Molluscum contagiosum effectively treated with a topical acidified nitrite, nitric oxide liberating cream

A double-blind, group-sequential clinical trial of acidified nitrite was performed to demonstrate the efficacy of this nitric oxide donor in treating molluscum contagiosum. Subjects received either 5% sodium nitrite co-applied with 5% salicylic acid under occlusion, or identical cream with 5% salicylic acid, omitting sodium nitrite. Active and control treatment groups were well matched for the number and duration of lesions and made a similar number of applications. We found a 75% cure rate in the active treatment group and 21% cure with control treatment (P = 0.01). The mean time to cure was 1.83 months. Staining of the skin and irritation were frequent side-effects but did not prevent successful treatment.     

Treatment of psoriasis with topical agents: Recommendations from a Tuscany Consensus

Psoriasis is a chronic and relapsing inflammatory skin disease, clinically characterized by erythematous and scaly plaques. Treatment approach is mainly driven by disease severity, though several factors should be considered in order to identify the optimal therapeutic choice. Mild psoriasis may be treated with a wide array of topical agents including corticosteroids, vitamin D analogs, keratolytics, and calcipotriol/betamethasone propionate compound. Because guidelines may not provide practical indications regarding the therapeutic approach, the use of topical agents in psoriasis is more individually tailored. In order to homogenize the standard of care, at least in a local setting, we collected the real‐life‐based recommendations for the use of topical therapies from an expert panel, the Tuscany Consensus Group on Psoriasis, representing all leading centers for psoriasis established in Tuscany. With this document, this consensus group sought to define principles guiding the selection of therapeutic agents with straightforward recommendations derived from a real‐life setting.     

Expression of the neuronal isoform of nitric oxide synthase (nNOS) and its inhibitor, protein inhibitor of nNOS, in pigment cell lesions of the skin

Nitric oxide (NO) is involved in many physiological processes. In cancer, low levels of NO are thought to enhance tumour progression and metastasis. NO is generated from arginine by NO synthase (NOS); the Ca2+-dependent neuronal isoform or nNOS (expressed by neurones and inhibited by the protein inhibitor of nNOS, PIN), is also expressed by cultured normal melanocytes and by all malignant melanoma (MM) cell lines. We studied the expression of nNOS and PIN in paraffin sections of 177 and 58 pigment cell lesions, respectively, using immunohistochemistry; the activity of the necessary cofactor NADPH was studied in 26 frozen cases. Normal melanocytes in situ lacked nNOS and PIN expression, but were NADPH +. Almost half of common acquired benign naevi expressed nNOS; however, halo naevi and congenital naevi expressed nNOS very frequently. Dysplastic naevi and MM showed variable nNOS immunoreactivity in 72% and 83% of cases, respectively. Early (Clark I and Clark II) MM displayed nNOS staining most frequently, and all MM with an invasive radial growth phase expressed nNOS in the papillary dermis. In contrast, only 67% of metastatic MM were nNOS +. PIN was coexpressed with nNOS in 40 of 58 lesions. NADPH activity was present in all nNOS + naevi, but in two malignant cases, NADPH activity was not accompanied by nNOS expression. We conclude that nNOS expression is induced de novo in benign and malignant pigment cell lesions which have all the requirements (NADPH, PIN) necessary for the production and modulation of NO. We postulate that the frequent expression of nNOS in the junctional part of dysplastic naevi may be responsible for their particular histological features. NO generated by the neoplastic dermal cells in the invasive radial growth phase may contribute to the increased number of blood vessels in the papillary dermis.     

Memory effector (CD45RO+) and cytotoxic (CD8+) T cells appear early in the margin zone of spreading psoriatic lesions in contrast to cells expressing natural killer receptors, which appear late

BACKGROUND: An influx of immunocytes, increased epidermal proliferation and abnormal keratinization are hallmarks of the psoriatic lesion. T-lymphocyte subsets in particular activated effector memory T cells and natural killer (NK) T cells have been suggested to play an important role in the pathogenesis of psoriasis. OBJECTIVES: In the present study we investigated the number of T-cell subsets (CD4, CD8, CD45RO, CD45RA, CD2, CD25), cells expressing NK receptors (CD94 and CD161), the proliferation marker Ki67 and the keratinization marker keratin (K10) across the margin of the spreading psoriatic plaque: distant uninvolved skin, the outer margin (immediately outside the clinical edge), the inner margin (immediately inside the clinical edge) and the central area. PATIENTS AND METHODS: Eight patients with active psoriasis vulgaris participated in this study. Biopsies were taken from the spreading psoriatic lesion from the distant uninvolved skin, the outer margin, the inner margin and the central area. Biopsies were processed for immunohistochemical staining. RESULTS: In the outer margin CD8+ (cytotoxic T cells) and CD45RO+ (memory effector T cells) T lymphocytes invade the epidermis and in this early stage the activation markers CD2 and CD25 also show a substantial increase. The next phase, from the outer to the inner margin, shows a statistically significant increase of these markers, and especially, the cells expressing NK receptors (CD94 and CD161) show a massive increase together with a significant increase of epidermal proliferation (Ki67) and a decrease of the K10+ epidermal surface. CONCLUSIONS: CD8+, CD45RO+, CD2+ and CD25+ T cells have a role in the early phase of the psoriatic process, whereas CD94- and CD161-expressing cells together with epidermal proliferation and keratinization are involved in a later phase.     

Treatment of psoriasis with topical sirolimus: preclinical development and a randomized, double-blind trial

BACKGROUND: Systemically administered sirolimus has demonstrated efficacy in psoriasis in a multicentre European study. OBJECTIVES: To determine the efficacy and safety of topically applied sirolimus in treating psoriasis. METHODS: In vitro studies were followed by a pilot study designed to determine if sirolimus penetrates human skin, and by a randomized, double-blind, left-right comparative, dose-ranging study consisting of treatment with 2.2% sirolimus for 6 weeks and 8% sirolimus for an additional 6 weeks in 24 patients with stable, chronic plaque psoriasis. The primary outcome measure was clinical score. Secondary measures were ultrasound plaque thickness, plaque erythema, and computerized image analysis of immunohistochemical stains for immunocytes and proliferating cells. Pharmacokinetics and blood chemistry monitoring for safety were also performed. RESULTS: A significant reduction in the clinical score (P = 0.03) (mean score 9.1 following sirolimus vs. 11.2 in control) was achieved with topical sirolimus. Measurements of plaque thickness and erythema did not show significant improvement with treatment. Computerized image analysis of biopsies showed a significant reduction in CD4+ cells (P = 0.0054) and proliferating cells (stained by Ki-67) in the epidermis (P = 0.0153) with sirolimus treatment compared with control. CONCLUSIONS: Topically applied sirolimus penetrates normal skin and may have some antipsoriatic and immunosuppressive activity.     

激光联合外用血管生成抑制剂治疗鲜红斑痣

鲜红斑痣是一种发生在真皮浅层的先天性毛细血管后微静脉扩张畸形。脉冲染料激光是目前治疗鲜红斑痣的标准方法,对各种不同类型的鲜红斑痣均能达到一定程度的褪色,但对大部分鲜红斑痣仍需多次治疗或采取综合疗法,并存在着治疗后色斑复发或加深的现象。近期有学者提出,鲜红斑痣激光成功治疗后的复发或色斑加深,是由于光热作用诱导的人体伤口正常修复反应而导致的新生血管增生,并尝试在激光治疗后辅助外用血管生成抑制剂,如咪喹莫特和雷帕霉素。本文结合多年临床治疗经验和文献资料简要介绍并讨论相关的新进展。     

Treatment of severe nail psoriasis with acitretin: an impressive therapeutic result

Nail psoriasis is common in adult psoriatic patients. Although several new drugs have recently been introduced for the treatment of skin psoriasis, treatment of nail psoriasis still remains a challenge. Topical treatments (e.g., corticosteroids, tazarotene, 5‐fluorouracil, calcipotriol) are the first line in the management of skin psoriasis. The efficacy of these drugs in nail disease, however, is limited, mainly due to the difficulty in penetrating the nail bed and nail matrix. In cases of nail disease resistant to topical treatment, methotrexate, ciclosporin, acitretin, or biological agents can be used. The present authors introduce a 73‐year‐old patient affected by impressive psoriatic nail disease involving all her fingernails and toenails treated by acitretin, a traditional systemic treatment. After 2 months of treatment there was a marked improvement. The clinical improvement of the nails was progressive and 6 months later it was stable and satisfactory. The remarkable response to treatment in this case suggests that oral acitretin, in association to urea nail lacquer, might be useful in the management of disabling severe nail psoriasis even in absence of severe cutaneous involvement.     

SLE患者外周血单个核细胞一氧化氮合酶mRNA的表达

探讨原生型一氧化氮合酶(cNOS)和诱生型一氧化氮合酶(iNOS)在系统性红斑狼疮(SLE)患者外周血单个核细胞(PBMC)中的表达水平及其意义,应用逆转录-聚合酶链反应(RT-PCR)检测了34例活动期SLE患者和30名正常人PBMC中cNOS和iNOSmRNA的表达水平。结果表明,活动期SLE患者iNOS和cNOS的阳性表达率与正常人对照组相比均无明显差异(P>0.05);活动期SLE患者PBMC中iNOSmRNA的平均表达水平(0.7710±0.1050)明显高于正常人对照组(0.5249±0.0770),差异非常显著(P<0.01);活动期SLE组cNOS的平均表达水平与正常人对照组处于同一表达水平,差异无统计学意义(P>0.05)。提示活动期SLE患者外周血单个核细胞中iNOSmRNA的表达增加,可能通过诱导一氧化氮(NO)及其代谢产物的产生参与SLE的发病过程。特异性iNOS抑制剂的开发与研制可能是治疗SLE新药发展的一个方向。     

结节性红斑患者皮损中一氧化氮合酶、血管内皮生长因子的表达

目的 :　探讨一氧化氮合酶 (NOS)和血管内皮生长因子 (VEGF)在结节性红斑中的表达。方法 :用ABC免疫组化方法检测了 4 2例结节性红斑患者皮损和 15例正常人皮肤组织中NOS和VEGF。结果 :结节性红斑皮损中NOS和VEGF的检出率分别为 80 .95 %及 6 6 .6 7% ,阳性信号的表达与分布基本一致(χ2 =2 .2 2 <3.84 ,P >0 .5 ,u =0 .36 6 <0 .6 78,P >0 .5 ) ,主要位于表皮角质层和部分棘细胞、真皮及皮下脂肪层小血管内皮细胞和腺上皮细胞内 ,正常人皮肤组织中NOS和VEGF的表达微弱 ,分布于表皮角质层和部分棘细胞 ,真皮及皮下脂肪层未见。结论 :　结节性红斑皮损中有NOS和VEGF的强阳性表达 ,可能与病毒等微生物引起的免疫反应有关。     

Role of neutrophils in induction of acute inflammation in T-cell-mediated immune dermatosis, psoriasis: a neutrophil-associated inflammation-boosting loop

A growing body of evidence has indicated that T-cell-mediated immunity plays an important role in triggering and maintenance of psoriatic lesions. In this review we present our own experimental results as well as those from the literature related to the pathomechanism of the development of inflammatory changes in psoriatic lesions. First of all it is important to acknowledge the fact that psoriatic lesions are not uniform as assumed by many authors but that they are actually rather heterogeneous both clinically and histologically even within the same plaques. Lymphokines produced by activated T cells in psoriatic lesions have a strong influence on the proliferation of the epidermis, whose stimulated kertinocytes released several cytokines, which in turn enhance the activation state of T cells. Thus, they form a vicious cycle, a T-cell-mediated inflammation-sustaining loop. Although the interaction between T-cell-mediated immunity and epidermal keratinocytes may well explain the maintenance of background "chronic" inflammatory changes diffusely observed throughout psoriatic lesions, it is not enough to explain the island-like, "acute" inflammatory changes observed within and at the border of the plaque lesions. Characteristic neutrophil accumulation under the stratum corneum can be observed in the highly inflamed and therapeutically recalcitrant areas of psoriatic lesions. They are chemotactically attracted and activated there by synergistic action of chemokines, IL-8 and Gro-a released by the stimulated keratinocytes, and particularly C5a/C5a des arg produced via the alternative complement pathway activation possibly on the surface of corneocytes. In this review, we emphasize that the accumulation of neurophils is not simply a passive event. We think that those stimulated neutrophils are able to influence not only the growth and differentiation of epidermal keratinocytes but also the activation-state of T cells by aberrant expression of HLA-DR on their surfaces as well as by their effects. These T cells in turn influence the transepidermal neutrophil migration through the effect of their lymphokines on the keratinocyte production of pro-inflammatory mediators including C3. Therefore, we propose a neutrophil-associated inflammation-boosting loop that may well explain the localized "acute" inflammatory changes scattered over the "chronic" psoriatic plaques as well as in the acutely inflamed lesions of pustular psoriasis.     

寻常型银屑病患者外周血髓系树突状细胞CD47的表达

目的：检测寻常型银屑病患者外周血髓系树突状细胞（mDCs）表面整合素相关蛋白（CD47）的表达水平。方法：流式细胞仪检测寻常型银屑病患者和健康对照者外周血mDCs表面CD47及CD4+调节性T细胞（Treg）表达水平；Luminex液相芯片技术检测上清液IL-23、IL-17和TNF-α浓度。结果：共检测46例患者和46名健康对照，患者组mDCs细胞CD47表达水平为32.8低于对照组的63.6，差异有统计学意义（P<0.05）。患者组mDCs细胞CD47表达水平与银屑病皮损面积和严重程度指数（PASI）负相关（r=-0.651, P<0.05）；患者组Treg细胞比例显著低于对照组，差异具有统计学意义（P<0.05）；IL-23、IL-17和TNF-α浓度显著高于对照组，差异具有统计学意义（P<0.05）。结论：银屑病外周血mDCs表面CD47及Treg细胞表达下降。     

Correlation of psoriasis activity with abundance of CD25+CD8+ T cells: conditions for cloning T cells from psoriatic plaques

The role of T cells in the pathogenesis of psoriasis is widely acknowledged. However, key aspects of their precise function in the disease as well as the relative pathogenic contribution of T-cell subsets are still unknown. T-cell clones have been isolated from psoriatic plaques but a study of conditions affecting the isolation and expansion of T-cell clones from psoriatic skin has not been reported to date. Here, we observe a correlation of disease activity with the frequency of the CD3(+)CD8(+)CD25(+) subset. We show that prolonged in vitro culture changes the phenotypic subset distribution of T-cell lines derived from psoriatic skin and that T-cell clones can be isolated by sorting of CD25(+) cells emigrated from skin fragments after 7 days. We evaluate various conditions affecting expansion of psoriatic T-cell clones in vitro and show that blocking apoptosis can facilitate proliferation of activated T-cell clones in vitro. Our results indicate a prominent role of the CD8(+)CD25(+) T-cell subset in disease pathogenesis and should be useful in the design of experiments aiming at a systematic analysis of the specificity of clones present in psoriatic plaques.     

Functional characterization of CD4+CD25+ regulatory T cells differentiated in vitro from bone marrow-derived haematopoietic cells of psoriasis patients with a family history of the disorder

BACKGROUND: In psoriasis CD4+CD25+ regulatory T cells are functionally deficient. The imbalance between regulatory and effector T-cell functions is important for inducing psoriasis. It is reasonable to speculate that the dysfunctional activity of CD4+CD25+ regulatory cells may originate partly from the abnormal haematopoietic cells determined mainly by genetic background. OBJECTIVES: To test the hypothesis that haematopoietic stem cells are responsible for dysfunctional CD4+CD25+ regulatory cells in psoriasis. METHODS: Bone marrow-derived CD34+ haematopoietic cells from patients with psoriasis (with a family history of psoriasis) and from normal controls were differentiated into T cells in vitro. CD4+CD25+ T cells were isolated by an immunomagnetic bead method, and proliferation activity and capacity for cytokine secretion were determined. Furthermore, the ability of CD4+CD25+ T cells to suppress the proliferative responses of allogeneous peripheral blood CD4+CD25- effector T cells was assessed in vitro. RESULTS: The differentiated CD4+CD25+ T cells of psoriatic origin showed similar characteristics to those of normal volunteers, including proliferation activity and secretion profile of the cytokines interleukin (IL)-2, IL-4, IL-8, IL-10 and interferon (IFN)-gamma. However, proliferation and secretion levels of the cytokines IL-2 and IL-10 for CD4+CD25+ cells of psoriatic CD34+ cell origin were significantly lower than those of normal controls in response to streptococcal superantigen (Strep-A). In particular, CD4+CD25+ T cells differentiated from psoriatic CD34+ cells were functionally insufficient to restrain effector T-cell proliferation. CONCLUSIONS: CD4+CD25+ T cells differentiated in vitro from haematopoietic cells of patients with psoriasis are impaired in regulatory function. The dysfunction of psoriatic CD4+CD25+ T cells may be due to inherent genetic programming passed down from bone marrow-derived haematopoietic cells.     

局部外用一氧化氮供体对屏障功能破坏的小鼠表皮增生的影响

目的:探讨一氧化氮（NO）对屏障功能破坏的小鼠表皮增生的影响。方法:将15只SKH1无毛小鼠按随机数字表法分为正常对照组（3只）、S-亚硝基-N-乙酰青霉胺（SNAP）处理组（4只）、屏障破坏组（4只）、屏障破坏+SNAP处理组（4只）;将15只C57BL/6J小鼠随机分为正常对照组、屏障破坏组、屏障破坏+硝普钠（SN...     

Extremely low frequency electromagnetic fields modulate expression of inducible nitric oxide synthase,endothelial nitric oxide synthase and cyclooxygenase‐2 in the human keratinocyte cell line HaCat: potential therapeutic effects in wound healing

Background Extremely low frequency (ELF) electromagnetic fields (EMF) are known to produce a variety of biological effects. Clinical studies are ongoing using EMF in healing of bone fractures and skin wounds. However, little is known about the mechanisms of action of ELF‐EMF. Several studies have demonstrated that expression and regulation of nitric oxide synthase (NOS) and cyclooxygenase‐2 (COX‐2) are vital for wound healing; however, no reports have demonstrated a direct action of ELF‐EMF in the modulation of these inflammatory molecules in human keratinocytes. Objectives The present study analysed the effect of ELF‐EMF on the human keratinocyte cell line HaCaT in order to assess the mechanisms of action of ELF‐EMF and to provide further support for their therapeutic use in wound healing. Methods Exposed HaCaT cells were compared with unexposed control cells. At different exposure times, expression of inducible NOS (iNOS), endothelial NOS (eNOS) and COX‐2 was evaluated by Western blot analysis. Modulation of iNOS and eNOS was monitored by evaluation of NOS activities, production of nitric oxide (NO) and O₂^? and expression of activator protein 1 (AP‐1). In addition, catalase activity and prostaglandin (PG) E₂ production were determined. Effects of ELF‐EMF on cell growth and viability were monitored. Results The exposure of HaCaT cells to ELF‐EMF increased iNOS and eNOS expression levels. These ELF‐EMF‐dependent increased expression levels were paralled by increased NOS activities, and increased NO production. In addition, higher levels of AP‐1 expression as well as a higher cell proliferation rate were associated with ELF‐EMF exposure. In contrast, ELF‐EMF decreased COX‐2 expression, PGE₂ production, catalase activity and O₂^? production. Conclusions Mediators of inflammation, such as reactive nitrogen and PGE₂, and keratinocyte proliferation are critical for the tissue regenerative processes. The ability of ELF‐EMF to upmodulate NOS activities, thus nitrogen intermediates, as well as cell proliferation, and to downregulate COX‐2 expression and the downstream intermediate PGE₂, highlights the potential therapeutic role of ELF‐EMF in wound healing processes.     

Treatment of nail psoriasis with adalimumab: an open label unblinded study

Background Despite numerous advances in the therapeutic management of cutaneous psoriasis, there is a lack of standardized therapeutic regimens for psoriatic nail disease. Objective An open, non‐randomized, unblinded study was designed to evaluate the efficacy and safety of adalimumab in the treatment of nail psoriasis. Patients/methods Seven patients suffering from severe plaque‐type psoriasis and 14 with psoriatic arthritis and cutaneous psoriasis with concomitant nail involvement were enrolled into the study. The applied dose regimen of adalimumab was the same as the one recommended for cutaneous psoriasis. Outcome measures were assessed at baseline and at weeks 12 and 24 using the Nail Psoriasis Severity Index (NAPSI). Patients also filled in a Greek translation of the international onychomycosis‐specific questionnaire to assess the impact of the nail improvement on their quality of life. Results All 21 patients completed the study and were eligible for statistical analysis. Significant improvement was recorded after the eighth injection. Mean NAPSI (NAPSIm) at baseline was 10.57 ± 1.21 for the fingernails and 14.57 ± 2.50 for the toenails in patients with just cutaneous psoriasis and 23.86 ± 2.00 for the fingernails and 29.29 ± 2.87 for the toenails in patients with psoriatic arthritis. NAPSIm at week 12 was 5.57 ± 0.78 for the fingernails and 9.57 ± 2.17 for the toenails in patients with just cutaneous psoriasis and 12.86 ± 1.05 for the fingernails and 19.21 ± 2.07 for the toenails in patients with psoriatic arthritis. NAPSIm after 24 weeks of treatment was 1.57 ± 0.20 for the fingernails and 4.14 ± 1.58 for the toenails in patients with cutaneous psoriasis and 3.23 ± 0.32 for the figernails and 10.00 ± 1.40 for the toenails in patients with psoriatic arthritis. Treatment was well tolerated with minimal and temporary side‐effects limited to the site of injection. All patients were satisfied, while marked improvement in their quality of life was recorded based on the reduction of the scores obtained from the international quality of life questionnaire. Conclusions Despite the lack of a control group, our results demonstrate a beneficial effect of adalimumab on psoriatic nail disease.     

系统性红斑狼疮患者皮损及血清黏附分子及一氧化氮水平的研究

目的：探讨血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）、E-选择素水平及一氧化氮（N0）在皮损表达和血清水平与系统性红斑狼疮（SEE）活动性的关系。方法：①应用ELISA试剂盒测定血清细胞黏附分子。血清NO的检测使用NO硝酸还原酶试剂盒;②采用SABC免疫组化技术检测细胞黏附分子和NO的表达。结果：①血清中可溶性VCAM-1（sVCAM—Ⅰ）、可溶性ICAM-1（sICAM—Ⅰ）、NO水平病例组均较对照组明显升高（P均〈0．01）;病例组活动期较非活动期升高（P〈0．01）。②SLE活动期皮损处血管内皮细胞VCAM-1、ICAM-1、E-选择素和NO的表达与对照组比较．均明显上调（P〈0．05）。③SLE患者sICAM-1水平与SLE疾病活动指数（SLEDAI）有相关性（r=0．590,P=0．026）,NO水平与抗ds—DNA抗体呈正相关（r=0．777,P=0．001）。④血管内皮细胞内各黏附分子、NO表达的强度依次为VCAM-1〉ICAM—1〉NO〉E-选择素。结论：VCAM-1、ICAM-1、E-选择素和NO可能在SLE的发生、发展中起重要的组织损伤作用。