Topical immunomodulators in dermatology

Immunomodulators include both immunostimulatory and immunosuppressive agents. Obligate contact sensitizers such as diphencyprone or dinitrochlorobenzene have been used against viral and autoimmune diseases. Newer agents such as the toll-like receptor agonists imiquimod and resiquimod have been clinically used to treat viral infections and skin cancers in immunocompetent and immunosuppressed patients. On the other hand, the topical immunosuppressive agents tacrolimus and pimecrolimus have been used with great success in the treatment of chronic inflammatory diseases in children and adults. The introduction of this new class of drugs (i.e. Calcineurin inhibitors) marked the beginning of the post-cortisone era in clinical dermatology. Toll-like receptor agonists and calcineurin antagonists will supplement corticosteroids to improve specific dermatological therapy. Topical immunotherapy with both immunostimulatory and immunosuppressive agents show potential for effective and patient-friendly treatment of inflammatory, infectious and neoplastic skin diseases. Long-term evaluation will define the tolerability and the safety profile.     

Kaposi's sarcoma and other manifestations of human herpesvirus 8

Kaposi's sarcoma (KS) was described by Moritz Kaposi in 1872 and was known for an entire century as a rare disorder of older men usually of Eastern European, Mediterranean, and/or Jewish origin. In the early 1980s, the prevalence of KS began to increase dramatically and soon became the most common malignancy in patients with AIDS, especially those who were male homosexuals. In 1994, a new human herpesvirus (HHV) was found to be present in almost 100% of KS lesions. This virus was found to be a gammaherpesvirus, closely related to Epstein-Barr virus, and was designated HHV-8. Subsequently, HHV-8 DNA was found in almost all specimens of classic KS, endemic KS, and iatrogenic KS, as well as epidemic KS (ie, AIDS KS). It is now believed that HHV-8 is necessary, but not sufficient, to cause KS and that other factors such as immunosuppression play a major role. The use of highly active antiretroviral therapy (HAART) since 1996 has markedly reduced the prevalence of AIDS KS in western countries, but because 99% of the 40 million patients with AIDS in the world cannot afford HAART, KS is still a very common problem. Primary effusion lymphoma and multicentric Castleman's disease are also thought to be due to HHV-8. Although HHV-8 DNA has been described in a number of other cutaneous disorders, there is little evidence that HHV-8 is of etiologic significance in these diseases. The mechanism by which HHV-8 causes KS, primary effusion lymphoma, and multicentric Castleman's disease is not well understood but is thought to involve a number of molecular events, the study of which should further our understanding of viral oncology. (J Am Acad Dermatol 2002;47:641-55.) Learning objective: At the completion of this learning activity, participants should be familiar with Kaposi's sarcoma and other manifestations of human herpesvirus 8.     

Topische Immunmodulation in der Dermatologie

Summary: Immunomodulators include both immunostimulatory and immunosuppressive agents.
If successful, topical immunotherapy may represent an important improvement in the therapy of inflammatory dermatoses, viral infections and cancers of the skin and genital mucosa. This rather old concept
has emerged some 100 years ago, but only recently have its basic mechanisms been elucidated. Topical immunotherapy using obligate contact sensitizers such
as diphencyprone or dinitrochlorobenzene elicit hapten‐mediated immune responses, which involve specific antigens or act merely by the induction of an inflammatory infiltrate. They have been used against viral (e. g. common warts) and autoimmune diseases (e. g. alopecia areata). Newer agents such as imidazoquinolines (imiquimod and resiquimod) act by cytokine secretion from monocytes/macrophages (interferon‐α, interleukin‐12, tumour‐necrosis factor‐α). The locally generated immune milieu leads to a
Th₁‐dominance and cell‐mediated immunity that have been clinically used to treat viral infections such as HPV, HSV and mollusca and cancerous lesions including initial squamous cell and basal cell carcinoma in immunocompetent and immunosuppressed patients. While these agents improve antigen‐presentation by dendritic cells, they also act on B‐cells leading to the synthesis of antibodies such as IgG_2a much
like the recently discovered immunostimulatory CpG sequences that stimulate innate immunity. These sequences act as ?danger signals” as they occur in bacterial and viral DNA but are selectively methylated and inactivated in the mammalian genome. They share the induction of the same cytokines like imidazoquinolines, while they display different magnitudes and kinetics of the response. On the other hand, the topical immunosuppressive tacrolimus has been used with great success in the treatment of chronic inflammatory diseases such as atopic dermatitis in children and adults. Topical immunotherapy with both immunostimulatory and immunosuppressive agents bears potential for effective and patient‐friendly treatment of inflammatory, infectious and cancerous skin diseases. Due to their adjuvant properties immunoenhancers may also improve conventional (protein) and DNA vaccination against cancer, atopy and allergies.     

Progress and prospects of skin gene therapy: a ten year history

Significant progress has been made in corrective gene therapy of the skin in the last decade. This includes advances in vector technology, targeted gene expression, gene replacement, gene correction, and the availability of appropriate animal models for a variety of candidate diseases. While non-viral integration of large genes such as essential basement membrane proteins has been mastered, new challenges such as the control of immune responses lie ahead of the research community until skin gene therapy will become clinical reality. Among the first skin diseases patients with junctional epidermolysis bullosa and xeroderma pigmentosum have entered clinical trials.     

Neurokutane Melanose und malignes Melanom

A 36-year-old man presented with a giant congenital melanocytic nevus and multiple disseminated melanocytic nevi. After he had developed neurological symptoms (grand mal seizures), a cerebral metastasis of a malignant melanoma without a primary melanoma was found. The patient was diagnosed as having a neurocutaneous melanosis with a cerebral metastasis. In spite of a variety of therapeutic attempts (surgery, radiation therapy and chemotherapy) he followed a rapidly progressive, lethal course with increased intracranial pressure, hydrocephalus and spinal metastases.     

HAX-1, identified by differential display reverse transcription polymerase chain reaction,is overexpressed in lesional psoriasis

Psoriasis is a chronic inflammatory disease characterized by epidermal hyperplasia and an inflammatory infiltrate. The normal differentiation from basal to granular keratinocytes with subsequent apoptosis and cornification is disturbed in the akanthotic epidermis. This could be due to both an excess of mitogenic stimuli with hyperproliferation and/or resistance to apoptosis. By mRNA differential display we found HAX-1 to be overexpressed in lesional psoriatic skin. The overexpression of HAX-1 was verified at the mRNA level by Northern blot and in situ hybridization, as well as at the protein level by Western blot and immunohistochemistry. Detection of HAX-1 in mRNA from different tissues showed strong expression in the brain, pancreas, skeletal muscle, and heart. In contrast to primary keratinocytes and melanocytes we found HAX-1 highly expressed in human immortalized keratinocytes (HaCaT) and different melanoma cell lines. In HaCaT cells as a model for psoriatic keratinocytes we found an increased ultraviolet-induced apoptosis after expression of HAX-1 antisense mRNA. In psoriasis, the epidermal differentiation could be disturbed due to the increased expression of HAX-1 and hence a prolonged resistance to terminal differentiation. Antiapoptotic mechanisms are an emerging concept for the understanding of the pathogenesis of this disease possibly leading to clinical applications.     

Zervikales Talgdrüsenkarzinom

Extraocular sebaceous carcinoma is a rare skin neoplasm that resembles clinically pyogenic granuloma, hemangioma or squamous cell cancer. The clinical and histological findings are described. The differential diagnosis of common tumors of the face should include this rare malignancy.     

糖尿病与高龄老年人群认知功能障碍发生的相关性

目的探讨高龄老年认知功能障碍人群中糖尿病与认知功能障碍之间的相关性,明确糖尿病对于高龄老年认知功能障碍的影响。 方法 本研究为横断面研究,对解放军总医院2009年1月~2012年12月神经内科住院及门诊有记忆力障碍主诉的80岁以上高龄老人采集病史,神经系统查体和神经心理量表测定,明确不同认知功能障碍人群糖尿病的患病率及糖尿病与认知功能障碍评分的相关性。 结果 共纳入286病例,其中正常组60例(21.0%),MCI组85例(29.7%),痴呆组141例(49.3%)。糖尿病在正常组患病率为8.33%(95%CI 18.5%~30.3%),MCI组23.53%(95%CI 14.4%~36.3%),痴呆组为29.79%(95%CI 21.5%~40.3%)。糖尿病患病率在正常组与痴呆组相比有统计学意义(P<0.05)。Spearman等级相关分析表明,糖尿病与MMSE(r=-0.154,P=0.00924)和CDT(r=-0.155,P=0.0115)存在显著负相关。多因素logistic回归分析表明,该人群原发性高血压病与糖尿病显著相关(P<0.05)。 结论 在高龄痴呆病人中糖尿病的患病率显著升高,与认知功能减退具有显著相关性,积极控制糖尿病对于高龄痴呆的防治具有重要意义。      

S1 Guideline onychomycosis

Onychomycosis is a fungal infection of the fingernails and toenails. In Europe, tinea unguium is mainly caused by dermatophytes. The diagnostic workup comprises microscopic examination, culture and/or molecular testing (nail scrapings). Local treatment with antifungal nail polish is recommended for mild or moderate nail infections. In case of moderate to severe onychomycosis, oral treatment is recommended (in the absence of contraindications). Treatment should consist of topical and systemic agents. The aim of this update of the German S1 guideline is to simplify the selection and implementation of appropriate diagnostics and treatment. The guideline was based on current international guidelines and the results of a literature review conducted by the experts of the guideline committee. This multidisciplinary committee consisted of representatives from the German Society of Dermatology (DDG), the German-Speaking Mycological Society (DMykG), the Association of German Dermatologists (BVDD), the German Society for Hygiene and Microbiology (DGHM), the German Society of Pediatric and Adolescent Medicine (DGKJ), the Working Group for Pediatric Dermatology (APD) and the German Society for Pediatric Infectious Diseases (DGPI). The Division of Evidence-based Medicine (dEBM) provided methodological assistance. The guideline was approved by the participating medical societies following a comprehensive internal and external review.