Inflammation and thrombo-occlusive vessel signalling in benign atrophic papulosis (Köhlmeier-Degos disease).

BACKGROUND: Although the merely cutaneous, benign form of the extremely rare disease atrophic papulosis (Köhlmeier-Degos disease) may occasionally develop into the systemic, malignant form with time, it is unclear whether it exhibits any systemic characteristics. OBJECTIVE: To determine whether benign atrophic papulosis exhibits inflammatory and thrombo-occlusive signals and to classify it according to the Chapel-Hill classification of vasculitis. METHODS: In a monocentric, controlled study, levels of cytokines (IL-1ß, IL-6, IL-8, IFNγ, MCP-1, VEGF, TNFα, TGF-ß1), antiphospholipid antibodies (cardiolipin IgG/A/M, cardiolipin IgG, cardiolipin IgM, ß2-glycoprotein IgG/A/M, phosphatidyl choline, phosphatidyl serine, phosphatidyl inositol, phosphatidyl ethanolamine and sphingomyelin A), antibodies against proteinase-3 IgG and myeloperoxidase IgG, antinuclear antibodies and extractable nuclear antigen were assessed in blood samples of six benign atrophic papulosis patients and six age- and sex-matched healthy controls. RESULTS: IL-8 was only detectable in patients' serum. VEGF was reduced and cardiolipin IgG/A/M and ß2-glycoprotein antibodies were increased in the patients' group. ANA were only detected in three patients, and ENA were negative throughout. No differences were detected between the other investigated markers. CONCLUSIONS: This is the first study evaluating systemic inflammatory and thrombo-occlusive vessel signalling in benign atrophic papulosis and provides evidence of a non-antineutrophil cytoplasmatic antibodies immune-complex small vessel vasculitis according to the Chapel-Hill classification. These findings corroborate its systemic character despite the apparent missing involvement of systemic organs.

[Hyperandrogenism, adrenal dysfunction, and hirsutism]. / Hyperandrogenismus, adrenale Dysfunktion und Hirsutismus.

Hyperandrogenism or hyperandrogenemia are medical conditions characterized by excessive levels of androgens in the periphery or systemically. Clinical manifestations of hyperandrogenism include hirsutism, seborrhea, acne, androgenetic alopecia, and virilization. Hirsutism, defined as excessive growth of terminal hair in women in a male-like pattern, is the most commonly used clinical diagnostic criterion of hyperandrogenism and is determined by using a standardized scoring system of hair growth. Acne and alopecia are further common androgenic skin changes and might be observed without hirsutism in some women. Clitoris hypertrophy, increase of muscle mass, irregular menstrual cycle, and metabolic syndrome can also accompany this condition. Among others polycystic ovary syndrome (PCOS), Cushing disease, and late-onset adrenogenital syndrome belong to the most frequent causes of hyperandrogenemia. Virilization is a relatively uncommon feature of hyperandrogenemia and its presence often suggests an androgen-producing tumor. Management of symptoms include the use of antiandrogens such as cyproterone acetate, spironolactone, and flutamide. A thorough history, a focused clinical examination and an interdisciplinary approach together with gynecologists and endocrinologists are extremely helpful in the diagnostic evaluation and therapy of patients with suspected hyperandrogenism.

Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa.

BACKGROUND: The large unmet need of hidradenitis suppurativa/acne inversa (HS) therapy requires the elucidation of disease-driving mechanisms and tissue targeting. OBJECTIVE: Robust characterization of the underlying HS mechanisms and detection of the involved skin compartments. METHODS: Hidradenitis suppurativa/acne inversa molecular taxonomy and key signalling pathways were studied by whole transcriptome profiling. Dysregulated genes were detected by comparing lesional and non-lesional skin obtained from female HS patients and matched healthy controls using the Agilent array platform. The differential gene expression was confirmed by quantitative real-time PCR and targeted protein characterization via immunohistochemistry in another set of female patients. HS-involved skin compartments were also recognized by immunohistochemistry. RESULTS: Alterations to key regulatory pathways involving glucocorticoid receptor, atherosclerosis, HIF1α and IL17A signalling as well as inhibition of matrix metalloproteases were detected. From a functional standpoint, cellular assembly, maintenance and movement, haematological system development and function, immune cell trafficking and antimicrobial response were key processes probably being affected in HS. Sixteen genes were found to characterize HS from a molecular standpoint (DEFB4, MMP1, GJB2, PI3, KRT16, MMP9, SERPINB4, SERPINB3, SPRR3, S100A8, S100A9, S100A12, S100A7A (15), KRT6A, TCN1, TMPRSS11D). Among the proteins strongly expressed in HS, calgranulin-A, calgranulin-B and serpin-B4 were detected in the hair root sheath, koebnerisin and connexin-32 in stratum granulosum, transcobalamin-1 in stratum spinosum/hair root sheath, small prolin-rich protein-3 in apocrine sweat gland ducts/sebaceous glands-ducts and matrix metallopeptidase-9 in resident monocytes. CONCLUSION: Our findings highlight a panel of immune-related drivers in HS, which influence innate immunity and cell differentiation in follicular and epidermal keratinocytes as well as skin glands.

Prevalence of skin diseases in hospitalized geriatric patients : Association with gender, duration of hospitalization and geriatric assessment.

BACKGROUND: Improvement of quality of life in old age and prevention of age-associated diseases have become the main focus of research into aging; however, information regarding the skin health status of geriatric patients still remains sparse. GOAL: To investigate the extent of dermatological diseases in hospitalized geriatric patients, map the most prevalent ones, check for any gender differences and document any correlations with duration of hospitalization and results of geriatric assessments. PATIENTS AND METHODS: A total of 110 hospitalized geriatric patients underwent a complete dermatological examination at the Evangelical Geriatric Hospital (Evangelisches Geriatriezentrum) Berlin. The collected information was stratified according to dermatological diagnosis, results of geriatric assessments, duration of hospitalization, age and gender of the patients. RESULTS: The average number of diagnosed skin diseases per patient was 3.7 ± 1.8 for the female population and 4.3 ± 2.0 for the male population. After categorizing all diagnosed skin diseases, infectious diseases were found to be most common in both female and male patients (55 % and 58 %, respectively) followed by vascular diseases (46.7 % and 54 %, respectively). Precancerous skin lesions and epithelial skin cancer were more frequent in men than in women (20 % vs. 6.7 %, p < 0.037 and 34 % vs. 13.3 %, p < 0.010, respectively). Pruritus showed a positive correlation with the duration of hospitalization and a negative correlation with the Barthel index and Tinetti score on the day of discharge, indicating that pruritus may have a significant impact on the physical condition of elderly multimorbid patients and on the static and dynamic balance abilities. CONCLUSION: Our results demonstrate that skin health in the elderly is compromised and disregarded and this should constitute one of the top priorities of healthcare specialists and physicians in the future.

Diabetes mellitus and the skin.

Diabetes is a debilitating, life-threatening disease accounting in 2015 for the death of 5 million people worldwide. According to new estimations, 415 million adults currently suffer from the disease, and this number is expected to rise to 642 million by 2040. High glucose blood levels also affect the skin among systemic organs, and skin disorders can often predict the onset of this metabolic disorder. In this review, we address the pathomechanistic effects of diabetes on the skin and give an overview on the most common skin diseases associated with diabetes.

[Intrinsic factors, genes, and skin aging]. / Endogene Faktoren, Gene und Hautalterung.

Skin aging is determined by a combination of endogenous and environmental influences, including epigenetic, posttranslational, microbial, and lifestyle factors. In particular genetic changes, programmed or not, play a pivotal role and understanding of these complex mechanisms may contribute to the prevention of age-related diseases and extension of healthy lifespan. In this article, new knowledge about genes and biological processes that can significantly affect skin homeostasis in old age and can lead to the typical morphological and physiological characteristics of aging skin are summarized.

[Experimental models of human skin aging]. / Experimentelle Modelle humaner Hautalterung.

The skin is a representative model for the study of human aging. Despite the high regenerative capacity of the skin, skin physiology changes over the course of life. Medical and cosmetic research is trying to prevent aging, to slow, to stop, or to reverse it. Effects of age-related DNA damage and of changing skin structure on pharmacological parameters are largely unknown. This review article summarizes the state of scientific knowledge in the field of experimental models of human skin aging and shows approaches to improve organotypic skin models, to develop predictive models of aging, and improve aging research.

[Skin aging: Molecular understanding of extrinsic and intrinsic processes]. / Hautalterung : Molekulares Verständnis der ex- und intrinsischen Vorgänge.

In an ever-aging society, a better understanding of the underlying mechanisms accompanying skin aging has become essential. Most age-related morphological skin changes are triggered by a combination of intrinsic factors (e.g., genetics, hormones) and extrinsic ones (e.g., ultarviolet/infrared light exposure, smoking, pollution). In this article, new insights on the latest findings regarding the pathogenesis of skin aging are summarised, addressing the extent to which the aforementioned factorsmay influence the progress of skin aging and identifying the consequences on the morphology and physiology of skin.

Malignant and benign forms of atrophic papulosis (Köhlmeier-Degos disease): systemic involvement determines the prognosis.

BACKGROUND: Atrophic papulosis (Köhlmeier-Degos disease) is a rare disease of unknown aetiology. The cutaneous signs--papular skin lesions with central porcelain-white atrophy and surrounding telangiectatic rim--are almost pathognomonic. Extracutaneous, systemic involvement includes multiple limited infarcts of the gastrointestinal system, central nervous system and other organs. OBJECTIVES: To assess prospectively the demographics, epidemiological data and prognosis of patients with atrophic papulosis evaluated in a single centre. METHODS: A prospective, single-centre, cohort study at diagnosis was performed on a series of 39 patients with atrophic papulosis, first seen between 2000 and 2007 and evaluated up to 2012. RESULTS: The occurrence of cutaneous lesions defined the onset of disease in all cases. The mean age of onset was 35.4 ± 12.3 years and the male-to-female ratio was 1 : 1.4. In total, 9% of patients reported familial occurrence. Extracutaneous (systemic) signs were recorded in 29% of the patients, whereas the median time for development of systemic manifestations was 1 year (0.03-0.97 quantiles: 0-7 years) after the occurrence of cutaneous lesions. The prognosis was determined mainly by the presence of systemic involvement. 73% of the patients with systemic manifestations (73% developed intestinal perforation) died, while none of the patients with only cutaneous disease had a lethal outcome. The cumulative 5-year survival rate in patients with systemic disease was 54.5%. CONCLUSIONS: Atrophic papulosis, previously called malignant atrophic papulosis, should be classified into a malignant, systemic form and a benign, cutaneous one, the latter being more common. The probability of having a benign form of the disease at onset is approximately 70%, increasing to 97% after 7 years of monosymptomatic cutaneous course.

[Skin diseases in geriatric patients. Epidemiologic data]. / Hauterkrankungen beim geriatrischen Patienten. Epidemiologische Daten.

The incidence of skin diseases more common in older patients, e.g. inflammatory and autoimmune diseases, benign and malignant tumors and paraneoplastic syndromes, is increasing worldwide rapidly mainly due to early or lifelong UV-overexposure and to an aging population. In order to transform this demographic change into a chance a better understanding of the pathomechanisms of these diseases, an early diagnosis and therapy are essential steps. In addition, a joint effort to raise public awareness, patient education, preventive measures and consistent monitoring of high-risk groups is of great importance. In this article, the relationship between aging and associated skin diseases will be presented with a particular focus on the epidemiology and risk factors.

Hormonal therapy of intrinsic aging.

Intrinsic skin aging represents the biological clock of the skin cells per se and reflects the reduction processes that are common in internal organs. The reduced secretion of the pituitary, adrenal glands, and the gonads contributes to characteristic aging-associated body and skin phenotypes as well as behavior patterns. Our knowledge of whether there is a direct or indirect connection between hormonal deficiency and skin aging still remains limited. In females, serum levels of 17ß-estradiol, dehydroepiandrosterone, progesterone, growth hormone (GH), and its downstream hormone insulin-like growth factor I (IGF-I) are significantly decreased with increasing age. In males, serum levels of GH and IGF-I decrease significantly, whereas it can decrease in late age in a part of the population. Hormones have been shown to influence skin morphology and functions, skin permeability, wound healing, sebaceous lipogenesis, and the metabolism of skin cells. Prevention of skin aging by estrogen/progesterone replacement therapy is effective if administered early after menopause and influences intrinsically aged skin only. Vitamin D substitution and antioxidant treatment may also be beneficial. Replacement therapy with androgens, GH, IGF-I, progesterone, melatonin, cortisol, and thyroid hormones still remains controversial.

[Molecular etiology of skin aging. How important is the genetic make-up?]. / Molekulare Ätiologie der Hautalterung. Wie wichtig ist das genetische Make-up?

Although the fundamental mechanisms in the pathogenesis of skin aging are still poorly understood, a growing body of evidence points toward the involvement of multiple pathways. Recent data obtained by expression profiling studies and studies upon progeroid syndromes illustrate that among the most important biological processes involved in skin aging are alterations in DNA repair and stability, mitochondrial function, cell cycle and apoptosis, extracellular matrix, lipid synthesis, ubiquitin-induced proteolysis and cellular metabolism. One of the major factors which have been proposed to play an exquisite role in the initiation of aging is the physiological decline of hormones occurring with age. However, hormones at age-specific levels may not only regulate age-associated mechanisms but also modulate tumor suppressor pathways that influence carcinogenesis. In conclusion, understanding the molecular mechanisms of ageing may open new strategies to deal with the various diseases accompanying advanced age including cancer.

[Dermatoendocrinology. Skin aging]. / Dermatoendokrinologie: Hautalterung.

Hormones and their imbalances have significant effects on the morphology and physiology of the skin and influence various skin functions, especially wound healing and lipogenesis. With increasing age, the concentrations of important circulating hormones, including growth hormone and sex-related steroids, decrease continuously. As a result, physiologic processes are negatively influenced and various age-associated disorders may develop. As the population aged 80 and over is expected to rise in the next decades, the understanding of the molecular mechanisms accompanying skin aging and disease prevention will become even more important and play a role in preventing disease.

Molecular mechanisms of skin aging: state of the art.

The process of skin aging in humans is complex and is induced by multiple factors, including genetic and various environmental ones. In particular, the superposition of environmental factors, such as UV irradiation on skin, results in massive wound-like morphological alterations mainly of the dermis. In sun-protected areas the most pronounced changes occur within the epidermis and affect mostly the basal cell layer. As a result, while sun-protected aged skin appears thin, finely wrinkled, and dry, photoaged skin is characterized by deep wrinkles, laxity, and roughness. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward the involvement of multiple pathways in the generation of aged skin. Recent data obtained by expression-profiling studies and studies of progeroid syndromes (e.g., Hutchinson-Gilford progeria, Werner syndrome, Rothmund-Thomson syndrome, Cockayne syndrome, ataxia teleangiectasia, and Down syndrome) illustrate that among the most important biological processes involved in skin aging are alterations in DNA repair and stability, mitochondrial function, cell cycle and apoptosis, ubiquitin-induced proteolysis, and cellular metabolism. One of the major factors that has been proposed to play an exquisite role in the initiation of aging is the physiological hormone decline occurring with age. However, hormones at age-specific levels may not only regulate age-associated mechanisms but also regulate tumor-suppressor pathways that influence carcinogenesis. Understanding the molecular mechanisms of aging may open new strategies in dealing with the various diseases accompanying aging, including cancer.

Testosterone metabolism to 5alpha-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferator-activated receptor ligand linoleic acid in human sebocytes.

BACKGROUND: Despite the clinical evidence that androgens stimulate sebaceous lipids, androgens in vitro have shown no similar effects. This contradiction led to the assumption that cofactors may be required for lipid regulation and peroxisome proliferator-activated receptor (PPAR) ligands were suggested to be adequate candidates. OBJECTIVES: The influence of testosterone and linoleic acid, a PPAR ligand, as single agents and in combination with of LY191704, a 5alpha-reductase type I inhibitor, was examined on 5alpha-dihydrotestosterone (5alpha-DHT) synthesis and lipid content in human SZ95 sebocytes. METHODS: Cell proliferation and viability were measured by the 4-methylumbelliferyl heptanoate fluorescence assay and by the Boehringer Lactate Dehydrogenase Assay kit, respectively. 5alpha-DHT enzyme-linked immunosorbent assay was used for the detection of 5alpha-DHT synthesis in cell supernatants after treatment, whereas lipid production was documented by means of the Nile red lipid microassay and fluorescence microscopy. RESULTS: Testosterone promoted 5alpha-DHT synthesis (P < 0.001), whereas linoleic acid increased sebaceous lipids (P < 0.001). The combination of testosterone and linoleic acid exhibited a synergistic effect on the synthesis of 5alpha-DHT (P < 0.01 vs. testosterone) and sebaceous lipids (P < 0.01 vs. linoleic acid). Furthermore, LY191704 reduced 5alpha-DHT and sebaceous lipid levels (P < 0.01 and P < 0.001 in comparison with testosterone/linoleic acid, respectively). Cell proliferation and viability remained unchanged under treatment with all compounds tested. CONCLUSIONS: These data suggest a catalytic effect of PPAR ligands on cellular testosterone activation by 5alpha-reduction and the importance of the latter for the regulation of sebaceous lipids.