Disseminated cutaneous Mycobacterium kansasii infection presenting with Rosai-Dorfman disease-like histological features in a patient carrying anti-interferon-γ autoantibodies.

Typical cutaneous non-tuberculous mycobacteria (NTM) infections show a histopathology pattern of granulomas with admixed Langhans giant cells, and abscesses may be observed in acute lesions. Herein, we describe a patient carrying a high titer of autoantibodies to interferon (IFN)-γ with disseminated Mycobacterium kansasii infection presenting with emperipolesis and Rosai-Dorfman disease (RDD)-like histopathological features characterized by remarkable, large, pale-staining "RD cells", which were CD68 and S100 positive and CD1a negative. The patient was misdiagnosed with RDD initially, but exhibited a poor response to all interventions. A re-biopsy revealed Langhans-type multinucleated giant cells; multiple definite acid-fast bacilli were also found. M. kansasii was isolated from cultured tissues. Anti-NTM treatment was initiated. After treatment, all lesions resolved almost completely within the following month. High-titer anti-IFN-γ autoantibodies were detected during follow up, leading to the diagnosis of adult-onset immunodeficiency syndrome. In conclusion, patients carrying high-titer autoantibodies to IFN-γ who also have a disseminated cutaneous M. kansasii infection may present with RDD-like histopathological features, which may be a pitfall in the diagnosis of disseminated cutaneous NTM infections.

Pyoderma gangrenosum preceding the onset of extranodal natural killer/T-cell lymphoma: A case report.

INTRODUCTION: Pyoderma gangrenosum (PG) is a neutrophilic dermatosis that may be associated with systemic diseases. The association of PG with lymphoid malignancies has rarely been reported. Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare but aggressive entity with a poor prognosis. Here, we report the case of a patient who had idiopathic PG refractory to systemic steroids and subsequently developed ENKTL. CASE REPORT: A 70-year-old man presented with a 2-month history of intermittent fever and multifocal painful papules, plaques, and ulcerations on his extremities. The histological and culture results of the lesions were consistent with those of PG. A thorough work-up was performed and did not demonstrate any underlying systemic diseases including malignancy. The PG lesions were refractory to systemic steroid therapy. An enlarging nodule was observed over his right infraorbital area 4 months after the onset of the skin eruptions. The nodule was later biopsied and diagnosed as ENKTL by using histopathological and immunohistochemical studies. Fludeoxyglucose positron emission tomography/computed tomography revealed multiple intense fludeoxyglucose-avid masses in the bones and lungs, suggesting multiorgan metastases. The patient rejected chemotherapy and died 4 weeks after the diagnosis. CONCLUSION: The present case indicates that in any patient with idiopathic PG refractory to conventional therapy, the presence of any underlying disease or malignancy must be thoroughly evaluated. The present case serves as a reminder that when assessing patients with PG, clinicians should increase their awareness regarding the delayed association with malignancy, even in the absence of a concomitant systemic disease at presentation. Furthermore, the prompt evaluation of any suspicious lesions in the context of PG for the possibility of a malignant nature can improve the prognosis, particularly in cases of aggressive malignancy. Understanding the cutaneous spectrum of ENKTL is crucial because of its variable clinical appearance and aggressive nature. Our case demonstrates that PG can be a presenting sign of ENKTL.

Atypical angioma serpiginosum.

Angioma serpiginosum is an uncommon, acquired vascular nevoid disorder with capillary dilation and proliferation in the papillary dermis. The eruptions are asymptomatic and characterized by grouped, erythematous to violaceous, serpiginous and punctate macules. The condition usually appears in females during adolescence on unilateral lower extremities and the buttocks. We report a rare case with a late onset and atypical distribution of lesions in a 48-year-old female patient who had groups of punctate lesions on her left foot for four to five years. Histopathological examination showed hyperkeratosis and multiple dilated and proliferated capillaries in the papillary dermis. Inflammation and extravasation of red blood cells were not found. According to the clinical and pathological findings, we established a diagnosis of angioma serpiginosum. She was treated with a pulsed dye laser, and the angiomatous lesions subsequently improved.

Erbium:YAG laser-mediated oligonucleotide and DNA delivery via the skin: an animal study.

Topical delivery of antisense oligonucleotides (ASOs) and DNA is attractive for treatment of skin disorders. However, this delivery method is limited by the low permeability of the stratum corneum (SC). The objective of this study was to enhance and optimize the skin absorption of gene-based drugs by an erbium:yttrium-aluminum-garnet (Er:YAG) laser. The animal model utilized nude mice. In the in vitro permeation study, the Er:YAG laser treatment produced a 3-30-fold increase in ASO permeation which was dependent on the laser fluence and ASO molecular mass used. The fluorescence microscopic images showed a more-significant localization of a 15-mer ASO in the epidermis and hair follicles after laser application as compared with the control. The expressions of reporter genes coding for beta-galactosidase and green fluorescent protein (GFP) in skin were assessed by X-gal staining and confocal laser scanning microscopy. The SC ablation effect and photomechanical waves produced by the Er:YAG laser resulted in DNA expression being extensively distributed from the epidermis to the subcutis. The GFP expression in 1.4 J/cm2-treated skin was 160-fold higher than that in intact skin. This non-invasive, well-controlled technique of using an Er:YAG laser for gene therapy provides an efficient strategy to deliver ASOs and DNA via the skin.

Microdermabrasion as a novel tool to enhance drug delivery via the skin: an animal study.

BACKGROUND: Microdermabrasion is a widely performed skin rejuvenation procedure. It can partly ablate and homogenize the stratum corneum (SC) layers. OBJECTIVE: The effect of microdermabrasion treatment on the skin permeation of hydrophilic and lipophilic drugs was examined in this study. METHODS: 5-Fluorouracil (5-FU) and clobetasol 17-propionate were used as the hydrophilic and lipophilic permeants, respectively. In vitro skin delivery using porcine skin and in vivo topical application employing nude mouse as the animal model were both used to examine the effect of microdermabrasion. The vacuum pressures used in this study (15-25 cmHg) were much lower than those used for therapeutic purposes. RESULTS: The 5-FU permeation across microdermabrasion-treated skin was 8- to 24-fold higher than that across intact skin and depended on differences in treatment pressure and duration. An intensity of 15 cmHg for 10 seconds showed the greatest enhancement of 5-FU delivery via the skin. In contrast to the results for 5-FU, microdermabrasion reduced the skin permeation and deposition of topically applied clobetasol. The partitioning effect of clobetasol from the vehicle to the SC may have predominated this result. Microdermabrasion also enhanced the skin delivery of the hydrophilic 5-aminolevulinic acid (ALA). Confocal laser scanning microscopy (CLSM) of microdermabrasion-treated skin revealed intense red fluorescence of ALA-transformed protoporphyrin (PpIX) within the epidermis and upper dermis. CONCLUSIONS: Microdermabrasion can improve the skin permeation of hydrophilic molecules.

Inhibition of inflammatory nitric oxide production and epidermis damages by Saccharomycopsis Ferment Filtrate.

BACKGROUND: Yeast extracts have been shown to perform anti-inflammatory and cytoprotective activities. However, the effects of yeast extracts on lipopolysaccharide (LPS)-induced nitric oxide (NO) production and epidermal damages are still unclear. OBJECTIVE: To investigate the effect of Saccharomycopsis Ferment Filtrate (SFF) on LPS-induced NO production in RAW264.7 macrophages and epidermal damages. METHOD: RAW264.7 cells are incubated with LPS (25 ng/mL) and different concentrations of SFF. The amount of NO production is detected by Griess reaction. Additionally, the expression of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) are detected by Western blotting. Artificial epidermis is also used to mimic the in vivo condition to investigate the protective effects of SFF on LPS- or ultraviolet radiation (UVR)-induced damages by histology and electron microscopy. RESULTS: The results show that SFF addition inhibits LPS-induced NO production and iNOS protein expression in a concentration-dependent manner without notable cytotoxicity in RAW264.7 cells, and induction of HO-1 protein expression by SFF was observed. Interestingly, both HO-1 inducers, hemin and CoCl2, significantly attenuated LPS-induced NO production and iNOS protein expression. The addition of CoCl2 potentiated the inhibitory effect of SFF on LPS-induced NO production. It seems that HO-1 protein participates in SFF inhibition of LPS-induced NO production. Furthermore, SFF exhibits significant protective effect on LPS- or UVR-induced damages in the artificial epidermis via histological and electron microscopic observations. CONCLUSION: This study provided the first evidence to indicate the beneficial effects of SFF in preventing NO production in macrophages and damages in epidermis, respectively. It suggests that SFF possesses potential to be further developed.

In vitro percutaneous absorption and in vivo protoporphyrin IX accumulation in skin and tumors after topical 5-aminolevulinic acid application with enhancement using an erbium:YAG laser.

5-aminolevulinic acid (ALA) is used as a precursor of protoporphyrin IX (PpIX) for photodynamic therapy (PDT) of superficial skin cancers and subcutaneous metastases of internal malignancies. The permeability of ALA across intact skin is always low, making it difficult to achieve the desired therapeutic benefits. Hence new methods for enhancing ALA permeation are urgently needed. The aim of this study was to determine the in vivo kinetics of PpIX generation in mouse tissues after topical ALA application enhanced by an erbium (Er):yttrium-aluminum-garnet (YAG) laser. The in vitro permeation of ALA was also used to screen the optimal method for the in vivo study. The efficacy of the improved drug delivery was determined as a function of various laser fluences and cancer models. ALA applied to laser-treated skin produced a higher accumulations of PpIX within superficial skin and subcutaneous tumors as compared to those of the non-treated group (t-test, p < 0.05). The enhancement ratios (ER) of laser-treated skin ranged from 1.7 to 4.9 times as compared to the control depending to the fluences used. The enhanced PpIX level of laser-treated skin was generally more pronounced in normal and lesional skin than in subcutaneous nodular tumors. Confocal laser scanning microscopy (CLSM) of laser-treated skin revealed intense red fluorescence within the epidermis and upper dermis, and a much-weaker fluorescence within the bottom layers of the skin. On the other hand, the fluorescence intensity of the control group was much lower than that of laser-treated group. The barrier properties of the skin irradiated by the laser had completely recovered within 3 days. Pretreatment of skin using an Er:YAG laser was useful in increasing the amount of Pp IX within skin tumors.

Development of fungal mycelia as a skin substitute: characterization of keratinocyte proliferation and matrix metalloproteinase expression during improvement in the wound-healing process.

SACCHACHITIN membranes, prepared from the waste residue of the fruiting body of Ganoderma taugae, were used in our previous study to enhance skin wound healing in animal models. In the present study, the effects of the membrane on the growth of keratinocytes and the activity of matrix metalloproteinases (MMPs), as well as on the healing of skin wounds in humans, were estimated. Fresh human foreskin was employed as the source of the keratinocyte culture, and a modified keratinocyte-SFM medium supplemented with 0.2 ng/mL of recombinant epidermal growth factor and 30 microg/mL bovine pituitary extract was used to enhance the successful growth of keratinocytes under an atmosphere of 5% CO2, at 37 degrees C. The results indicated that 0.01% SACCHACHITIN enhanced the proliferation of keratinocytes in the culture on the fourth and fifth days, and cells showed neither morphological alteration nor disordered proliferation. This evidence clearly indicated that SACCHACHITIN was not cytotoxic to and was safe for the growth of keratinocytes. Thus, SACCHACHITIN might play a positive role in the proliferation and differentiation of keratinocytes around wounds and in accelerated wound healing of epidermal tissue. In addition, microscopic observations during the growth of keratinocytes showed that normal proliferation and differentiation took place along the margin of the SACCHACHITIN membrane. This indicates that SACCHACHITIN is possibly cytocompatible with keratinocytes. Electrophoretic analysis and inhibition tests for the binding effect of SACCHACHITIN on MMPs showed that SACCHACHITIN reduced MMPs in extracellular matrix degradation and facilitated establishment of an extracellular matrix around wounds; these effects resulted in rapid wound healing. SACCHACHITIN was used as a skin dressing for patients who had skin chronicle ulcer, which had not healed for over 7 months. Preliminary clinical observations showed that the wound improved and began to heal. An analysis of MMPs by ELISA in tissue of the wound indicated a significant decrease in MMP levels.

Transdermal delivery of macromolecules by erbium:YAG laser.

The aim of this study was to assess the effect of molecular weight (MW) on the transdermal delivery of macromolecules by erbium:yttrium-aluminum-garnet (Er:YAG) laser treatment. Fluorescein isothiocyanate (FITC)-labeled dextran (FD) of increasing MWs (4.4, 19.4, 38, and 77 kDa) was used as the model macromolecules to investigate the skin permeation in vitro. Fluorescence microscopy and scanning electron microscopic (SEM) images were utilized to examine the transport mechanisms of the macromolecules via the skin after laser treatment. The results indicate a significant increase in the permeation of FITC and FD across skin treated by the laser. The MWs of macromolecules and laser fluences were found to play important roles in controlling macromolecular absorption. Transdermal delivery of FD with a MW of at least 77 kDa could be achieved with laser treatment. Follicular routes were significant for FITC permeation, whereas intercellular pathways played important roles on the delivery of FD. Ablation of the stratum corneum (SC) layer, photomechanical stress on intercellular regions, and alterations of the morphology and arrangement of corneocytes are possible mechanisms of how the Er:YAG laser promotes macromolecular delivery. No alteration of viable skin morphology was observed after laser treatment and the partly ablation of the SC may be reversible. Hexameric insulin showed higher skin permeation than did FD with similar MWs (38 kDa) with laser enhancement. From the study presented herein, it is concluded that the Er:YAG laser can be effective for transdermal delivery of macromolecules and hydrophilic permeants such as peptides and protein-based drugs.

Milium-like syringoma: a case study on histogenesis.

BACKGROUND: Milium-like syringoma is a variant of syringoma first described in 1987. Only few cases have been reported in the literature. It may be misleading clinically, and its histogenesis has not been clarified. CASE REPORT: We present a case of periorbital milium-like syringoma, with studies on the histopathologic, histochemical, and immunohistochemical features. RESULTS: Histology showed a large keratin-filled cyst in the upper portion of the lesion approximating the epidermis. Serial sections revealed that the cyst connected with the underlying syringomatous epithelial strands. Melanin was absent in the wall of the cyst, as demonstrated by Fontana-Masson stain. Cytokeratin 7 was expressed neither in the milia nor in the solid epithelial parts. Carcinoembryonic antigen (CEA) reactivity was seen in the luminal cells of the keratinous cysts. However, in the largest keratin-filled cyst clinically suggesting a milium, only the lower half of the cyst was positive for CEA. These results proved that the milia were part of syringoma with eccrine duct differentiation. Fusion of the upper half of the largest cyst with the epidermis may explain the absence of CEA positivity in this part, analogous with eccrine duct milia. Review of the literature indicated that this variant of syringoma occurs more often in Asians. CONCLUSION: We present evidence, and propose the histogenesis of milium-like syringoma, that it is a variant of syringoma with a prominent cystic component showing features of eccrine duct milia. Recognition of its nature is of therapeutic significance. Further studies are required to verify its clinical characteristics as compared with ordinary syringomas.

Erbium:YAG laser pretreatment accelerates the response of Bowen's disease treated by topical 5-fluorouracil.

BACKGROUND: Topical 5-fluorouracil (5-FU) is a standard treatment for Bowen's disease. However, its efficacy may be limited by the presence of stratum corneum. The Er:YAG laser has shown a dramatic enhancement effect on the delivery of 5-FU in vitro by ablation of the stratum corneum. The efficacy of laser-assisted delivery of 5-FU has not been tested in human. OBJECTIVE: To see whether Er:YAG laser pretreatment can improve the efficacy of topical 5-FU in the treatment of Bowen's disease. METHODS: Three target lesions from a patient with multiple Bowen's disease were selected for a half-side comparison study. The Er:YAG laser was used to remove the cornified layer on one side of each lesion, followed by twice-daily application of 5-FU cream to both sides. Clinical and histologic responses were compared. RESULTS: Lesions pretreated with the Er:YAG laser showed more rapid clinical and histologic responses to topical 5-FU than those treated with 5-FU alone. Evaluation at 9 months after treatment showed no recurrences of lesions on both sides. CONCLUSIONS: Our preliminary study demonstrates that this Er:YAG laser-assisted modality is effective and shows accelerated clinical response and shortened treatment time compared with topical 5-FU as a single treatment.

Lasers and microdermabrasion enhance and control topical delivery of vitamin C.

The objective of this study was to evaluate the ability of lasers and microdermabrasion, both of which are skin resurfacing modalities, to enhance and control the in vitro skin permeation and deposition of vitamin C. The topical delivery of magnesium ascorbyl phosphate, the pro-drug of vitamin C, was also examined in this study. All resurfacing techniques evaluated produced significant increases in the topical delivery of vitamin C across and/or into the skin. The erbium:yttrium-aluminum-garnet (Er:YAG) laser showed the greatest enhancement of skin permeation of vitamin C among the modalities tested. The laser fluence and spot size were found to play important parts in controlling drug absorption. An excellent correlation was observed in the Er:YAG laser fluence and transepidermal water loss, which is an estimation of skin disruption. Permeation of magnesium ascorbyl phosphate was not enhanced by the Er:YAG laser. The CO2 laser at a lower fluence promoted vitamin C permeation with no ablation of the stratum corneum or epidermal layers. Further enhancement was observed with the CO2 laser at higher fluences, which was accompanied by a prominent ablation effect. Microdermabrasion ablated the stratum corneum layers with minimal disruption of the skin barrier properties according to transepidermal water loss levels. The flux and skin deposition of vitamin C across microdermabrasion-treated skin was approximately 20-fold higher than that across intact skin. The techniques used in this study may be useful for basic and clinical investigations of enhancement of topical vitamin C delivery.

The effect of laser treatment on skin to enhance and control transdermal delivery of 5-fluorouracil.

The effect of three lasers (i.e., the ruby, erbium:YAG, and CO2) on the ability to enhance and control skin permeation of 5-fluorouracil (5-FU) was studied in vitro. Light microscopic and ultrastructural (scanning electron microscopic) changes in the nude mouse skin were also compared for these lasers. The histological observations and permeation profiles of each laser differed because the three lasers produce different physical and physiologic effects when striking the skin. The skin permeation of 5-FU could be moderately promoted by a single photomechanical wave generated by the ruby laser (at 4.0 and 7.0 J/cm(2)) without adversely affecting the viability or structure of the skin. The stratum corneum (SC) layer in the skin was partly ablated by an erbium:YAG laser, resulting in a greater enhancement effect on skin permeation of 5-FU. The flux of 5-FU across erbium:YAG laser-treated skin was 53-133-fold higher than that across intact skin. Both SC ablation and a thermal effect may contribute to the effect of the CO2 laser on skin structure. Lower energies of the CO2 laser did not modulate 5-FU permeation. A 36-41-fold increase in 5-FU flux was observed after exposure to higher fluences (4.0 and 7.0 J/cm(2)) of the CO2 laser. Histological changes induced by both the erbium:YAG and CO2 lasers had completely recovered within 4 days.