of vitamin C in the plasma and level of total Cer in the epidermis. However, levels of epidermal total lipids including triglyceride, cholesterol, and free fatty acid (FFA) were not associated with either SCORAD score or level of vitamin C in the plasma of all subjects.CONCLUSIONSAs the clinical severity of AD increased, level of vitamin C in the plasma and level of epidermal Cer decreased, and there was a positive association between these two parameters, implying associations among plasma vitamin C, epidermal Cer, and the clinical severity of AD.

Assessing the Threat of Amphibian Chytrid Fungus in the Albertine Rift: Past, Present and Future.

Batrachochytrium dendrobatidis (Bd), the cause of chytridiomycosis, is a pathogenic fungus that is found worldwide and is a major contributor to amphibian declines and extinctions. We report results of a comprehensive effort to assess the distribution and threat of Bd in one of the Earth’s most important biodiversity hotspots, the Albertine Rift in central Africa. In herpetological surveys conducted between 2010 and 2014, 1018 skin swabs from 17 amphibian genera in 39 sites across the Albertine Rift were tested for Bd by PCR. Overall, 19.5% of amphibians tested positive from all sites combined. Skin tissue samples from 163 amphibians were examined histologically; of these two had superficial epidermal intracorneal fungal colonization and lesions consistent with the disease chytridiomycosis. One amphibian was found dead during the surveys, and all others encountered appeared healthy. We found no evidence for Bd-induced mortality events, a finding consistent with other studies. To gain a historical perspective about Bd in the Albertine Rift, skin swabs from 232 museum-archived amphibians collected as voucher specimens from 1925–1994 were tested for Bd. Of these, one sample was positive; an Itombwe River frog (Phrynobatrachus asper) collected in 1950 in the Itombwe highlands. This finding represents the earliest record of Bd in the Democratic Republic of Congo. We modeled the distribution of Bd in the Albertine Rift using MaxEnt software, and trained our model for improved predictability. Our model predicts that Bd is currently widespread across the Albertine Rift, with moderate habitat suitability extending into the lowlands. Under climatic modeling scenarios our model predicts that optimal habitat suitability of Bd will decrease causing a major range contraction of the fungus by 2080. Our baseline data and modeling predictions are important for comparative studies, especially if significant changes in amphibian health status or climactic conditions are encountered in the future.

Opposing Effects of Zac1 and Curcumin on AP-1-Regulated Expressions of S100A7.

ZAC, an encoding gene mapped at chromosome 6q24-q25 within PSORS1, was previously found over-expressed in the lower compartment of the hyperplastic epidermis in psoriatic lesions. Cytokines produced in the inflammatory dermatoses may drive AP-1 transcription factor to induce responsive gene expressions. We demonstrated that mZac1 can enhance AP-1-responsive S100A7 expression of which the encoding gene was located in PSORS4 with HaCaT keratinocytes. However, the mZac1-enhanced AP-1 transcriptional activity was suppressed by curcumin, indicating the anti-inflammatory property of this botanical agent and is exhibited by blocking the AP-1-mediated cross-talk between PSORS1 and PSORS4. Two putative AP-1-binding sites were found and demonstrated to be functionally important in the regulation of S100A7 promoter activity. Moreover, we found curcumin reduced the DNA-binding activity of AP-1 to the recognition element located in the S100A7 promoter. The S100A7 expression was found to be upregulated in the lesioned epidermis of atopic dermatitis and psoriasis, which is where this keratinocyte-derived chemoattractant engaged in the pro-inflammatory feedback loop. Understanding the regulatory mechanism of S100A7 expression will be helpful to develop therapeutic strategies for chronic inflammatory dermatoses via blocking the reciprocal stimuli between the inflammatory cells and keratinocytes.

Acanthome à grandes cellules : étude anatomoclinique

Large-cell acanthoma (LCA) is a benign tumour initially described in 1970, since when it has been subject to controversy and remains poorly understood. We carried out a single-centre anatomoclinical study in order to identify the clinical and histological characteristics of the disease. Slides classed as LCA in our cutaneous histopathology laboratory were re-read and subjected to Melan-A and HMB45 immunohistochemical labelling. Diagnosis was based upon the presence of a clearly delineated epidermal lesion comprising keratinocytes twice as large as cells adjacent to the lesion. Clinical information was obtained through the analysis of existing requests and clinical files. We identified 20 cases of LCA. Mean patient age was 70 years and the sex ratio was 0.25. The mean disease duration was 1.6 years. In most cases, a pigmented macule or papule was seen, sometimes with a verrucous surface. LCA had not been diagnosed by the clinician in any of the cases seen. In terms of histology, all lesions were clearly delineated, with hypergranulosis beneath hyperorthokeratosis, occasionally with accentuation of the papillary outline. An accentuated stratum lucidum was noted in 80% of cases. In the pigmented forms, immunohistochemical labelling showed no increase in melanocyte count. LCA is a benign lesion that is most likely underdiagnosed since it is poorly known to clinicians and to certain pathologists. It is seen primarily in adult women and is found on the limbs and on the face. Some debate surrounds the definition of LCA as a separate entity, and some authors assimilate it with solar lentigo, but this hypothesis is countered by the existence of hypopigmented forms and we consider it to be a specific anatomoclinical entity.

Detection of human papillomavirus-6b/11 E7 proteins in condyloma acuminatum lesions with home-made polyclonal antibodies

Objective To detect the expressions of human papillomavirus (HPV) -6b/11 E7 proteins in condyloma acuminatum lesions in external genitalia with home-made polyclonal antibodies against HPV-6b/11 E7 proteins, and to estimate the clinical application value of the polyclonal antibodies. Methods Fifty-five tissue specimens were collected from the lesions of patients with clinically and pathologically comfirmed condyloma acuminatum, and subjected to paraffin embedding. An immunohistochemical study was conducted to detect the expressions of HPV-6b/11 E7 proteins in the 55 specimens with home-made polyclonal antibodies against HPV-6b/11 E7 proteins. Reverse transcription (RT) -PCR was performed to quantify the mRNA expressions of HPV-6b/11 E7 in 18 frozen specimens from these patients. The coincidence rate between the two methods was analyzed. Results Immunohistochemical staining showed that HPV-6b/11 E7 proteins were expressed in the nuclei of cells throughout the whole epidermis of the lesions, and especially in the basal layer. Of the 55 specimens, 42 (76.36%) stained positive for the HPV-6b E7 protein, 32 (58.18%) for the HPV11 E7 protein, 22 (40.00%) for both of them, 3 (5.45%) for neither of them, with the positive rate of E7 proteins being 94.55% (52/55). As RT-PCR showed, the HPV-6b and HPV 11 E7 mRNAs were positive in 15 and 10 out of the 18 frozen specimens, respectively, and both positive in 7 specimens. The HPV types identified by RT-PCR in the 15 specimens were fully consistent with those by the immunohistochemical study. Conclusion The immunohistochemical assay using the home-made anti-HPV-6b/11 E7 polyclonal antibodies can be performed to detect condyloma acuminatum lesions and to observe the distribution of HPV-6b/11-infected cells in an intuitionistic way. Key words: Condylomata acuminata; Human papillomavirus 6; Human papillomavirus 11; Papillomavirus E7 proteins

Altered expression of keratin 14 in lesional epidermis of autoimmune skin diseases.

Keratin 14 (K14) is an intermediate filament protein that is mainly expressed in the basal layer of healthy stratified epithelia. K14 has been identified as an autoantigen in the autoimmune-mediated skin disease of Scurfy mice and patients with the "immune dysregulation polyendocrinopathy, enteropathy, and X-linked" syndrome. To examine whether K14 is a target protein in autoimmune skin diseases (ASD), we analyzed the expression pattern of K14 in lesional skin of patients with lichen ruber, cutaneous lupus erythematosus, dermatomyositis, graft-versus-host disease, psoriasis, and pemphigus vulgaris, and evaluated the reactivity of patient sera with recombinantly expressed and epidermis-derived K14. K14 expression was analyzed by immunohistochemistry on paraffin-embedded tissue sections of 17 healthy individuals and 58 patients with ASD. Sera from 10 healthy individuals and 41 patients with ASD were analyzed by Western blot for the presence of anti-K14 autoantibodies. In skin of patients with ASD, K14 expression is retained in suprabasal layers. In ASD with interface dermatitis, we observed focal loss of K14 within the basal layer and in hair follicles as well. A scattered dot-like K14 staining is seen in papillary dermis, most prominently in cutaneous lupus erythematosus and lichen ruber. Using Western blot, we show that sera of different patients with ASD recognize recombinantly expressed K14. We show focal loss of K14 in the basal epidermis correlating with interface dermatitis and hair follicle involvement. Moreover, enhanced reactivity of sera of patients with atopic dermatitis with K14 suggests K14 may function as an autoantigen in ASD.

Efficacy and Tolerability of a Novel Biopsy Device for Removing Benign Epidermal Skin Lesions.

The shave biopsy using a razor with an open blade is the current standard of care for sampling superficial skin lesions. To enhance safety, the authors developed a novel biopsy device with a closed blade design for removing the epidermal layer of skin and evaluated against the open razor blade for tolerability, scarring, and accuracy in histological diagnosis. Shave biopsies were performed using the novel device or razor blade on benign epidermal skin lesions in 10 patients on comparable body parts. Digital photography, colorimetry, scar scale evaluations, and questionnaires were used to evaluate the efficacy and tolerability of the devices. For all patients, accurate histological diagnoses were made regardless of device type. No statistically significant differences were detected between the novel device and razor blade in terms of scar scale assessments, colorimetry, and questionnaire responses. Both patients and the participating dermatologist reported satisfaction with the safety and performance of the novel device. No injuries to the provider occurred with either instrument. The rotating sphere biopsy device is a potential alternative to the razor blade with comparable tolerability, scarring, and accuracy in histological diagnoses, offering improved safety for patients and health care providers.

Decreased Expression of Caveolin-1 Contributes to the Pathogenesis of Psoriasiform Dermatitis in Mice

Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation and abnormal keratinocyte development, in which T helper type 17 cells and signal transducer and activator of transcription 3 (STAT3) activation have pivotal roles. Moreover, caveolin-1 (CAV-1) has been implicated in the regulation of signal transduction, and aberrant CAV-1 expression is involved in a variety of diseases. However, whether CAV-1 is involved in psoriasis is unknown. Here we examined CAV-1 expression in the psoriatic epidermis and investigated its role in the pathogenesis of psoriasis. CAV-1 was markedly reduced in lesional epidermis of psoriasis patients. CAV1 silencing in keratinocytes in vitro revealed significant activation of STAT3, leading to increased expression of keratin 16 and several cytokine/chemokines, such as IL-6, C-X-C chemokine ligand 8 (CXCL8), CXCL9, and C-C chemokine ligand 20. In addition, psoriasis-related cytokines, including tumor necrosis factor-α (TNF-α), decreased CAV-1 expression in keratinocytes. Finally, administration of CAV-1 scaffolding domain peptide in a murine model of psoriasis-like skin inflammation induced by imiquimod improved the skin phenotype and reduced epidermal thickness and infiltrating cell counts. Furthermore, expression of TNF-α, IL-17A, and IL-23 was significantly suppressed by this treatment. Collectively, our study indicated that CAV-1 participates in the pathogenesis of psoriasis by regulating the STAT3 pathway and cytokine networks.

Nevus Sebaceous and Its Association With Neurologic Involvement

Several terms are widely used to define cutaneous lesions affecting the epidermis in association with extracutaneous lesions. Recently, based on the wide spectrum of cutaneous epidermal lesions, the various underlying molecular mechanisms and patterns of associated features have led to improved definitions of these disorders. Nevus sebaceous syndrome has been placed under the umbrella term of epidermal nevus syndrome, in which the nevus sebaceous, a congenital hamartomatous lesion of the epidermis, is associated with anomalies involving the brain, eyes, and bones. Nevus sebaceous and neurologic manifestations were evaluated particularly based on their degree of intellectual delay, seizure type, treatment response, and electroencephalography and neuroradiological findings. A review of the literature in this topic is reported.

The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization

Atopic dermatitis (AD) shows very high prevalence in Asia, with a large unmet need for effective therapeutics. Direct comparisons between European American (EA) and Asian patients with AD are unavailable, but earlier blood studies detected increased IL-17(+)-producing cell counts in Asian patients with AD. We sought to characterize the Asian AD skin phenotype and compare it with the EA AD skin phenotype. We performed genomic profiling (real-time PCR) and immunohistochemistry on lesional and nonlesional biopsy specimens from 52 patients with AD (25 EAs and 27 Asians), 10 patients with psoriasis (all EAs), and 27 healthy subjects (12 EAs and 15 Asians). Although disease severity/SCORAD scores were similar between the AD groups (58.0 vs 56.7, P = .77), greater acanthosis, higher Ki67 counts, and frequent parakeratosis were characteristics of lesional epidermis from Asian patients with AD (P < .05). Most (24/27) Asian patients had high IgE levels. A principal component analysis using real-time PCR data clustered the Asian AD phenotype between the EA AD and psoriasis phenotypes. TH2 skewing characterized both Asian and EA patients with AD but not patients with psoriasis. Significantly higher TH17 and TH22 (IL17A, IL19, and S100A12 in lesional and IL-22 in nonlesional skin; P < .05) and lower TH1/interferon (CXCL9, CXCL10, MX1, and IFNG in nonlesional skin; P < .05) gene induction typified AD skin in Asian patients. The Asian AD phenotype presents (even in the presence of increased IgE levels) a blended phenotype between that of EA patients with AD and those with psoriasis, including increased hyperplasia, parakeratosis, higher TH17 activation, and a strong TH2 component. The relative pathogenic contributions of the TH17 and TH2 axes in creating the Asian AD phenotype need to be tested in future clinical trials with appropriate targeted therapeutics.

Interleukin 17 affects early and late biomarkers of terminal differentiation in a three-dimensional model of normal human skin

Interleukin (IL)-17 expression has been correlated with the pathogenesis of mul- tiple autoimmune diseases, as rheumatoid arthritis, multiple sclerosis, and, more recently, psoriasis (1). During plaque formation, the interplay between immunocytes and keratinocytes is deregulated, resulting in the altered expression of keratin (K) 17, occludin, and filaggrin in psoriatic lesional epidermis (2, 3). The involvement of IL-17 in psoriasis pathogenesis has been identified (4), but the specific and intrinsic effects exerted by this cytokine have not been thoroughly investigated. The aim of the pre- sent work was to study by indirect immunofluorescence the expressions of K17, K10, filaggrin, and occludin in a three-dimensional model of normal human skin stand- ardized in our laboratory (5). Human skin samples (n = 5) obtained from healthy 20-40 years-old women after plastic surgery, were exposed to IL-17 in a Transwell system at air-liquid interface as previously described (5). Samples were harvested 24 (T24), 48 (T48), and 72 (T72) hours after IL-17 stimulation and processed for paraffin embedding and immunofluorescence analysis for expressions of K17, K10, filaggrin, and occludin. After IL-17 exposition, K17 immunostaining progressively increased with time in the upper stratum spinosum, while K10 expression resulted homogene- ously distributed in the suprabasal layers. In IL-17 treated samples occludin staining became irregular starting from 24 hours. On the other hand, filaggrin distribution was affected in T48 samples, where the immunolabelling was discontinuously punc- tuate. In conclusion, our results strongly support the use of this experimental setting for investigating the time-dependent early effects induced by IL-17 in normal human skin.

Abstract 3201: Complement component C3 and complement factor B regulate growth of cutaneous squamous cell carcinoma

Abstract Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and its incidence is increasing globally. We have examined the role of complement component C3 and complement factor B (CFB) in the progression of cSCC. Significantly elevated mRNA levels for C3 and CFB were detected din cSCC cell lines (n = 8) compared to normal human epidermal keratinocytes (n = 11) by quantitative real-time reverse transcriptase-PCR. Increased production of C3 and CFB by cSCC cell lines was detected by western blotting. The mRNA levels for C3 and CFB were also markedly higher in cSCC tumors (n = 6) than in normal skin (n = 10). Tumor cell specific staining for C3 and CFB was detected in cSCC tumors in vivo by immunohistochemistry and the staining intensity was stronger in invasive cSCCs (n = 71) than in cSCC in situ (n = 69), premalignant epidermal lesions (actinic keratoses, n = 65) and normal skin (n = 5). Significant upregulation of C3 and CFB mRNA expression was also noted in chemically induced mouse skin cSCCs (n = 27) compared to benign papillomas (n = 17). The expression of C3 and CFB at mRNA and protein level was markedly higher in invasive tumorigenic Ha-ras-transformed HaCaT cell line than in benign tumorigenic ras-transformed HaCaT cells and parental non-tumorigenic HaCaT cells. The expression of both C3 and CFB was significantly upregulated by IFN-γ and TNF-α in cSCC cells. Knockdown of CFB and C3 by specific siRNAs inhibited migration of cSCC cells. Knockdown of CFB inhibited proliferation of cSCC cells and this was associated with potent inhibition of ERK1/2 activation. Knockdown of C3 and CFB also significantly inhibited growth of human cSCC xenograft tumors in vivo in SCID mice. These results provide evidence for the role of C3 and CFB in progression of cSCC and identify them as specific biomarkers and putative therapeutic targets for invasive cSCC. Citation Format: Pilvi Riihila, Mehdi Farshchian, Markku Kallajoki, Atte Kivisaari, Seppo Meri, Reidar Grenman, Ritva Heljasvaara, Taina Pihlajaniemi, Juha Peltonen, Sirkku Peltonen, Veli-Matti Kahari. Complement component C3 and complement factor B regulate growth of cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3201. doi:10.1158/1538-7445.AM2015-3201

Mast-cell interleukin-1β, neutrophil interleukin-17 and epidermal antimicrobial proteins in the neutrophilic urticarial dermatosis in Schnitzler's syndrome.

Schnitzler's syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin (IL)-1β is pivotal in the pathophysiology. Here we investigated the cellular source of proinflammatory mediators in the skin of patients with SchS. Skin biopsies of lesional and nonlesional skin from eight patients with SchS and healthy controls, and patients with cryopyrin-associated periodic syndrome (CAPS), delayed-pressure urticaria (DPU) and cold-contact urticaria (CCU) were studied. We studied invivoIL-1β, IL-17 and antimicrobial protein (AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the invitro effect of IL-1β, IL-17 and polyinosinic-polycytidylic acid (poly:IC) stimulation on cultured epidermal keratinocytes. Remarkably, we found IL-1β-positive dermal mast cells in both lesional and nonlesional skin of patients with SchS, but not in healthy control skin and CCU, and fewer in CAPS. IL-17-positive neutrophils were observed only in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared with nonlesional skin and that of healthy controls. When exposed to IL-1β, poly:IC or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts. Dermal mast cells of patients with SchS produce IL-1β. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis.

Treatment of Epidermal Pigmented Lesions with 578 nm Yellow Laser

Treatment of Epidermal Pigmented Lesions with 578 nm Yellow Laser

Identification of Novel Cetacean Poxviruses in Cetaceans Stranded in South West England

Poxvirus infections in marine mammals have been mainly reported through their clinical lesions and electron microscopy (EM). Poxvirus particles in association with such lesions have been demonstrated by EM and were previously classified as two new viruses, cetacean poxvirus 1 (CePV-1) and cetacean poxvirus 2 (CePV-2). In this study, epidermal pox lesions in cetaceans stranded in South West England (Cornwall) between 2008 and 2012 were investigated by electron microscopy and molecular analysis. PCR and sequencing of a highly conserved region within the viral DNA polymerase gene ruled out both parapox- and orthopoxviruses. Moreover, phylogenetic analysis of the PCR product clustered the sequences with those previously described as cetacean poxviruses. However, taking the close genetic distance of this gene fragment across the family of poxviridae into account, it is reasonable to postulate further, novel cetacean poxvirus species. The nucleotide similarity within each cluster (tentative species) detected ranged from 98.6% to 100%, whilst the similarity between the clusters was no more than 95%. The detection of several species of poxvirus in different cetacean species confirms the likelihood of a heterogeneous cetacean poxvirus genus, comparable to the heterogeneity observed in other poxvirus genera.

Leukocyte-derived koebnerisin (S100A15) and psoriasin (S100A7) are systemic mediators of inflammation in psoriasis

BackgroundPsoriasis is a systemic immune-mediated chronic inflammatory disease. In the skin, the antimicrobial proteins koebnerisin (S100A15) and psoriasin (S100A7) are overexpressed in the epidermis of psoriatic lesions and mediate inflammation as chemoattractants for immune cells. Their role for systemic inflammation in circulating leukocytes is unknown. ObjectiveThe aim of the study was to identify circulating leukocyte populations as a source of koebnerisin and psoriasin. Further, immune-stimulatory effects of these S100A proteins on circulating leukocytes were evaluated and their role as therapeutic response markers in patients with psoriasis was analyzed upon UVB treatment. MethodsThe expression and production of koebnerisin and psoriasin by leukocytes were assessed by quantitative real-time PCR (qRT-PCR) and immunoblotting. The S100A protein mediated regulation of proinflammatory cytokines by peripheral blood mononuclear cells (PBMCs) was measured with qRT-PCR and cytometric bead assay. ResultsWe identified circulating leukocytes as novel sources of koebnerisin (S100A15) and psoriasin (S100A7). Circulating leukocytes (PBMCs) of patients with psoriasis produced increased levels of koebnerisin and psoriasin compared to healthy individuals. Both S100A proteins further acted as ‘alarmins’ on PBMC to induce proinflammatory cytokines implicated in the pathogenesis of psoriasis, such as IL-1β, TNF-α, IL-6 and IL-8. Koebnerisin levels were suppressed in PBMC of psoriatic patients when effectively treated with narrow-band UVB. ConclusionsData suggest that koebnerisin and psoriasin are systemic pro-inflammatory mediators and koebnerisin acts as a therapeutic response marker in psoriasis.

Dermal dendrocytes FXIIIa+ are essential antigen-presenting cells in indeterminate leprosy.

Indeterminate leprosy (IL) is the early phase of Hansen disease and reword (APCs). Langerhans cells and dermal dendrocytes FXIIIa positive (DDFXIIIa) are the major APCs in the skin and can be identified by the expression of CD1a and FXIIIa, respectively, by immunohistochemical techniques. Plasmacytoid dendritic cells (PDCs) are another type of dermal dendrocytes with a questionable antigen-presenting function and can be highlighted by anti-CD123 expression. To our knowledge, there are no studies evaluating DDFXIIIa and PDC in IL. The purpose was to investigate the involvement of these cells in the pathogenesis of IL. The authors performed a retrospective study on 18 cases of IL (10 confirmed and 8 suspected) to investigate expression of FXIIIa, CD1a, and CD123. The results were compared with normal skin (for CD1a and FXIIIa only). A higher amount of FXIIIa-positive cells (P , 0.05) in confirmed and suspected IL cases was noted when comparing with normal skin. However, CD1a showed no quantitative differences in the epidermis of IL lesions when comparing with normal skin and CD123 expression was negligible. Based on these findings, the authors postulate that Langerhans cells and PDCs do not have a major role in IL and that DDFXIIIa may be the main APCs in IL. Further study is required to establish this.

Distribution profile of gadolinium in gadolinium chelate-treated renally-impaired rats: Role of pharmaceutical formulation

While not acutely toxic, chronic hepatic effect of certain gadolinium chelates (GC), used as contrast agent for magnetic resonance imaging, might represent a risk in renally-impaired patients due to free gadolinium accumulation in the liver. To answer this question, this study investigated the consequences of the presence of small amounts of either a soluble gadolinium salt (“free” Gd) or low-stability chelating impurity in the pharmaceutical solution of gadoteric acid, a macrocyclic GC with high thermodynamic and kinetic stabilities, were investigated in renally-impaired rats. Renal failure was induced by adding 0.75% adenine in the diet for three weeks. The pharmaceutical and commercial solution of gadoteric acid was administered (5 daily intravenous injections of 2.5mmolGd/kg) either alone or after being spiked with either “free” gadolinium (i.e., 0.04% w/v) or low-stability impurity (i.e., 0.06 w/v). Another GC, gadodiamide (low thermodynamic and kinetic stabilities) was given as its commercial solution at a similar dose. Non-chelated gadolinium was tested at two doses (0.005 and 0.01mmolGd/kg) as acetate salt. Gadodiamide induced systemic toxicity (mortality, severe epidermal and dermal lesions) and substantial tissue Gd retention. The addition of very low amounts of “free”, non-chelated gadolinium or low thermodynamic stability impurity to the pharmaceutical solution of the thermodynamically stable GC gadoteric acid resulted in substantial capture of metal by the liver, similar to what was observed in “free” gadolinium salt-treated rats. Relaxometry studies strongly suggested the presence of free and soluble gadolinium in the liver. Electron microscopy examinations revealed the presence of free and insoluble gadolinium deposits in hepatocytes and Kupffer cells of rats treated with gadoteric acid solution spiked with low-stability impurity, free gadolinium and gadodiamide, but not in rats treated with the pharmaceutical solution of gadoteric acid. The presence of impurities in the GC pharmaceutical solution may have long-term biological consequences.

Characteristics of keratinocytes in facial solar lentigo with flattened rete ridges: comparison with melasma.

Flattened rete ridges occurring on the face are not uncommon in solar lentigo (SL). To investigate the morphological changes of keratinocytes in facial SL with flattened rete ridges and melasma. In total, 25 patients with facial SL showing flattened rete ridges and 20 patients with melasma, in which rete ridge flattening is also a common feature, were included in the study. Skin biopsies were performed on lesional skin and perilesional normal skin. The histological findings showed that the epidermis was significantly thicker in SL skin with flattened rete ridges compared with perilesional normal skin. Comparative quantitative analysis of epidermal morphology revealed that the individual keratinocytes were larger in size in lesional skin, without a significant change in the number of cells. Anti-p16 antibody staining was more intense in lesional epidermis, suggesting senescence of keratinocytes in the thickened epidermis. By contrast, melasma samples showed no significant difference in epidermal thickness or keratinocyte morphology in terms of number or size compared with normal skin. These findings suggest that senescent changes in keratinocytes are important in the development of SL, even in the absence of rete ridge elongation, and the removal of keratinocytes harbouring melanin could be a possible strategy for SL treatment.

Complement Factor I Promotes Progression of Cutaneous Squamous Cell Carcinoma

The incidence of cutaneous squamous cell carcinoma (cSCC) is rising worldwide. We have examined the role of complement components in the progression of cSCC. Analysis of cSCC cell lines (n=8) and normal human epidermal keratinocytes (n=11) with whole transcriptome profiling (SOLiD), quantitative real-time reverse transcriptase-PCR, and western blotting revealed marked overexpression of complement factor I (CFI) in cSCC cells. Immunohistochemical analysis for CFI in vivo showed stronger tumor cell-specific labeling intensity in invasive sporadic cSCCs (n=83) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n=7) than in cSCC in situ (n=65), premalignant epidermal lesions (actinic keratoses, n=64), benign epidermal papillomas (seborrheic keratoses, n=39), and normal skin (n=9). The expression of CFI was higher in the aggressive Ha-ras-transformed cell line (RT3) than in less tumorigenic HaCaT cell lines (HaCaT, A5, and II-4). The expression of CFI by cSCC cells was upregulated by IFN-γ and IL-1β. Knockdown of CFI expression inhibited proliferation and migration of cSCC cells and resulted in inhibition of basal extracellular signal-regulated kinase (ERK) 1/2 activation. Knockdown of CFI expression potently inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the role of CFI in the progression of cSCC and identify it as a potential therapeutic target in this nonmelanoma skin cancer.