[Phlebology in German departments of dermatology. An analysis on behalf of the German Society of Phlebology]. / Phlebologie an deutschen Hautkliniken. Eine Bestandsaufnahme im Auftrag der Deutschen Gesellschaft für Phlebologie.

BACKGROUND: Phlebologic diseases have become extremely common and have major socio-economic impact. However, the percentage of dermatologists working in phlebology appears to be decreasing according to the data of the German Society of Phlebology (DGP). METHODS: To investigate the reasons for this development, we--on behalf of the DGP--sent a questionnaire to 120 German Departments of Dermatology in autumn 2012. RESULTS: In 76 returned questionnaires, the number of physicians with additional fellowship training in phlebology averaged 1.5; the average number of those who fulfill the criteria for training fellows in phlebology was 0.9. In 71.1 % of the departments there was a phlebologist. A special phlebologic outpatient clinic existed in 73.7 % of the departments. Sonography with Doppler (89.5 %) and duplex (86.8 %) was used as the most frequent diagnostic tool. For therapy, compression (94.7 %), sclerotherapy (liquid 78.9 %, foam 63.2 %, catheter 18.4 %), endoluminal thermic procedures (radio wave 28.9 %, laser 17.1 %) and surgery (especially crossectomy and stripping 67.1 %, phlebectomy of tributaries 75 %) were used. The average number of treatments was very heterogenous in the different departments. CONCLUSIONS: Phlebology definitely plays an important role in dermatology. Most departments fulfill the formal criteria for the license to conduct advanced training in phlebology. A wide spectrum of phlebological diagnostic and therapeutic procedures is available.

Dermocosmetics for dry skin: a new role for botanical extracts.

Dry skin is associated with a disturbed skin barrier and reduced formation of epidermal proteins and lipids. During recent years, skin-barrier-reinforcing properties of some botanical compounds have been described. Searching the PubMed database revealed 9 botanical extracts that specifically improve skin barrier and/or promote keratinocyte differentiation in vivo after topical application. The topical application of Aloe vera (leaf gel), Betula alba (birch bark extract), Helianthus annuus (sunflower oleodistillate), Hypericum perforatum (St. John's wort extract), Lithospermum erythrorhizon (root extract), Piptadenia colubrina (angico-branco extract) and Simarouba amara (bitter wood extract) increased skin hydration, reduced the transepidermal water loss, or promoted keratinocyte differentiation in humans in vivo. The topical application of Rubia cordifolia root extract and rose oil obtained from Rosa spp. flowers stimulated keratinocyte differentiation in mouse models. The underlying mechanisms of these effects are discussed. It is concluded that some botanical compounds display skin-barrier-reinforcing properties that may be used in dermocosmetics for dry skin. However, more investigations on the mode of action and more vehicle-controlled studies are required.

New perspectives on eye development and the evolution of eyes and photoreceptors.

Recent experiments on the genetic control of eye development have opened up a completely new perspective on eye evolution. The demonstration that targeted expression of one and the same master control gene, that is, Pax6 can induce the formation of ectopic eyes in both insects and vertebrates, necessitates a reconsideration of the dogma of a polyphyletic origin of the various eye types in all the animal phyla. The involvement of Pax6 and six1 and six3 genes, which encode highly conserved transcription factors, in the genetic control of eye development in organisms ranging from planarians to humans argues strongly for a monophyletic origin of the eye. Because transcription factors can control the expression of any target gene provided it contains the appropriate gene regulatory elements, the conservation of the genetic control of eye development by Pax6 among all bilaterian animals is not due to functional constraints but a consequence of its evolutionary history. The prototypic eyes postulated by Darwin to consist of two cells only, a photoreceptor and a pigment cell, were accidentally controlled by Pax6 and the subsequent evolution of the various eye types occurred by building onto this original genetic program. A hypothesis of intercalary evolution is proposed that assumes that the eye morphogenetic pathway is progressively modified by intercalation of genes between the master control genes on the top of the hierarchy and the structural genes like rhodopsin at the bottom. The recruitment of novel genes into the eye morphogenetic pathway can be due to at least two different genetic mechanisms, gene duplication and enhancer fusion.In tracing back the evolution of eyes beyond bilaterians, we find highly developed eyes in some box-jellyfish as well as in some Hydrozoans. In Hydrozoans the same orthologous six genes (six1 and six3) are required for eye regeneration as in planarians, and in the box jellyfish Tripedalia a pax B gene, which may be a precursor of Pax6, was found to be expressed in the eyes. In contrast to the adults, which have highly evolved eyes, the Planula larva of Tripedalia has single- celled photoreceptors similar to some unicellular protists. For the origin of photoreceptor cells in metazoa, I propose two hypotheses, one based on cellular differentiation and a more speculative one based on symbiosis. The former assumes that photoreceptor cells originated from a colonial protist in which all the cells were photosensitive and subsequent cellular differentiation to give rise to photoreceptor cells. The symbiont hypothesis, which I call the Russian doll model, assumes that photosensitivity arose first in photosynthetic cyanobacteria that were subsequently taken up into red algae as primary chloroplasts. The red algae in turn were taken up by dinoflagellates as secondary chloroplasts and in some species evolved into the most sophisticated eye organelles, as found, for example, in some dinoflagellates like Erythropsis and Warnovia, which lack chloroplasts. Because dinoflagellates are commonly found as symbionts in cnidarians, the dinoflagellates may have transferred their photoreceptor genes to cnidarians. In cnidarians such as Tripedalia the step from photoreceptor organelles to multicellular eyes has occurred. These two hypotheses, the cellular differentiation and the symbiont hypothesis, are not mutually exclusive and are the subject of further investigations.

Nicotinic acid/niacinamide and the skin.

Nicotinic acid (also generally known as niacin) and niacinamide (also known as nicotinamide) are similarly effective as a vitamin because they can be converted into each other within the organism. The blanket term vitamin B(3) is used for both. Niacinamide is a component of important coenzymes involved in hydrogen transfer. Here, the two codehydrogenases, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) are of central importance. Topical application of niacinamide has a stabilizing effect on epidermal barrier function, seen as a reduction in transepidermal water loss and an improvement in the moisture content of the horny layer. Niacinamide leads to an increase in protein synthesis (e.g. keratin), has a stimulating effect on ceramide synthesis, speeds up the differentiation of keratinocytes, and raises intracellular NADP levels. In ageing skin, topical application of niacinamide improves the surface structure, smoothes out wrinkles and inhibits photocarcinogenesis. It is possible to demonstrate anti-inflammatory effects in acne, rosacea and nitrogen mustard-induced irritation. Because of its verifiable beneficial effects, niacinamide would be a suitable component in cosmetic products for use in disorders of epidermal barrier function, for ageing skin, for improving pigmentary disorders and for use on skin prone to acne.

O/W emulsions compromise the stratum corneum barrier and improve drug penetration.

BACKGROUND: W/O emulsions improve the stratum corneum barrier, while microemulsions tend to compromise it. We, therefore, were interested to explore the effects of O/W emulsions on the stratum corneum barrier. METHODS: Aqueous Cream BP 2001, Clioquinol Cream BP 1999 without clioquinol, Nonionic Hydrophilic Cream DAB 2001 without glycerol, Hydrophilic Skin Emulsion Base NRF S. 25., point of time 2001, without glycerol, and Base Cream DAC were tested versus untreated controls in 29 healthy volunteers for 7 days. Outcome measures included transepidermal water loss (TEWL), skin redness (chromametry a*-value) and erythrocyte circulation in the subpapillary vessels (laser Doppler). Barrier compromise was subsequently explored by performing the hydrocortisone blanching test using Hydrocortisone Cream 0.5% NRF 11.36. (outcome measure: a*-value) in 15 subjects and the sodium lauryl sulfate (SLS) irritation test (outcome measures: TEWL, a*-value, laser Doppler) in 14 subjects. RESULTS: Pretreatment with the test emulsions produced increases in TEWL (statistically significant for all test emulsions), a*-value (statistically significant for Aqueous Cream BP 2001 and Base Cream DAC), and laser Doppler value (statistically significant for all emulsions except Base Cream DAC). Hydrocortisone penetration was statistically significantly increased with all test emulsions versus untreated contols. SLS irritation was mostly statistically significantly increased versus untreated controls when analyzing the study endpoint-baseline difference. CONCLUSIONS: O/W emulsions may compromise the stratum corneum barrier and improve drug penetration.

Transgenic planarian lines obtained by electroporation using transposon-derived vectors and an eye-specific GFP marker.

To generate transgenic planarians we used a set of versatile vectors for animal transgenesis based on the promiscuous transposons, mariner, Hermes and piggyBac, and a universal enhanced GFP (EGFP) marker system with three Pax6 dimeric binding sites, the 3xP3-EGFP developed by Berghammer et al. [Berghammer, A. J., Klinger, M. & Wimmer, E. A. (1999) Nature 402, 370-371]. This marker is expressed specifically in the eyes of various arthropod taxa. Upon microinjection into the parenchyma of adult planarians and subsequent electroporation, these vectors transpose efficiently into the planarian genome. One of the cell types transformed are the totipotent "neoblast" stem cells present in the adults, representing 30% of total cells. The neoblast represents a unique cell type with the capacity to proliferate and to differentiate into all somatic cell types as well as into germ cells. All three transposon vectors have high transformation efficiency, but only Hermes and piggyBac show stable integration. The mariner vector is frequently lost presumably because of the presence of active mariner-type transposons in the genome of the Girardia tigrina. Transformed animals are mosaics containing both transformed and untransformed neoblasts. These differentiate to form EGFP-positive and -negative photoreceptor cells. Such mosaicism is maintained through several cycles of regeneration induced by decapitation or asexual reproduction. Transformed neoblasts also contribute to the germ line, and can give rise to pure transgenic planarian lines in which EGFP is expressed in all photoreceptor cells after sexual reproduction. The presence of the transgenes was confirmed by PCR, plasmid rescue assay, inverse PCR, and Southern blotting. Our results with the 3xP3-EGFP marker confirm the presence of Pax6 activity in the differentiated photoreceptor cells of planarian eyes. Transgenesis will be an important tool to dissect developmental molecular mechanisms in planarian regeneration, development and stem cell biology, and may also be an entry point to analyze the biology of parasitic Platyhelminthes.

[Effects of emulsions on the stratum corneum barrier and hydration]. / Eigenwirkungen von Emulsionen auf die Hornschichtbarriere und -hydratation.

The appearance of the skin depends greatly on the hydration of the stratum corneum which is regulated by water binding substances of the corneocytes and also by the quality of the stratum corneum lipids. Furthermore these lipids are responsible for the barrier function. In patients with atopic dermatitis, the water binding capacity and the barrier function of the stratum corneum are reduced even in clinically healthy skin areas. Emollients can damage the stratum corneum and lead to desiccation and a disturbance of the barrier. This effect is a result of an increased permeability of the barrier lipids and direct damage to the keratinocytes and corneocytes. The degree of damage of the barrier caused by emollients in dermatological vehicles has not been sufficiently investigated. As suggested by hypothetical considerations, such an effect is not expected and cannot be demonstrated in water-in-oil-emulsions. Oil-in-water-emulsions without glycerol as well as lipophilic and hydrophilic microemulsions do damage the barrier function. Both types of microemulsions additionally lead to a dehydration of the stratum corneum. The damaging effect of oil-in-water-emulsions can be reduced by the addition of glycerol and urea.

Do urea/ammonium lactate combinations achieve better skin protection and hydration than either component alone?

Twenty subjects with healthy skin were treated with the following formulations for two weeks: drug-free W/O vehicle, 5% ammonium lactate (CAS 52003-58-4) in W/O vehicle, 5% urea (CAS 57-13-6) in W/O vehicle, 3% ammonium lactate + 3% urea in W/O vehicle, 5% ammonium lactate + 5% urea in W/O vehicle. These formulations were applied in randomized order to 6 test areas on the forearms; one area was left untreated. Repetitive washings were additionally performed in the second treatment week. TEWL, stratum corneum water content (corneometry-determined electrical capacitance), and cutaneous blood flow (laser Doppler) were measured at baseline, day 7, and day 14. 5% urea and both ammonium lactate/urea combinations produced significant stratum corneum hydration and improved stratum corneum barrier function; there were no significant differences between these three treatments.

Functions of the medial frontal cortex in the processing of conflict and errors.

A principal function of the medial frontal cortex, in particular the anterior cingulate cortex (ACC), is to monitor action. The error-related negativity (ERN, or N(E)), an event-related brain potential, reflects medial frontal action-monitoring processes. Specifically, the error-detection theory of the ERN states that the ERN reflects ACC processing that is directly related to detecting the error. This theory predicts that ERN and ACC activity should increase directly with the dissimilarity of the error from the correct response, with similarity defined with respect to the common movement features of the responses. In contrast, the conflict-detection theory claims that ACC and ERN activity represent the detection of response conflict. This theory predicts that the activity should increase directly with the similarity of the error and the correct response. To test these theories, we investigated the effects of response similarity and conflict on the ERN, using a task that involved hand and foot movements. ERN activity was largest under conditions of high response conflict, where the error was similar to the correct response. This finding favors the conflict-detection theory over the error-detection theory, although the ERN was not associated with posterror slowing, as predicted by proponents of both theories. Discrepancies between our results and those of past studies may stem from the use in previous studies of four-finger response tasks which are subject to unique physiological and biomechanical constraints. We conclude that the ERN reflects medial frontal activity involved in the detection or affective processing of response conflict.

[Clinical effect of salicylic acid and high dose urea applied according to the standardized New German Formulary]. / Klinische Wirkung von Salicylsäure und hochdosiertem Harnstoff bei Applikation in standardisierten Magistralrezepturen aus dem Neuen Rezeptur Formularium (NRF).

OBJECTIVE: To determine whether salicylic acid and high dose urea in five different NRF (New German Formulary) formulations have an effect on stratum corneum. METHODS: 20 healthy volunteers had their stratum corneum blacked with silver nitrate and a photographic developer, and a chromameter (a*-value) was used to determine the amount of discoloration produced by the study products and the drug free vehicles after 24 hours semiocclusive application and 24 hours later. The change in fingerpad ridge width produced by the study formulations and drugfree vehicles was determined at the same time, using the Hikoscope Dermatoscope after 30 and 35 minutes' use under an occlusive dressing. The results obtained with the two methods were correlated. RESULTS: All study formulations were effective. There were differences in the time course of the effects on the stratum corneum. The fingerpad ridge width method is not a measure of keratolytic activity because there were no significant correlations between the results obtained with the two methods. Also, 40% urea was keratolytic in the silver nitrate test, but had no effect of fingerpad ridge width. CONCLUSIONS: All NRF study formulations were effective in the stratum corneum. The fingerpad ridge width method is not a measure of keratolytic activity but rather of an other unknown effect of salicylic acid.

The eyeless homeodomain is dispensable for eye development in Drosophila.

Pax-6 genes, known to be essential for eye development, encode an evolutionarily conserved transcription factor with two DNA-binding domains. To corroborate the contribution of each DNA-binding domain to eye formation, we generated truncated forms of the Drosophila Pax-6 gene eyeless and tested their capacity to rescue the ey(2) mutant. Surprisingly, EY deleted of the homeodomain rescued the ey(2) mutant and triggered ectopic eyes morphogenesis. In contrast, EY lacking the paired domain failed to rescue the ey(2) mutant, led to truncation of appendages, and repressed Distal-less when misexpressed. This result suggests distinct functions mediated differentially by the two DNA-binding domains of eyeless.

Differential expression and function of the Drosophila Pax6 genes eyeless and twin of eyeless in embryonic central nervous system development.

We analyzed the expression and function of eyeless (ey) and twin of eyeless (toy) in the embryonic central nervous system (CNS) of Drosophila. Both genes are differentially expressed in specific neuronal subsets (but not in glia) in every CNS neuromere, and in the brain, specific cell populations co-expressing both proteins define a longitudinal domain which is intercalated between broad exclusive expression domains of ey and toy. Studies of genetic null alleles and dsRNA interference did not reveal any gross neuroanatomical effects of ey, toy, or ey/toy elimination in the embryonic CNS. In contrast, targeted misexpression of ey, but not of toy, resulted in profound axonal abnormalities in the embryonic ventral nerve cord and brain.

Molecular basis for the inhibition of Drosophila eye development by Antennapedia.

Hox genes encoding homeodomain transcriptional regulators are known to specify the body plan of multicellular organisms and are able to induce body plan transformations when misexpressed. These findings led to the hypothesis that duplication events and misexpression of Hox genes during evolution have been necessary for generating the observed morphological diversity found in metazoans. It is known that overexpressing Antennapedia (Antp) in the head induces antenna-to-leg as well as head-to-thorax transformation and eye reduction. At present, little is known about the exact molecular mechanism causing these phenotypes. The aim of this study is to understand the basis of inhibition of eye development. We demonstrate that Antp represses the activity of the eye regulatory cascade. By ectopic expression, we show that Antp antagonizes the activity of the eye selector gene eyeless. Using both in vitro and in vivo experiments, we demonstrate that this inhibitory mechanism involves direct protein-protein interactions between the DNA-binding domains of EY and ANTP, resulting in mutual inhibition.

Do shake lotions, zinc oil and polyethylene glycol gels produce dehydration or moisturization?

We carried out three studies to evaluate the effects of white zinc shake lotion (Zinkschüttelmixtur DAC), zinc oil ( Zinköl NRF 11.20), Lotio Cordes, PEG ointment (Polyethylenglykolsalbe DAB) and PEG paste on nonmoisturized and moisturized skin. The aim of the study was a clear indication for these vehicles in the clinical practice. Studies 1 and 2 were performed on 20 healthy volunteers. Study 1 was carried out on nonmoisturized skin, while test areas in study 2 were treated with the study products after 1-hour moisturization with hydrophilic aqueous ointment (hydrophile wasserhaltige Salbe DAB), covered with a semiocclusive film dressing. Study 3, carried out on 10 subjects, differed from study 2 by a longer follow-up period. The water content of the horny layer before and after application of the different vehicles was estimated by the capacitance measurement (Corneometer CM 820) and the conductance measurement (Skikon). The glycerol-containing zinc shake lotion and both PEG gels (with or without zinc oxide) produced hydration under the conditions of study 1 and 2. Zinc oil and moisturizer-free Lotio Cordes had little impact on stratum corneum hydration under the conditions of studies 1-3. Therefore, zinc shake lotion and the two PEG ointments can be used in the treatment of dry atopic skin, but not in overhydrated skin, e.g. in intertriginous regions. Zinc oil and Lotio Cordes can be used in overhydrated skin but not in dry skin, for the missing water-binding capacity in the horny layer. On the other hand an effective dehydrating effect cannot be expected.

Effect of topically applied dexpanthenol on epidermal barrier function and stratum corneum hydration. Results of a human in vivo study.

In a randomized, double-blind, placebo-controlled study the effect of topical dexpanthenol (CAS 81-13-0) formulated in two different lipophilic vehicles on epidermal barrier function in vivo was carried out. Seven days' treatment with dexpanthenol improved stratum corneum hydration and reduced transepidermal water loss. Active treatment was statistically different from the vehicle control on both measures. Our results suggest that topical dexpanthenol formulated in either lipophilic vehicle stabilizes the skin barrier function.

Characterization and expression analysis of an ancestor-type Pax gene in the hydrozoan jellyfish Podocoryne carnea.

We characterized a Pax gene from the hydrozoan Podocoryne carnea. It is most similar to cnidarian Pax-B genes and encodes a paired domain, a homeodomain and an octapeptide. Expression analysis demonstrates the presence of Pax-B transcripts in eggs, the ectoderm of the planula larva and in a few scattered cells in the apical polyp ectoderm. In developing and mature medusae, Pax-B is localized in particular endodermal cells, oriented toward the outside. Pax-B is not expressed in muscle cells. However, if isolated striated muscle tissue is activated for transdifferentiation, the gene is expressed within 1 h, before new cell types, such as smooth muscle and nerve cells, have formed. The expression data indicate that Pax-B is involved in nerve cell differentiation.