From Hippocrates to modern medicine.

Hippocrates was the first to introduce the concept of 'physis' and to transform hieratic or theocratic medicine into rational medicine. The overall construction of the Asclepieion on Kos clearly indicates that he and his school followed a holistic concept, combining scientific thought with drug therapy, diet schedules, and physical and mental exercise, also asking for God's help. Hippocrates also formulated the first standards and ethical rules to be followed in medical profession, which are still valid today. The knowledge of Graeco-Roman medicine has been transferred by Arab scholars into the West, whereas renaissance, urbanization, and industrialisation have changed its face over the centuries. With the entrance of molecular technology and economy, modern medicine now faces the risk of becoming itself industrialized. Correct use of new scientific knowledge, individualized management with a Hippocratic holistic approach and compassionate sympathy for the patient who suffers, should be considered in the years to come for maintaining the level of medical profession. The venue of our European Congress in Rhodes is very close to Kos, another historic Aegean island, the place where Hippocrates has given the first professional standards in European medicine and in medicine in general. They were established 2600 years ago and are still valid today.(1,2) If one draws a red line and marks some cornerstones of the evolution that has taken place in medicine over the past centuries, it is evident that these first rules formulated by Hippocrates and his school also reveal the future responsibilities for our profession and make them better recognizable and more conclusive.

Downregulation of cell cycle modulators p21, p27, p53, Rb and proapoptotic Bcl-2-related proteins Bax and Bak in cutaneous melanoma is associated with worse patient prognosis: preliminary findings.

BACKGROUND: Cutaneous melanoma is a tumor with high metastatic potential, but the mechanisms leading to progression are still not fully understood. To provide further molecular basis for understanding the progression of melanoma, the aim of this study was to examine the expression pattern of cell cycle modulators (p21, p27, p53 and Rb) and proapoptotic multidomain Bcl-2 related proteins (Bax and Bak) and to analyze its differences in patients with and without progression stages. METHODS: We have studied 31 patients with cutaneous melanoma at stage IIa (Breslow thickness 1.5-4.0 mm), and follow them for 10-year period. Eighteen of these patients developed metastasis. The determination of selected molecular markers participating in cell cycle regulation and apoptosis was performed by immunohistochemistry. RESULTS: We have observed a significant increase in the loss of expression of the Bax, Bak, p21, p27, p53 and Rb. The analysis of the relationship between these downregulated markers and Breslow thickness showed significant positive correlation (r=0.556, p=0.029) and predictive value if thickness below 2.3 mm (OR=3.0, 95% CI=0.312-28.84). CONCLUSIONS: Our study showed that the downregulation of the markers associated with cell cycle control and apoptosis is of great value in predicting malignant transformation and in assessing the risk of metastases development for 10-year follow-up period.

Antigen mimicry, epitope spreading and the pathogenesis of pemphigus.

The molecular and cellular pathogenesis of pemphigus remains unclear. However, the integrity of intraepidermal and dermoepidermal adhesion appears to be of special importance, and the presence of antibodies directed against desmosomal plaque proteins can provoke pemphigus-like pathologies. Antibodies reactive with various tissue antigens have been detected in pemphigus-like skin conditions. Two major factors determining the occurrence of different pemphigus subforms are antigen mimicry and epitope spreading, as these two phenomena underpin antibody generation in response to different antigens. This multiplicity of target antigens and antibody responses may lead to diagnostic problems early in the disease and may also explain the apparent transformation of one disease subform into another as time progresses.

Intravenous cidofovir treatment for recalcitrant warts in the setting of a patient with myelodysplastic syndrome.

Cidofovir is an acyclic nucleoside phosphonate with broad-spectrum activity against DNA viruses, including human papilloma virus (HPV). However, data on the efficacy of cidofovir in an immunosuppressive setting remain contradictory. We report for the first time on the promotion of the healing of recalcitrant warts in a patient with myelodysplastic syndrome with intravenous cidofovir treatment.

HIV - associated and non - HIV associated types of Kaposi's sarcoma in an African population in Tanzania. Status of immune suppression and HHV-8 seroprevalence.

In this study 77 patients with histologically confirmed Kaposi's sarcoma (KS) were seen at the Regional Dermatology Training Centre (RDTC) in Moshi, Tanzania. Sixty six patients (85.7%) were HIV-seropositive KS-patients (40 males, 26 females; male: female ratio 1.5:1), whereas another 11 (14.3%) KS-patients, all males, were found HIV-seronegative, thus corresponding to the endemic African KS-type. In both groups the CD4+ cell counts were generally low, the CD8+ population increased and the CD4+/CD8+ ratio inverted. Immune suppression was, however, more prominent in the HIV-seropositive group.HHV-8 seroprevalence was high in patients with HIV-associated KS (94.6%), nevertheless, 3 (5.4%) patients in this group remained HHV-8 seronegative. All nine patients with the HIV-seronegative African type of KS were found positive for HHV-8. Of the entire group seen, males were more likely to be HHV-8 seropositive than females (OR = 3.348 95% CI, 0.96-11.65; p < 0.05). The relative risk to develop KS in individuals seropositive to both HIV and HHV-8 was high (OR = 10.6, 95% CI; 2.981-37.688; p < 0.001).Overall, HIV-associated KS differed from the non-HIV-associated by its widespread clinical dissemination on the trunk, the frequent involvement of the oral mucosa and the craniofacial region, and its more rapidly progressive course. No histological differences between the two KS-groups were seen, although spindle cell infiltrates were more often found in the HIV-associated KS-group.

Transition of Sézary syndrome into mycosis fungoides after complete clinical and molecular remission under extracorporeal photophoresis.

Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common clinical variants of cutaneous T cell lymphoma. Although thought to be closely related to mature T helper cells, the relation between the neoplastic cells in MF and SS is still not fully clarified. This report describes a patient with complete remission of SS under treatment with extracorporeal photophoresis (ECP), who subsequently developed typical plaques of MF and large cell lymphoma (LCL). Serial polymerase chain reaction analyses confirmed identical T cell receptor beta and gamma gene rearrangements in SS, MF, and LCL, and complete disappearance of the circulating malignant T cell clone from the peripheral blood after ECP. These findings indicate that the neoplastic cells in SS, MF, and LCL are derived from a common precursor T cell, despite the change in clinical phenotype.

Nitrogen-containing bisphosphonates inhibit cell cycle progression in human melanoma cells.

Cutaneous melanoma is one of the highly malignant human tumours, due to its tendency to generate early metastases and its resistance to classical chemotherapy. We recently demonstrated that pamidronate, a nitrogen-containing bisphosphonate, has an antiproliferative and proapoptotic effect on different melanoma cell lines. In the present study, we compared the in vitro effects of three different bisphosphonates on human melanoma cell lines and we demonstrated that the two nitrogen-containing bisphosphonates pamidronate and zoledronate inhibited the proliferation of melanoma cells and induced apoptosis in a dose- and time-dependent manner. Moreover, cell cycle progression was altered, the two compounds causing accumulation of the cells in the S phase of the cycle. In contrast, the nonaminobisphosphonate clodronate had no effect on melanoma cells. These findings suggest a direct antitumoural effect of bisphosphonates on melanoma cells in vitro and further support the hypothesis of different intracellular mechanisms of action for nitrogen-containing and nonaminobisphosphonates. Our data indicate that nitrogen-containing bisphosphonates may be a useful novel therapeutic class for treatment and/or prevention of melanoma metastases.

Cutaneous T cell lymphoma and classic Hodgkin lymphoma of the B cell type within a single lymph node: composite lymphoma.

Composite lymphomas are defined as two unrelated, morphologically and genetically distinct lymphomas occurring at the same point in time within the same tissue or organ. Since their original definition, several composite lymphomas have been reported exclusively based on morphological grounds. However, with the application of immunohistological and molecular biological techniques it has become evident that many so called "composite" lymphomas do not fulfil the necessary criteria, because they merely represent two different morphological phenotypes of the same malignant clone. This report describes the manifestation of a true composite lymphoma within a single cervical lymph node, which is composed of a cutaneous T cell lymphoma and a classic Hodgkin lymphoma of B cell type--a very rare finding indeed.

Serum of patients with Behçet's disease induces classical (pro-inflammatory) activation of human macrophages in vitro.

BACKGROUND: Although several immunological abnormalities have been demonstrated in Behçet's disease (BD), the exact mechanism of the inflammatory changes occurring is still unknown. Antigen-presenting cells, such as mononuclear phagocytes, play a major role in the regulation of immune-mediated as well as of non-specific inflammation. OBJECTIVE: To investigate the serum activity of patients with BD on antigen and chemokine expression of human macrophages in vitro. METHODS: Serum of 15 patients (8 women, 7 men; mean age 33 +/- 10 years) with BD was incubated with cultured macrophages isolated from peripheral blood of healthy volunteers. Macrophages maintained in patients' serum, fetal calf serum with/without dexamethasone and interleukin (IL)-4 or gamma-interferon were investigated for alternative macrophage-activation-associated CC-chemokine 1 (AMAC-1) and IL-8 mRNA expression by Northern blotting. In addition, cytocentrifuge macrophage preparations were stained with monoclonal antibodies against proteins indicating alternative (anti-inflammatory) macrophage activation, such as MS-1 high-molecular-weight protein (MS-1-HMWP), RM3/1 antigen (CD163) and 25F9, as well as classical (pro-inflammatory) macrophage activation, such as CD11c, class I receptor binding the Fc part of IgG (FcgammaRI: CD64) and class III receptor binding the Fc part of IgG (FcgammaRIII: CD16). RESULTS: Macrophages treated with patients' serum showed neither AMAC-1 expression nor staining with monoclonal antibodies for MS-1-HMWP, CD163 or 25F9. Concomitant treatment with IL-4/dexamethasone up-regulated significantly the expression of CD163. In contrast, IL-8 mRNA expression and staining for CD11c and CD64 were strongly positive after treatment with serum of patients with BD. CD64 positivity and IL-8 mRNA expression were more prominent in patients with active BD than in patients with inactive disease. CONCLUSION: Taken together, our results indicate that serum of patients with BD induces classical (pro-inflammatory) activation of human peripheral blood macrophages in vitro. Our findings suggest that serum factor(s) may be responsible for inflammatory changes in BD.

Standard and innovative therapy of psoriasis.

Psoriasis is one of the most common skin diseases. A variety of molecular alterations has been identified in the active, lesional epidermis and dermis of psoriasis, but the pathogenesis still remains unexplained. Therefore, all antipsoriatic therapeutic regimens are symptomatic. Although there is no cure for psoriasis, a variety of therapeutic modalities is available to reduce the severity and increase the life quality of the patient. In cases with mild to moderate psoriasis, topical therapy (tars, dithranol, topical corticosteroids, and vitamin D derivatives) is the most appropriate choice for initial treatment. For patients with more severe, recalcitrant psoriasis, application of UV-radiation and systemic therapies (e.g. retinoids, methotrexate, cyclosporine A) are available. These modalities are more effective than topical therapy but they are also associated with significant cutaneous and/or systemic adverse effects and a risk-benefit ratio must be taken into account. In recent years, a variety of new approaches and substances has been developed. Their efficacy and safety should be proven in the future.

Effects of UVA and L-ascorbic acid on nuclear factor-kappa B in melanocytes and in HaCaT keratinocytes.

Nuclear factor-kappaB (NFkappaB) is a pleiotropic transcriptional activator, which is a sensitive transcriptional factor for free radicals and activates multiple target genes. UVA is very efficient in inducing free radicals in human skin cells. L-ascorbic acid is regarded as a scavenger of UVA-induced free radicals in human keratinocytes. In epidermis, melanocytes and keratinocytes play an important protective role against skin photodamage. In the present study, we aimed to investigate the role of NFkappaB on photodamage in melanocytes and keratinocytes. Normal human melanocytes (NHM) and HaCaT keratinocytes were treated with UVA (500 mJ/cm(2), 1,000 mJ/cm(2)) and/or L-ascorbic acid (100 microM, 250 microM). NFkappaB binding activity was analysed by electrophoretic mobility shift assay. NFkappaB binding activity was increased by UVA irradiation in HaCaT keratinocytes, but it was not affected in NHM. On the other hand, L-ascorbic acid decreased NFkappaB binding activity both in UVA-irradiated and in non-irradiated NHM. In contrast, NFkappaB binding activity in HaCaT keratinocytes was increased after treatment with L-ascorbic acid. In addition, L-ascorbic acid synergistically induced NFkappaB binding activity with UVA irradiation. The contrary response on NFkappaB binding activity in NHM and HaCaT keratinocytes indicated that the redox regulation might be different on photoprotective action in melanocytes and keratinocytes.

[Perspectives for dermatology in the 21st century]. / Dermatologische Perspektiven im 21. Jahrhundert.

During the last decades dermatology has been profoundly transformed from its descriptive origin into an important part of modern medicine and biosciences. Areas of interest and expertise in the future will likely be focused on major topics on clinical dermatology (psoriasis, atopic dermatitis, skin infections including those sexually transmitted), dermatologic oncology (squamous cell carcinoma, malignant melanoma), gene technology in biopharmacy and dermatopharmacology, and also the areas dealing with the aging of the skin and its appendages (dermatologic endocrinology, cosmetic dermatology). Increasing knowledge in dermatology is not only relevant for treating skin disease but also for helping our patients to maintain healthy and appealing skin, thus improving their requirements for beautification and their quality of life. While this is an important aim, it should not become our main task. Overall, the perspectives for dermatology are promising; in the end, its further development will depend on how modern societies will recognize its significance and reward its efforts.