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The number of elderly patients with chronic pruritus has been gradually increasing in aging countries. Bullous pemphigoid, a common autoimmune blister disease in the elderly, is always heralded by pruritic eczematous dermatitis and is often associated with neurodegenerative diseases. We hypothesized that chronic eczematous dermatitis in patients with neurodegenerative diseases may be an early marker of bullous pemphigoid. By conducting retrospective chart review, we found neurodegenerative diseases are more prevalent in elderly patients with chronic eczematous dermatitis. The mean time delay between the diagnosis of neurodegenerative diseases and onset of skin lesions is 4.17years. In all 6 patients who received skin biopsy, eosinophils in the upper dermis or at the dermo-epidermal junction were obvious, which are remnant of the pathological finding of bullous pemphigoid. Together with the well-known association between bullous pemphigoid and neurodegenerative diseases, the results suggested that unlocalized eczematous dermatitis in the elderly may be an early manifestation of bullous pemphigoid. Inter-discipline communication among neurology, dermatology and geriatrics/gerontology is required to tailor specific managements for elderly patients with pruritus and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

• Photodynamic therapy provides a safe and effective strategy for treating large Bowen's disease lesions. • Photodynamic therapy may enhance topical imiquimod therapeutic effects. • Optical coherence tomography provides a useful and noninvasive diagnosis of early Bowen's disease recurrence. Bowen's disease, a form of skin cancer, is an intraepithelial carcinoma involving keratinocytes. It is associated with a risk of developing invasive squamous cell carcinoma in 3-5% of cases. Ultraviolet exposure, arsenic, human papillomavirus infection, immunosuppression, and genetic factors have been reported to be the causes. Clinically, it presents as symptomless and slowly growing, well-demarcated, irregular erythematous patches or plaques with scaly or crusted surfaces. Surgical excision remains common; however, for large (>20 mm) or multiple Bowen's disease lesions, alternative therapies need to be considered. Here, we present a case of extremely large Bowen's disease lesions in the lower extremities successfully treated with combination therapy using topical aminolevulinic acid-based photodynamic therapy followed by topical 5% imiquimod cream. Optical coherence tomography revealed disorganized and uneven nuclei of keratinocytes in the recurrent lesions, which became relatively small and uniform upon resolution. We demonstrated that photodynamic therapy provides a generally safe and effective strategy for treating large Bowen's disease lesions and optical coherence tomography provides a useful and noninvasive diagnosis of early Bowen's disease recurrence. [ABSTRACT FROM AUTHOR]

Highlights: [•] Frizzled-3 is constitutively expressed in melanocyte lineage cells. [•] Wnt3a stimulates the proliferation of melanocyte precursors and melanocytes. [•] Wnt3a stimulates melanogenesis and dendrite formation in melanocytes. [•] Wnt3a cannot induce c-Kit− melanocyte precursors to express c-Kit. [•] Wnt3a does not affect migration of melanocyte precursors and melanocytes. [ABSTRACT FROM AUTHOR]

Summary: Background: In congenital or acquired dermal melanocytosis, attachment of melanocyte with elastic fiber was shown in electron microscopy of unknown biological meaning. We hypothesize elastin-derived peptide may play a role in activating dermal melanocyte precursors. Objectives: This study was designed to determine: (i) whether melanocyte precursors express elastin binding protein (EBP); (ii) ontogenic expression of EBP and elastin in murine embryonic skin; (iii) the effects of elastin-derived peptide (VGVAPG) on melanocyte precursors. Methods: Using immunohistochemistry or Western blot to identify EBP on murine embryonic sections, neural crest cell (NCC) primary culture explants, or two melanocyte precursor cell lines, NCCmelb4 and NCCmelan5. NCC explants or cells were treated with VGVAPG to compare its effect on proliferation, dendrite formation, melanosome maturation and tyrosinase mRNA expression of melanocyte precursors. Results: EBP was immunostained on c-kit+ melanocyte precursors. 67kDa EBP protein was immunoblotted on NCCmelb4 and NCCmelan5 cells. EBP was expressed early at embryonic day (E) 9.5, but elastin appeared later at E12.5 skin. VGVAPG increased DOPA-positive cell number and enhanced their dendrite formation in NCC explants. Electron microscopy showed advanced melanosome maturation in NCC explants or cells treated with VGVAPG. VGVAPG enhanced tyrosinase mRNA expression in NCCmelan5 cells. Conclusions: Melanocyte precursors expressed EBP. VGVAPG stimulated their melanogenesis and dendrite formation. In the developmental journey interaction between elastin and EBP-expressed melanocyte precursors in embryos happened mainly since the stage of tertiary melanoblasts. These findings first provide biological evidences for the interaction between melanocyte and elastic fiber. [Copyright &y& Elsevier]

Summary: Background: : Apoptosis sculptures the most complicated skin appendage, feathers, out of epidermal layers by playing a variety of roles (1). Human hair follicle formation is different from feathers in growth direction and pattern formation of proliferative zone. Objective: : To delineate the apoptotic events together with proliferation and differentiation in developing human hair follicle and emphasis on the mechanism and biological meaning of epidermal hair canal. Methods: : We used TUNEL to examine apoptosis and Ki-67, involucrin, filaggrin immuno-localization to examine proliferation and differentiation. Results: : In hair germs, apoptosis was diffuse in periderm, basal keratinocytes, and mesenchymal cells with high Ki-67 expression, but spared follicular germinative cells with low Ki-67 and high bcl-2 expression. In hair pegs, apoptosis was active in high Ki-67 expression area, like outer root sheath, hair follicle sheath, but spared dermal papilla with low Ki-67 and high bcl-2 expression. In bulbous pegs, apoptosis appeared in companion layer, precortical area, inner root sheath and outer root sheath, but spared bulge area with high bcl-2 expression. Apoptosis resulted in epidermal and subepidermal hair canal formation. Filaggrin and involucrin were expressed in the lining cells of hair canal. CD1a+ cells were densely distributed alone the hair canal before its opening Conclusion: : During human hair follicle morphogenesis, apoptosis coordinates with proliferation to shape the growth zone, creates space to free the hair shaft from follicular wall, and directs a driving force on hair shaft extension. Apoptosis accompanies the terminal differentiation of epidermal hair canal. The bottom becomes interfollicular epidermis after roof shedding and hair exposure. Langerhans cells also populate in the hair canal before its opening. The biological meaning of epidermal hair canal is supposed to prepare the barrier when hair perturbing the intact of epidermis. [Copyright &y& Elsevier]

Complex skin appendages are built from the epidermal cells through various cell events. Here we used TUNEL and caspase-3 immuno-localization to examine apoptosis in feather morphogenesis. We deduced three modes. In Mode 1A, apoptosis occurs within the localized growth zone (LoGZ) to regulate growth (feather buds). In Mode 1B, morphogen secreting cells are present adjacent to LoGZ and apoptosis may work to remove such signaling centers (barb ridges). In Mode 2, keratinocytes apoptosed before terminal differentiation and left spaces between branches (marginal plate). In Mode 3A, keratinocytes cornified and flaked off to free skin appendages (feather sheath, pulp epithelium). In Mode 3B, keratinized apoptosed epithelial cells became permanent structures (rachis, ramus, barbules). Thus, different apoptotic modes can have different impacts on morphogenesis. We further tested effects of imbalanced Shh on apoptosis. Shh suppression reduced marginal plate apoptosis and caused abnormal differentiation of barbule plates. Shh over-expression enhanced proliferation in barb ridges. Expression of Patched in the barbule plate epithelia implies a paracrine mechanism. The current work complements our recent work on LoGZ to show how adding and removing cell masses in temporally and spatially specific ways are coordinated to sculpt skin appendages from epidermal layers. [ABSTRACT FROM AUTHOR]

Skin morphogenesis occurs in successive stages. First, the skin forms distinct regions (macropatterning). Then skin appendages with particular shapes and sizes form within each region (micropatterning). Ectopic DKK expression inhibited dermis formation in feather tracts and individual buds, implying the importance of Wnts, and prompted the assessment of individual Wnt functions at different morphogenetic levels using the feather model. Wnt 1, 3a, 5a and 11 initially were expressed moderately throughout the feather tract then were up-regulated in restricted regions following two modes: Wnt 1 and 3a became restricted to the placodal epithelium, then to the elongated distal bud epidermis; Wnt 5a and 11 intensified in the inter-tract region and interprimordia epidermis or dermis, respectively, then appeared in the elongated distal bud dermis. Their role in feather tract formation was determined using RCAS mediated misexpression in ovo at E2/E3. Their function in periodic feather patterning was examined by misexpression in vitro using reconstituted E7 skin explant cultures. Wnt 1 reduced spinal tract size, but enhanced feather primordia size. Wnt 3a increased dermal thickness, expanded the spinal tract size, reduced interbud domain spacing, and produced non-tapering ‘giant buds’. Wnt 11 and dominant negative Wnt 1 enhanced interbud spacing, and generated thinner buds. In cultured dermal fibroblasts, Wnt 1 and 3a stimulated cell proliferation and activated the canonical beta-catenin pathway. Wnt 11 inhibited proliferation but stimulated migration. Wnt 5a and 11 triggered the JNK pathway. Thus distinctive Wnts have positive and negative roles in forming the dermis, tracts, interbud spacing and the growth and shaping of individual buds. [Copyright &y& Elsevier]

Skin appendage formation represents a process of regulated new growth. Bromodeoxyuridine labeling of developing chicken skin demonstrated the presence of localized growth zones, which first promote appendage formation and then move within each appendage to produce specific shapes. Initially, cells proliferate all over the presumptive skin. During the placode stage they are organized to form periodic rings. At the short feather bud stage, the localized growth zones shifted to the posterior and then the distal bud. During the long bud stage, the localized growth zones descended through the flank region toward the feather collar (equivalent to the hair matrix). During feather branch formation, the localized growth zones were positioned periodically in the basilar layer to enhance branching of barb ridges. Wnts were expressed in a dynamic fashion during feather morphogenesis that coincided with the shifting localized growth zones positions. The expression pattern of Wnt 6 was examined and compared with other members of the Wnt pathway. Early in feather development Wnt 6 expression overlapped with the location of the localized growth zones. Its function was tested through misexpression studies. Ectopic Wnt 6 expression produced abnormal localized outgrowths from the skin appendages at either the base, the shaft, or the tip of the developing feathers. Later in feather filament morphogenesis, several Wnt markers were expressed in regions undergoing rearrangements and differentiation of barb ridge keratinocytes. These data suggest that skin appendages are built to specific shapes by adding new cells from well-positioned and controlled localized growth zones and that Wnt activity is involved in regulating such localized growth zone activity. [ABSTRACT FROM AUTHOR]

Using immunofluorescence on dermal sheets of mouse ear, we identified novel Thy-1+ dermal dendritic cells in murine skin. These cells are resistant to topical corticosteroid treatment. The number of these dermal Thy-1+ dendritic cells is not altered with aging of the mice or with 3 d of culture. Dermal Thy-1+ dendritic cells have melanosomes in their cytoplasm; hence, phagocytic activity is likely to be present. Double immunofluorescence revealed that most of these dermal Thy-1+ dendritic cells express CD45. Furthermore, conventional immunofluorescence and confocal laser scanning microscopic findings showed that most of these Thy-1+ dermal dendritic cells express &gammaδ and Vγ3 T-cell receptors. The relationship between these dermal Thy-1 dendritic cells and dendritic epidermal T cells is discussed. [ABSTRACT FROM AUTHOR]

Azelastine hydrochloride (AZE) is an anti-allergic drug that inhibits the release of various chemical mediators from mast cells. We compared the immunosuppressive effects of AZE and FD-506 in vivo and in vitro. Topical application of AZE strongly inhibited the efferent phase of contact hypersensitivity, as did application of FK-506. In in vitro experiments, we found that 1) the suppression by AZE on interleukin (IL)-2 production from splenic T cells was partial and considerably large amounts of IL-2 were still produced, even in the presence of 10-5 M of AZE, which was in sharp contrast to the observed marked inhibition of [³H]-TdR incorporation; 2) AZE significantly inhibited the phorbol myristate acetate-induced IL-2 responsiveness; 3) AZE did not inhibit the IL-2 receptor α expression of activated T cells; and 4) the significant inhibitory action was still observed even when AZE was added at 48 h after the initiation of culture. In regard of FD-506, we found that 1) FD-506 completely blocked the production of IL-2; 2) exogeneous IL-2 consistently restored the FK-506-induced inhibition; 3) FK-506 affected the phorbol myristate acetate - induced IL-2 responsiveness very little, if any; and 4) the significant suppression was observed only when FK-506 was added within 24 h after the initiation of culture. Thus, AZE exerts its in vitro immunosuppressive activity preferentially by interfering with the IL-2 responsiveness. with partial inhibition of IL-2 production. Conversely, FK-506 acts as a strong inhibitor of IL-2 production without a prominent effect on IL-2 responsiveness. The immunosuppressive activity of AZE shown in vitro may also be operative in vivo and may be applicable for topical use. [ABSTRACT FROM AUTHOR]

Highlights: [•] There are intrinsic differences in repeated recurrence of nasopharyngeal carcinoma. [•] The co-regulation activity of miRNAs correlates with tumor relapse. [•] Analysis of miRNAs expressions improves diagnostic reliability of recurrent tumors. [Copyright &y& Elsevier]

Abstract: Latent membrane protein-1 (LMP-1) of the Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC), and in this study we sought to determine whether the pro-apoptotic activity of prostate apoptosis response-4 (Par-4) is modulated by LMP-1 in NPC cells. We found that LMP-1 diminished the pro-apoptotic activity of Par-4 and negatively regulated Par-4 protein by de novo synthesis; moreover, although LMP-1 accelerated a Par-4 activator, PKA, we demonstrated that LMP-1 also activated the PI3K/Akt pathway and increased Bcl-2 expression to suppress the activity of Par-4. Consequently, our results revealed a novel negative action of LMP-1 on the pro-apoptosis protein Par-4 by the coordination of multiple signaling pathways. [Copyright &y& Elsevier]