Christian Sander

Abstract For a successful analysis of the relation between amino acid sequence and protein structure, an unambiguous and physically meaningful definition of secondary structure is essential. We have developed a set of simple and physically motivated criteria for secondary structure, programmed as a pattern‐recognition process of hydrogen‐bonded and geometrical features extracted from x‐ray coordinates. Cooperative secondary structure is recognized as repeats of the elementary hydrogen‐bonding patterns “turn” and “bridge.” Repeating turns are “helices,” repeating bridges are “ladders,” connected ladders are “sheets.” Geometric structure is defined in terms of the concepts torsion and curvature of differential geometry. Local chain “chirality” is the torsional handedness of four consecutive C α positions and is positive for right‐handed helices and negative for ideal twisted β‐sheets. Curved pieces are defined as “bends.” Solvent “exposure” is given as the number of water molecules in possible contact with a residue. The end result is a compilation of the primary structure, including SS bonds, secondary structure, and solvent exposure of 62 different globular proteins. The presentation is in linear form: strip graphs for an overall view and strip tables for the details of each of 10.925 residues. The dictionary is also available in computer‐readable form for protein structure prediction work.

We have developed a new method for modelling protein dynamics using normal-mode analysis in internal co-ordinates. This method, normal-mode dynamics, is particularly well suited for modelling collective motion, makes possible direct visualization of biologically interesting modes, and is complementary to the more time-consuming simulation of molecular dynamics trajectories. The essential assumption and limitation of normal-mode analysis is that the molecular potential energy varies quadratically. Our study starts with energy minimization of the X-ray co-ordinates with respect to the single-bond torsion angles. The main technical task is the calculation of second derivative matrices of kinetic and potential energy with respect to the torsion angle co-ordinates. These enter into a generalized eigenvalue problem, and the final eigenvalues and eigenvectors provide a complete description of the motion in the basic 0.1 to 10 picosecond range. Thermodynamic averages of amplitudes, fluctuations and correlations can be calculated efficiently using analytical formulae. The general method presented here is applied to four proteins, trypsin inhibitor, crambin, ribonuclease and lysozyme. When the resulting atomic motion is visualized by computer graphics, it is clear that the motion of each protein is collective with all atoms participating in each mode. The slow modes, with frequencies of below 10 cm−1 (a period of 3 ps), are the most interesting in that the motion in these modes is segmental. The root-mean-square atomic fluctuations, which are dominated by a few slow modes, agree well with experimental temperature factors (B values). The normal-mode dynamics of these four proteins have many features in common, although in the larger molecules, lysozyme and ribonuclease, there is low frequency domain motion about the active site.

This editorial review summarizes the results of 5 meetings sponsored by the International Society for Cutaneous Lymphoma at which the clinicopathologic and ancillary features of early mycosis fungoides were critically examined. Based on this analysis, an algorithm was developed for the diagnosis of early mycosis fungoides involving a holistic integration of clinical, histopathologic, immunopathologic, and molecular biological characteristics. A novel aspect of this algorithm is that it relies on multiple types of criteria rather than just one, for example, histopathology. Before its finalization, the proposed diagnostic algorithm will require validation and possibly further refinement at multiple centers during the next several years. It is anticipated that a more standardized approach to the diagnosis of early mycosis fungoides will have a beneficial impact on the epidemiology, prognostication, treatment, and analysis of clinical trials pertaining to this most common type of cutaneous lymphoma. This editorial review summarizes the results of 5 meetings sponsored by the International Society for Cutaneous Lymphoma at which the clinicopathologic and ancillary features of early mycosis fungoides were critically examined. Based on this analysis, an algorithm was developed for the diagnosis of early mycosis fungoides involving a holistic integration of clinical, histopathologic, immunopathologic, and molecular biological characteristics. A novel aspect of this algorithm is that it relies on multiple types of criteria rather than just one, for example, histopathology. Before its finalization, the proposed diagnostic algorithm will require validation and possibly further refinement at multiple centers during the next several years. It is anticipated that a more standardized approach to the diagnosis of early mycosis fungoides will have a beneficial impact on the epidemiology, prognostication, treatment, and analysis of clinical trials pertaining to this most common type of cutaneous lymphoma.

Analysis of the amino acid sequence of transcription factor TFIIIA from Xenopus laevis reveals the presence of 12 repeating structures, each about 30 residues in length. These segments have been aligned and their secondary structure predicted. The repeats each contain two invariant cysteines and two invariant histidines, perhaps to coordinate a zinc cation. Possible nucleic acid interaction modes are discussed.

Polymorphonuclear leukocytes (PMNs) characterize the pathology of T cell-mediated autoimmune diseases and delayed-type hypersensitivity reactions (DTHRs) in the skin, joints, and gut, but are absent in T cell-mediated autoimmune diseases of the brain or pancreas. All of these reactions are mediated by interferon gamma-producing type 1 T cells and produce a similar pattern of cytokines. Thus, the cells and mediators responsible for the PMN recruitment into skin, joints, or gut during DTHRs remain unknown. Analyzing hapten-induced DTHRs of the skin, we found that mast cells determine the T cell-dependent PMN recruitment through two mediators, tumor necrosis factor (TNF) and the CXC chemokine macrophage inflammatory protein 2 (MIP-2), the functional analogue of human interleukin 8. Extractable MIP-2 protein was abundant during DTHRs in and around mast cells of wild-type (WT) mice but absent in mast cell-deficient WBB6F(1)-Kit(W)/Kit(W-)(v) (Kit(W)/Kit(W)(-v)) mice. T cell-dependent PMN recruitment was reduced >60% by anti-MIP-2 antibodies and >80% in mast cell-deficient Kit(W)/Kit(W)(-v) mice. Mast cells from WT mice efficiently restored DTHRs and MIP-2-dependent PMN recruitment in Kit(W)/Kit(W)-(v) mice, whereas mast cells from TNF(-/)- mice did not. Thus, mast cell-derived TNF and MIP-2 ultimately determine the pattern of infiltrating cells during T cell-mediated DTHRs.

The search for amino acid sequence homologies can be a powerful tool for predicting protein structure. Discovered sequence homologies are currently used in predicting the function of oncogene proteins. To sharpen this tool, we investigated the structural significance of short sequence homologies by searching proteins of known three-dimensional structure for subsequence identities. In 62 proteins with 10,000 residues, we found that the longest isolated homologies between unrelated proteins are five residues long. In 6 (out of 25) cases we saw surprising structural adaptability: the same five residues are part of an alpha-helix in one protein and part of a beta-strand in another protein. These examples show quantitatively that pentapeptide structure within a protein is strongly dependent on sequence context, a fact essentially ignored in most protein structure prediction methods: just considering the local sequence of five residues is not sufficient to predict correctly the local conformation (secondary structure). Cooperativity of length six or longer must be taken into account. Also, we are warned that in the growing practice of comparing a new protein sequence with a data base of known sequences, finding an identical pentapeptide sequence between two proteins is not a significant indication of structural similarity or of evolutionary kinship.

The three most widely used methods for the prediction of protein secondary structure from the amino acid sequence are tested on 62 proteins of known structure using a program package and data collection not previously available. None of these methods predicts better than 56% of the residues correctly, for a three state model (helix, sheet and loop). The algorithms of Robson [J. Mol. Biol. (1978) 120, 97–120] and Lim [J. Mol. Biol. (1974) 88, 873–894] are the best of those tested. New methods, now under development, can be tested against this benchmark.

Chronic systemic inflammation in obesity originates from local immune responses in visceral adipose tissue. However, assessment of a broad range of inflammation-mediating cytokines and their relationship to physical activity and adipometrics has scarcely been reported to date.To characterize the profile of a broad range of pro- and anti-inflammatory cytokines and the impact of physical activity and energy expenditure in individuals with general obesity, central obesity, and non-obese subjects.A cross-sectional study comprising 117 obese patients (body mass index (BMI) ≥ 30) and 83 non-obese community-based volunteers.Serum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured. Physical activity and energy expenditure (MET) were assessed with actigraphy. Adipometrics comprised BMI, weight, abdominal-, waist- and hip-circumference, waist to hip ratio (WHR), and waist-to-height-ratio (WHtR).General obesity was associated with significantly elevated levels of IL-5, IL-10, IL-12, IL-13, IFN-γ and TNF-α, central obesity with significantly elevated IL-5, IL-10, IL-12, IL-13 and IFN-γ-levels. In participants with general obesity, levels of IL-4, IL-10 and IL-13 were significantly elevated in participants with low physical activity, even when controlled for BMI which was negatively associated with physical acitivity. Cytokines significantly correlated with adipometrics, particularly in obese participants.Results confirm up-regulation of certain pro- and anti-inflammatory cytokines in obesity. In obese subjects, physical activity may lower levels and thus reduce pro-inflammatory effects of cytokines that may link obesity, insulin resistance and diabetes.

Abstract: The new WHO/EORTC classification for cutaneous lymphomas comprises mature T‐cell and natural killer (NK)‐cell neoplasms, mature B‐cell neoplasms, and immature hematopoietic malignancies. It reflects the unique features of lymphoproliferative diseases of the skin, and at the same time it is as compatible as possible with the concepts underlying the WHO classification for nodal lymphomas and the EORTC classification of cutaneous lymphomas. This article reviews the histological, phenotypical, and molecular genetic features of the various nosological entities included in this new classification. These findings always have to be interpreted in the context of the clinical features and biologic behavior. Aim: To review the histological, phenotypical and molecular genetic features of the various nosological entities of the new WHO/EORTC classification for cutaneous lymphomas. Methods: Extensive review of the literature cited in Medline and own data of the authors. Results: The WHO/EORTC classification of cutaneous lymphomas comprises mature T‐cell and NK‐cell neoplasms, mature B‐cell neoplasms and immature hematopoietic malignancies. It reflects the unique features of primary cutaneous lymphoproliferative diseases. Conclusion: This classification is as much as possible compatible with the concept of the WHO classification for nodal lymphomas and the EORTC classification of cutaneous lymphomas. The histological, phenotypical and molecular genetic features always have to be interpreted in the context of the clinical features and biologic behavior.

The Pittsburgh Sleep Quality Index (PSQI) is frequently used to assess sleep problems in patients. The aim of this study was to provide reference values for this questionnaire, to test psychometric properties, and to analyze associations with psychological, sociodemographic, and behavioral factors. A German community sample comprising 9284 adult residents (aged 18–80 years) was surveyed using the PSQI and several other questionnaires. According to the generally accepted cut-off (PSQI > 5), 36% of the general population slept badly. Females reported significantly more sleep problems than males (mean scores: M = 5.5 vs. M = 4.4, respectively; effect size d = 0.35), but there was no linear association between age and sleep quality. Sleep problems were correlated with fatigue, quality of life (physical as well as mental), physical complaints, anxiety, and lack of optimism. Sleep quality was also strongly associated with socioeconomic status, professional situation (poorest sleep quality in unemployed people), and obesity. In addition to the results of the PSQI total score, mean scores of specific components of sleep quality were presented (sleep latency, sleep duration, and use of sleep medication). The PSQI proved to be a suitable instrument for measuring sleep quality. Gender differences, psychological factors, and obesity should be taken into account when groups of patients are compared with respect to sleep problems.

Immune responses may arrest tumor growth by inducing tumor dormancy. The mechanisms leading to either tumor dormancy or promotion of multistage carcinogenesis by adaptive immunity are poorly characterized. Analyzing T antigen (Tag)-induced multistage carcinogenesis in pancreatic islets, we show that Tag-specific CD4+ T cells home selectively into the tumor microenvironment around the islets, where they either arrest or promote transition of dysplastic islets into islet carcinomas. Through combined TNFR1 signaling and IFN-gamma signaling, Tag-specific CD4+ T cells induce antiangiogenic chemokines and prevent alpha(v)beta(3) integrin expression, tumor angiogenesis, tumor cell proliferation, and multistage carcinogenesis, without destroying Tag-expressing islet cells. In the absence of either TNFR1 signaling or IFN-gamma signaling, the same T cells paradoxically promote angiogenesis and multistage carcinogenesis. Thus, tumor-specific T cells can directly survey multistage carcinogenesis through cytokine signaling.

The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies.The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography.The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.

Electronic mental health interventions for mood disorders have increased rapidly over the past decade, most recently in the form of various systems and apps that are delivered via smartphones.We aim to provide an overview of studies on smartphone-based systems that combine subjective ratings with objectively measured data for longitudinal monitoring of patients with affective disorders. Specifically, we aim to examine current knowledge on: (1) the feasibility of, and adherence to, such systems; (2) the association of monitored data with mood status; and (3) the effects of monitoring on clinical outcomes.We systematically searched PubMed, Web of Science, PsycINFO, and the Cochrane Central Register of Controlled Trials for relevant articles published in the last ten years (2007-2017) by applying Boolean search operators with an iterative combination of search terms, which was conducted in February 2017. Additional articles were identified via pearling, author correspondence, selected reference lists, and trial protocols.A total of 3463 unique records were identified. Twenty-nine studies met the inclusion criteria and were included in the review. The majority of articles represented feasibility studies (n=27); two articles reported results from one randomized controlled trial (RCT). In total, six different self-monitoring systems for affective disorders that used subjective mood ratings and objective measurements were included. These objective parameters included physiological data (heart rate variability), behavioral data (phone usage, physical activity, voice features), and context/environmental information (light exposure and location). The included articles contained results regarding feasibility of such systems in affective disorders, showed reasonable accuracy in predicting mood status and mood fluctuations based on the objectively monitored data, and reported observations about the impact of monitoring on clinical state and adherence of patients to the system usage.The included observational studies and RCT substantiate the value of smartphone-based approaches for gathering long-term objective data (aside from self-ratings to monitor clinical symptoms) to predict changes in clinical states, and to investigate causal inferences about state changes in patients with affective disorders. Although promising, a much larger evidence-base is necessary to fully assess the potential and the risks of these approaches. Methodological limitations of the available studies (eg, small sample sizes, variations in the number of observations or monitoring duration, lack of RCT, and heterogeneity of methods) restrict the interpretability of the results. However, a number of study protocols stated ambitions to expand and intensify research in this emerging and promising field.

Background: Depression is a severe disease with great burdens for the affected individuals and public health care systems. Autonomic nervous system (ANS) dysfunction indexed by measures of heart rate variability (HRV) has repeatedly been associated with depression. However, HRV parameters are subject to a wide range of multi-factorial influences and underlying mechanisms in depression are still unclear. HRV parameters have been proposed to be promising candidates for diagnostic or predictive bio-markers for depression but necessary longitudinal design studies investigating the relationship between HRV and depression are scarce. Methods: The sample in this study consisted of 62 depressive individuals without antidepressant medication prior to assessment and 65 healthy controls. Fifteen minute blocks of resting ECGs were recorded 1-2 days before onset of antidepressant treatment and 2 weeks thereafter. The ECGs were pre-processed to extract inter-beat-intervals. Linear and non-linear methods were used to extract HRV parameters. ANOVAS were performed to investigate group differences between depressive patients and healthy controls. Associations between the change in severity of depression and HRV parameters were assessed in a repeated measurements design. Results: Analyses revealed HRV parameter differences between the groups of depressive patients and healthy controls at baseline. Further results show differences in HRV parameters within subjects after 2 weeks of antidepressant treatment. Change in HRV parameter values correlated with changes in symptom severity of depression. Discussion: The current results provide further insight into the relationship between HRV parameters and depression. This may help to underpin utilization of HRV parameters are bio-maker for disease state in depression. Results are discussed within a theoretical framework to link arousal and ANS regulation in depression.

While many structural and biochemical changes in the brain have previously been associated with older age, findings concerning functional properties of neuronal networks, as reflected in their electrophysiological signatures, remain rather controversial. These discrepancies might arise due to several reasons, including diverse factors determining general spectral slowing in the alpha frequency range as well as amplitude mixing between the rhythmic and non-rhythmic parameters. We used a large dataset (N = 1703, mean age 70) to comprehensively investigate age-related alterations in multiple EEG biomarkers taking into account rhythmic and non-rhythmic activity and their individual contributions to cognitive performance. While we found strong evidence for an individual alpha peak frequency (IAF) decline in older age, we did not observe a significant relationship between theta power and age while controlling for IAF. Not only did IAF decline with age, but it was also positively associated with interference resolution in a working memory task primarily in the right and left temporal lobes suggesting its functional role in information sampling. Critically, we did not detect a significant relationship between alpha power and age when controlling for the 1/f spectral slope, while the latter one showed age-related alterations. These findings thus suggest that the entanglement of IAF slowing and power in the theta frequency range, as well as 1/f slope and alpha power measures, might explain inconsistencies reported previously in the literature. Finally, despite the absence of age-related alterations, alpha power was negatively associated with the speed of processing in the right frontal lobe while 1/f slope showed no consistent relationship to cognitive performance. Our results thus demonstrate that multiple electrophysiological features, as well as their interplay, should be considered for the comprehensive assessment of association between age, neuronal activity, and cognitive performance.

Cutaneous lymphomas expressing a cytotoxic or natural killer (NK) cell phenotype represent a group of lymphoproliferative disorders for which there is currently much confusion and little consensus regarding the best nomenclature and classification.This study analyzes 48 cases of primary cutaneous lymphoma expressing cytotoxic proteins and/or the NK cell marker, CD56. These cases were collected for a workshop of the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Task Force, to better clarify the clinical, morphologic, and phenotypic features of these uncommon tumors.Several categories with different clinical and pathologic features were delineated: 1) aggressive, CD8+, epidermotropic, cytotoxic T-cell lymphoma; 2) mycosis fungoides, cytotoxic immunophenotype variant; 3) subcutaneous panniculitis-like T-cell lymphoma; 4) NK/T-cell lymphoma, nasal type; 5) CD4+, NK cell lymphoma; 6) blastoid NK cell lymphoma; (7) intravascular NK-like lymphoma; and 8) cytotoxic, peripheral T-cell lymphoma.Our data show that primary cutaneous cytotoxic/NK cell lymphomas include distinct groups of diseases, clinically, histologically, and biologically. Because the finding of a cytotoxic phenotype often has prognostic significance, the routine use of cytotoxic markers in the diagnosis and classification of cutaneous lymphomas should be expanded.

A single-point mutation in exon 15 of the BRAF gene has recently been reported in a high percentage in cultured melanoma cells and in 6 of 9 primary melanomas examined. To evaluate the impact of the T1796A BRAF mutation, we screened primary melanomas, various types of nevi and lesions where a melanoma developed in an underlying nevus. We could detect the mutation in 28 of 97 (29%) melanomas and in 39 of 187 (21%) nevi, including blue nevi (0/20) and Spitz nevi (0/69), which did not carry the mutation. In melanomas with an underlying nevus, either the mutation was present in both the laser-microdissected nevus cells and the laser-microdissected melanoma cells (3/14) or both lesions were negative for the BRAF mutation except one case. In conclusion, mutations in exon 15 of the BRAF gene are nonspecific for progression of a nevus to a melanoma. Other so far unknown cofactors seem to be of importance.

Abstract Cutaneous B-cell infiltrates showing a prominent follicular growth pattern with germinal centers are thought by some authors to represent either marginal zone lymphomas with reactive germinal centers or pseudolymphomas. To establish whether a true primary cutaneous follicular lymphoma exists, we studied biopsies from 15 patients with skin lesions characterized histopathologically by the presence of B-cell infiltrates with follicular pattern. Staging investigations, including bone marrow biopsy, were negative in all patients. All were negative for bcl-2 protein expression and did not present the t(14;18). In all biopsy specimens neoplastic follicles showed 1 or more morphologic or immunophenotypic criteria of malignancy (presence of a reduced mantle zone, absence of tingible body macrophages, reduced proliferation rate). In 9 specimens a monoclonal rearrangement of JH genes could be detected by polymerase chain reaction analysis. After laser beam microdissection, a band of the same length could be observed in 6 probes from different follicles from the same specimen, indicating the presence of the same monoclonal population of follicle center cells. Follow-up examinations in all patients revealed no evidence of extracutaneous spread (mean follow-up, 48.7 months). Our study demonstrates that primary cutaneous follicular lymphoma represents a distinct entity of the cutaneous B-cell lymphomas.

Dali and HSSP are derived databases organizing protein space in the structurally known regions. We use an automatic structure alignment program (Dali) for the classification of all known 3D structures based on all-against-all comparison of 3D structures in the Protein Data Bank. The HSSP database associates 1D sequences with known 3D structures using a position-weighted dynamic programming method for sequence profile alignment (MaxHom). As a result, the HSSP database not only provides aligned sequence families, but also implies secondary and tertiary structures covering 36% of all sequences in Swiss-Prot. The structure classification by Dali and the sequence families in HSSP can be browsed jointly from a web interface providing a rich network of links between neighbours in fold space, between domains and proteins, and between structures and sequences. In particular, this results in a database of explicit multiple alignments of protein families in the twilight zone of sequence similarity. The organization of protein structures and families provides a map of the currently known regions of the protein universe that is useful for the analysis of folding principles, for the evolutionary unification of protein families and for maximizing the information return from experimental structure determination. The databases are available from http://www.embl-ebi.ac.uk/dali/

On the assumption that the twist angles between adjacent base-pairs in the DNA molecule are additive a linear system of 40 equations was derived from experimental measurements of the total twist angles for different pieces of DNA of known sequences. This system of equations is found to be statistically consistent providing a solution for all ten possible twist angles of B-DNA by a least squares fitting procedure. Four of the calculated twist angles were not known before (τAC, τAG, τCA, τTA). The other six twist angles calculated are very close to the experimentally measured ones (τAA, τAT, τCC, τCG, τGA, τGC) .The data used were obtained by the electrophoretic band shift method (1–3), crystallography (4) and nuclease digestion of adsorbed to mica or Ca-phosphate surface (5,6). The validity of the principle of additivity of the twist angles implies that the angle between any particular two base-pairs is a function of only these base-pairs, independent of nearest neighbours.

Bartonella species are the only known bacterial pathogens causing vasculoproliferative disorders in humans (bacillary angiomatosis [BA]). Cellular and bacterial pathogenetic mechanisms underlying the induction of BA are largely unknown.Activation of hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in angiogenesis, was detected in Bartonella henselae-infected host cells in vitro by immunofluorescence, Western blotting, electrophoretic mobility shift, and reporter gene assays and by immunohistochemistry in BA tissue lesions in vivo. Gene microarray analysis revealed that a B henselae infection resulted in the activation of genes typical for the cellular response to hypoxia. HIF-1 was essential for B henselae-induced expression of vascular endothelial growth factor as shown by inhibition with the use of HIF-1-specific short-interfering RNA. Moreover, infection with B henselae resulted in increased oxygen consumption, cellular hypoxia, and decreased ATP levels in host cells. Infection with a pilus-negative variant of B henselae did not lead to cellular hypoxia or activation of HIF-1 or vascular endothelial growth factor secretion, suggesting a crucial role of this bacterial surface protein in the angiogenic reprogramming of the host cells.B henselae induces a proangiogenic host cell response via HIF-1. Our data provide for the first time evidence that HIF-1 may play a role in bacterial infections.

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 11, Issue s6 p. 1-116 GuidelinesFree Access Malignant Melanoma S3-Guideline “Diagnosis, Therapy and Follow-up of Melanoma” Annette Pflugfelder, Annette Pflugfelder Department of Dermatology, University Hospital Tübingen, Germany shared first authorshipSearch for more papers by this authorCorinna Kochs, Corinna Kochs Department of Dermatology, University Hospital Essen, Germany shared first authorshipSearch for more papers by this authorAndreas Blum, Andreas Blum Public, Private and Teaching Practice of Dermatology, Konstanz, GermanySearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorChristina Czeschik, Christina Czeschik Department of Dermatology, University Hospital Essen, GermanySearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik Lüdenscheidt, GermanySearch for more papers by this authorEdgar Dippel, Edgar Dippel Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorThomas Eigentler, Thomas Eigentler Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPetra Feyer, Petra Feyer Clinic of radiotherapy and radiooncology, Vivantes Clinics Neukölln, Berlin, GermanySearch for more papers by this authorMarkus Follmann, Markus Follmann The German Cancer Society Berlin, GermanySearch for more papers by this authorBernhard Frerich, Bernhard Frerich Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Rostock, GermanySearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorJan Gärtner, Jan Gärtner Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorJessica Hassel, Jessica Hassel German Cancer Research Center, Heidelberg, GermanySearch for more papers by this authorAxel Hauschild, Axel Hauschild Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, GermanySearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe University, Frankfurt am Main, GermanySearch for more papers by this authorMartin Kaatz, Martin Kaatz Department of Dermatology and Allergology, SRH Waldklinikum Gera Gmbh, GermanySearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisc-Onkologische Praxis Altona (HOPA), Struensee-Haus, Hamburg, GermanySearch for more papers by this authorOliver Kölbl, Oliver Kölbl Department of Radiotherapy, University Hospital Regensburg, GermanySearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Department of Radiation Therapy, University of Leipzig, GermanySearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorPeter Kurschat, Peter Kurschat Department of Dermatology and Venereology, University Hospital of Cologne, GermanySearch for more papers by this authorUlrike Leiter, Ulrike Leiter Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorHartmut Link, Hartmut Link Medical Clinic I, Westpfalz Klinikum, Kaiserslautern, GermanySearch for more papers by this authorCarmen Loquai, Carmen Loquai Department of Dermatology, University of Mainz, GermanySearch for more papers by this authorChristoph Löser, Christoph Löser Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Dept. of Internal Medicine 5 – Hematology/Oncology, University of Erlangen, GermanySearch for more papers by this authorFriedegund Meier, Friedegund Meier Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPeter Mohr, Peter Mohr Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Department of Dermatology, University Hospital Tübingen, Germany Praxisklinik Tübingen – Haut und Venen, GermanySearch for more papers by this authorDorothee Nashan, Dorothee Nashan Department of Dermatology, Klinikum Dortmund gGmbH, GermanySearch for more papers by this authorSven Reske, Sven Reske Department of Nuclear Medicine, University Clinic, Ulm, GermanySearch for more papers by this authorChristian Rose, Christian Rose Lübeck, GermanySearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. Georg, GermanySearch for more papers by this authorImke Satzger, Imke Satzger Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Department of Psychosocial Oncology, Fachklinik Hornheide, Münster, GermanySearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorLothar Swoboda, Lothar Swoboda German Society of Thoracic Surgery, Berlin, GermanySearch for more papers by this authorUwe Trefzer, Uwe Trefzer Department of Dermatology, University Hospital Charité Berlin, GermanySearch for more papers by this authorRaymond Voltz, Raymond Voltz Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorDirk Vordermark, Dirk Vordermark Department of Radiooncology, Universitätsklinikum Halle, Halle/Saale, GermanySearch for more papers by this authorMichael Weichenthal, Michael Weichenthal Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorAndreas Werner, Andreas Werner Tumor Center Rhineland Palatinate, Mainz, GermanySearch for more papers by this authorSimone Wesselmann, Simone Wesselmann The German Cancer Society Berlin, GermanySearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Bad Bentheim Hospital, Department of Dermatology and Allergy, Bad Bentheim, GermanySearch for more papers by this authorWolfgang Wick, Wolfgang Wick Dep. of Neurooncology, University Clinic, Heidelberg, GermanySearch for more papers by this authorClaus Garbe, Claus Garbe Department of Dermatology, University Hospital Tübingen, Germany shared last authorshipSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Department of Dermatology, University Hospital Essen, Germany shared last authorshipSearch for more papers by this author Annette Pflugfelder, Annette Pflugfelder Department of Dermatology, University Hospital Tübingen, Germany shared first authorshipSearch for more papers by this authorCorinna Kochs, Corinna Kochs Department of Dermatology, University Hospital Essen, Germany shared first authorshipSearch for more papers by this authorAndreas Blum, Andreas Blum Public, Private and Teaching Practice of Dermatology, Konstanz, GermanySearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorChristina Czeschik, Christina Czeschik Department of Dermatology, University Hospital Essen, GermanySearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik Lüdenscheidt, GermanySearch for more papers by this authorEdgar Dippel, Edgar Dippel Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorThomas Eigentler, Thomas Eigentler Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPetra Feyer, Petra Feyer Clinic of radiotherapy and radiooncology, Vivantes Clinics Neukölln, Berlin, GermanySearch for more papers by this authorMarkus Follmann, Markus Follmann The German Cancer Society Berlin, GermanySearch for more papers by this authorBernhard Frerich, Bernhard Frerich Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Rostock, GermanySearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorJan Gärtner, Jan Gärtner Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorJessica Hassel, Jessica Hassel German Cancer Research Center, Heidelberg, GermanySearch for more papers by this authorAxel Hauschild, Axel Hauschild Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, GermanySearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe University, Frankfurt am Main, GermanySearch for more papers by this authorMartin Kaatz, Martin Kaatz Department of Dermatology and Allergology, SRH Waldklinikum Gera Gmbh, GermanySearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisc-Onkologische Praxis Altona (HOPA), Struensee-Haus, Hamburg, GermanySearch for more papers by this authorOliver Kölbl, Oliver Kölbl Department of Radiotherapy, University Hospital Regensburg, GermanySearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Department of Radiation Therapy, University of Leipzig, GermanySearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorPeter Kurschat, Peter Kurschat Department of Dermatology and Venereology, University Hospital of Cologne, GermanySearch for more papers by this authorUlrike Leiter, Ulrike Leiter Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorHartmut Link, Hartmut Link Medical Clinic I, Westpfalz Klinikum, Kaiserslautern, GermanySearch for more papers by this authorCarmen Loquai, Carmen Loquai Department of Dermatology, University of Mainz, GermanySearch for more papers by this authorChristoph Löser, Christoph Löser Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Dept. of Internal Medicine 5 – Hematology/Oncology, University of Erlangen, GermanySearch for more papers by this authorFriedegund Meier, Friedegund Meier Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPeter Mohr, Peter Mohr Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Department of Dermatology, University Hospital Tübingen, Germany Praxisklinik Tübingen – Haut und Venen, GermanySearch for more papers by this authorDorothee Nashan, Dorothee Nashan Department of Dermatology, Klinikum Dortmund gGmbH, GermanySearch for more papers by this authorSven Reske, Sven Reske Department of Nuclear Medicine, University Clinic, Ulm, GermanySearch for more papers by this authorChristian Rose, Christian Rose Lübeck, GermanySearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. Georg, GermanySearch for more papers by this authorImke Satzger, Imke Satzger Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Department of Psychosocial Oncology, Fachklinik Hornheide, Münster, GermanySearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorLothar Swoboda, Lothar Swoboda German Society of Thoracic Surgery, Berlin, GermanySearch for more papers by this authorUwe Trefzer, Uwe Trefzer Department of Dermatology, University Hospital Charité Berlin, GermanySearch for more papers by this authorRaymond Voltz, Raymond Voltz Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorDirk Vordermark, Dirk Vordermark Department of Radiooncology, Universitätsklinikum Halle, Halle/Saale, GermanySearch for more papers by this authorMichael Weichenthal, Michael Weichenthal Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorAndreas Werner, Andreas Werner Tumor Center Rhineland Palatinate, Mainz, GermanySearch for more papers by this authorSimone Wesselmann, Simone Wesselmann The German Cancer Society Berlin, GermanySearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Bad Bentheim Hospital, Department of Dermatology and Allergy, Bad Bentheim, GermanySearch for more papers by this authorWolfgang Wick, Wolfgang Wick Dep. of Neurooncology, University Clinic, Heidelberg, GermanySearch for more papers by this authorClaus Garbe, Claus Garbe Department of Dermatology, University Hospital Tübingen, Germany shared last authorshipSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Department of Dermatology, University Hospital Essen, Germany shared last authorshipSearch for more papers by this author First published: 09 September 2013 https://doi.org/10.1111/ddg.12113_supplCitations: 85 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume11, Issues6Special Issue: Malignes Melanom S3‐Leitlinie “Diagnostik, Therapie und Nachsorge des Melanoms”/Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”. The German Society of Dermatology and Wiley have published this supplement without financial support.August 2013Pages 1-116 RelatedInformation

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTProperties of Helical Polycytidylic Acid*E. O. Akinrimisi, C. Sander, and P. O. P. Ts'oCite this: Biochemistry 1963, 2, 2, 340–344Publication Date (Print):March 1, 1963Publication History Published online1 May 2002Published inissue 1 March 1963https://doi.org/10.1021/bi00902a028RIGHTS & PERMISSIONSArticle Views171Altmetric-Citations115LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (582 KB) Get e-Alerts Get e-Alerts

In major depressive disorder, changes in cytokine levels have been reported to play a role in pathogenesis. Therefore, we sought to investigate a broad range of cytokines in depression. We compared serum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (INF-γ) and tumor necrosis factor (TNF)-α in 64 subjects with current depression and 206 non-depressed subjects. Depressed patients had higher levels of IL-2, IL-5, IL-12, IL-13, GM-CSF, INF-γ and TNF-α, compared to non-depressed subjects. Splitting groups into non-obese (BMI < 30) and obese (BMI ≥ 30), the non-obese depressed patients (n = 40) showed elevated IL-5, IL-12, IL-13, GM-CSF, INF-γ and TNF-α levels compared to non-obese and non-depressed subjects (n = 85). The obese and depressed patients (n = 24) showed elevated levels of IL-5, IL-12 and INF-γ compared to obese but not depressed subjects (n = 121). Levels of several cytokines were found to be associated with physical activity, employment status and presence of daily naps. The results support over-expression of pro-inflammatory cytokines in depression and extend the range of cytokines potentially associated with depression to include GM-CSF, IL-5 and IL-13. Changes in these cytokines may contribute to co-morbidity between depression and allergic and asthmatic diseases. The results also suggest inflammatory processes associated with obesity, and support an interaction between cytokine serum concentrations and behavioral aspects of both obesity and depression.

Determining changes in the composition of cell populations is made possible by technologies like single-cell transcriptomics, CyTOF, and microbiome sequencing. However, existing methods for differential abundance do not model some ...Cellular omics such as single-cell genomics, proteomics, and microbiomics allow the characterization of tissue and microbial community composition, which can be compared between conditions to identify biological drivers. This strategy has been critical to ...

Comparative information about the optical rotatory dipsersion and optical absorbancy of nucleotides, synthetic polynucleotides and nucleic acids has been obtained through a systematic investigation of solutions of these materials in formamide and in aqueous systems of varied pH and temperature. In formamide solution nucleic acid polymers were found to have only slightly higher specific rotations and slightly lower absorbancies than their corresponding monomers, and consequently were presumed to be devoid of all formal secondary structure. In aqueous solution, on the other hand, the difference between the optical properties of the monomer and polymer pairs was often large, indicating the influence of secondary structure. Preliminary results suggest that nucleic acids in salt-free formamide exist in an extended-chain conformation.

Objectives. This study tested the hypothesis that patients with depression show less and later declines into lower EEG vigilance stages (different global functional brain states) under resting conditions than healthy controls, as proposed by the vigilance theory of affective disorders. Methods. Thirty patients with Major Depressive Disorder (19 female; mean age: 37.2 years, SD: 12.6) without psychotropic medication and 30 carefully age- and sex-matched controls (19 female; mean age: 37.3 years, SD: 12.8) without past or present mental disorders underwent a 15-min resting EEG. EEG-vigilance regulation was determined with a computer-based vigilance classification algorithm (VIGALL, Vigilance Algorithm Leipzig), allowing a classification of vigilance stages A (with substages A1, A2 and A3), B (with substages B1 and B2/3) and C. Results. Depressive patients spent significantly more time in the highest EEG vigilance substage A1, and less time in substages A2, A3 and B2/3 than controls. In depressive patients, a significantly longer latency until the occurrence of substages A2, A3 and B2/3 was observed. No significant group differences in the percentage of B1 segments or the latency until occurrence of B1 were found. Conclusions. The results confirm the hypothesis that patients with depression show less (and later) declines into lower EEG vigilance stages under resting conditions than healthy controls, and support the vigilance theory of affective disorders linking a hyperstable vigilance regulation to depression.

Background/Objective: The Life Orientation Test-Revised (LOT-R) is often used to assess dispositional optimism. The aims of this study were to test psychometric properties of the LOT-R, to provide normative scores, and to test the association between optimism and several psychological, sociodemographic, and behavioral factors. Method: A randomly selected German general population community sample with an age range of 18-80 years (N = 9,711) was surveyed. Results: The Confirmatory Factor Analysis (CFA) proved two (correlated) factors: Optimism and Pessimism. Invariance tests across gender and age groups confirmed metric invariance. There were only small gender differences in the LOT-R total score (M = 16.4 for females and M = 16.1 for males). The correlation between the subscales Optimism and Pessimism was strong for young and well educated people. Low optimism mean scores were observed for unemployed people, people with low income, smokers, and obese people. Normative scores of the LOT-R are provided. Conclusions: The study confirmed the bidimensional structure of the LOT-R and invariance across age and gender. We can recommend using this instrument for measuring dispositional optimism and pessimism in epidemiological research and clinical practice.Antecedentes/Objetivo: La versión revisada del Life Orientation Test (LOT-R) se emplea a menudo para evaluar el optimismo disposicional. Los objetivos de este estudio fueron establecer las propiedades psicométricas del LOT-R, y probar la asociación entre optimismo y varios factores psicológicos, socio-demográficos y conductuales. Método: Para ello se entrevistó una muestra comunitaria aleatoriamente seleccionada de la población general alemana, con un rango de edad de 19-80 años (N = 9.711). Resultados: El Análisis Factorial Confirmatorio (CFA) sugiere dos factores (correlacionados): Optimismo y Pesimismo. Las pruebas de invarianza para género y edad confirmaron la invarianza métrica. Solamente se encontraron pequeñas diferencias de género en el puntaje total (M = 16,4 para mujeres y M = 16,1 para hombres). Se encontraron bajos puntajes medios en personas desempleadas, personas con bajos ingresos, fumadores y personas con obesidad. Se proveen valores normativos para el LOT-R. Conclusiones: El estudio confirma la estructura bidimensional del LOT-R y la invarianza en género y edad. El instrumento puede recomendarse para medir optimismo disposicional y pesimismo en investigación epidemiológica y en la práctica clínica.

Minor depression (MinD) and mild cognitive impairment (MCI) are common disorders in late life that often coexist. The aim of the present review is to demonstrate prevalence rates of minor depression in older patients with and without MCI. Electronic database searches were performed through Medline, ISI Web of Knowledge, Psycinfo, and Cochrane library. Two independent reviewers extracted the original studies based on inclusion criteria: representative study population aged 55 and older, diagnostics of MinD according to DSM. Data on prevalence rates, risk factors, comorbidity and health care usage were analyzed. Point prevalence for MinD is higher in medical settings (median 14.4%) than in the community-based settings (median 10.4%) and primary care patients (median 7.7%). Although minor depression is rarely investigated in elderly persons with MCI, nearly 20% of patients with MCI seem to suffer from MinD. No data was found on the prevalence of MCI in patients with MinD. Risk factors associated with MinD include female gender, history of cerebrovascular diseases, generalized anxiety disorder, loneliness, and long-term institutional care. Methodological differences of included studies resulted in a broad range of prevalence rates. No data is shown regarding the prevalence of MCI in MinD group due to insufficient evidence. Our review indicates that MinD is frequent in elderly population. MCI among those subjects has not been sufficiently investigated. Future studies based on clinical structured interviews should be performed in longitudinal design in order to differentiate late-life depression from progressive MCI or early manifestation of Alzheimer's disease.

Promulgating a continuum model of mental health and mental illness has been proposed as a way to reduce stigma by decreasing notions of differentness. This systematic review and meta-analysis examines whether continuum beliefs are associated with lower stigma, and whether continuum interventions reduce stigma.Following a pre-defined protocol (PROSPERO: CRD42019123606), we searched three electronic databases (PubMed, Web of Science, and PsycINFO) yielding 6726 studies. After screening, we included 33 studies covering continuum beliefs, mental illness, and stigma. Of these, 13 studies were included in meta-analysis.Continuum beliefs are consistently associated with lower stigma. Interventions were effective at manipulating continuum beliefs but differ in their effects on stigmatising attitudes.We discuss whether and to what extent attitudes towards people with mental illness can be improved by providing information on a mental health-mental illness continuum. It appeared to be relevant whether interventions promoted a feeling of 'us' and a process of identification with the person with mental illness. We discuss implications for the design of future interventions.

Journal Article Cohort Profile: The LIFE-Adult-Study Get access Christoph Engel, Christoph Engel Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyLeipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany Corresponding author. Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Haertelstrasse 16–18, 04107 Leipzig, Germany. E-mail: christoph.engel@imise.uni-leipzig.de https://orcid.org/0000-0002-7247-282X Search for other works by this author on: Oxford Academic PubMed Google Scholar Kerstin Wirkner, Kerstin Wirkner Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyLeipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Samira Zeynalova, Samira Zeynalova Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyLeipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Ronny Baber, Ronny Baber Leipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, GermanyInstitute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Hans Binder, Hans Binder Interdisciplinary Centre for Bioinformatics, Leipzig University, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Uta Ceglarek, Uta Ceglarek Leipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, GermanyInstitute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany https://orcid.org/0000-0002-4034-5535 Search for other works by this author on: Oxford Academic PubMed Google Scholar Cornelia Enzenbach, Cornelia Enzenbach Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyLeipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Fuchs, Michael Fuchs Leipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, GermanyDivision Otolaryngology, Head and Neck Surgery, Phoniatrics and Audiology, University of Leipzig Medical Center, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Andreas Hagendorff, Andreas Hagendorff Department of Cardiology, University of Leipzig Medical Center, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Sylvia Henger, Sylvia Henger Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyLeipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Andreas Hinz, Andreas Hinz Department of Medical Psychology and Medical Sociology, Leipzig University, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Franziska G Rauscher, Franziska G Rauscher Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyLeipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Matthias Reusche, Matthias Reusche Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyLeipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Steffi G Riedel-Heller, Steffi G Riedel-Heller Institute of Social Medicine, Occupational Medicine and Public Health (ISAP), Leipzig University, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Susanne Röhr, Susanne Röhr Institute of Social Medicine, Occupational Medicine and Public Health (ISAP), Leipzig University, Leipzig, GermanyGlobal Brain Health Institute (GBHI), Trinity College Dublin, Dublin, Ireland Search for other works by this author on: Oxford Academic PubMed Google Scholar Julia Sacher, Julia Sacher Cognitive Neurology, University of Leipzig Medical Center, Leipzig, GermanyDepartment of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Christian Sander, Christian Sander Leipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, GermanyDepartment of Psychiatry and Psychotherapy, University of Leipzig Medical Center, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Matthias L Schroeter, Matthias L Schroeter Cognitive Neurology, University of Leipzig Medical Center, Leipzig, GermanyDepartment of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Attila Tarnok, Attila Tarnok Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyDepartment of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Regina Treudler, Regina Treudler Department of Dermatology, Venerology and Allergology, University of Leipzig Medical Center, Leipzig, GermanyLeipzig Interdisciplinary Allergy Center (LICA)—Comprehensive Allergy Center, University of Leipzig Medical Center, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Arno Villringer, Arno Villringer Cognitive Neurology, University of Leipzig Medical Center, Leipzig, GermanyDepartment of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany https://orcid.org/0000-0003-2604-2404 Search for other works by this author on: Oxford Academic PubMed Google Scholar Rolf Wachter, Rolf Wachter Clinic and Policlinic for Cardiology, University of Leipzig Medical Center, Leipzig, Germany https://orcid.org/0000-0003-2231-2200 Search for other works by this author on: Oxford Academic PubMed Google Scholar A Veronica Witte, A Veronica Witte Cognitive Neurology, University of Leipzig Medical Center, Leipzig, GermanyDepartment of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Joachim Thiery, Joachim Thiery Leipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, GermanyInstitute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Markus Scholz, Markus Scholz Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyLeipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany https://orcid.org/0000-0002-4059-1779 Search for other works by this author on: Oxford Academic PubMed Google Scholar Markus Loeffler, Markus Loeffler Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyLeipzig Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar LIFE-Adult-Study working group LIFE-Adult-Study working group Search for other works by this author on: Oxford Academic PubMed Google Scholar International Journal of Epidemiology, Volume 52, Issue 1, February 2023, Pages e66–e79, https://doi.org/10.1093/ije/dyac114 Published: 28 May 2022 Article history Received: 21 September 2021 Editorial decision: 26 April 2022 Accepted: 10 May 2022 Published: 28 May 2022

Smart contracts are a promising means of formalizing and reliably enforcing agreements between entities using distributed ledger technology (DLT).Research has revealed that a significant number of smart contracts are subject to programming flaws, making them vulnerable to attacks and leading to detrimental effects, such as asset loss.Researchers and developers call for a thorough analysis of challenges to identify their causes and propose solutions.To respond to these calls, we conducted two literature reviews and diverse expert interviews and synthesized scattered knowledge on challenges and solutions.We identified 29 challenges (e.g., code visibility, code updateability, and encapsulation) and 60 solutions (e.g., gas limit specification, off-ledger computations, and shadowing).Moreover, we developed 20 software design patterns (SDPs) in collaboration with smart contract developers.The SDPs help developers adjust their programming habits and thus support them in their daily development practices.Our results provide actionable knowledge for smart contract developers to overcome the identified challenges and offer support for comparing smart contract integration concepts across three fundamentally different DLT protocols (i.e., Ethereum, EOSIO, and Hyperledger Fabric).Moreover, we support developers in becoming aware of peculiarities in smart contract development and the resulting benefits and drawbacks.

Pagetoid reticulosis (PR), also known as Woringer-Kolopp disease, is a form of cutaneous T-cell lymphoma that demonstrates striking epidermotropism on histologic examination. We present the histologic, immunologic, and molecular findings for seven patients who had PR. The patients ranged in age from 33 to 67 years. All patients presented with one or several thick plaques involving the distal extremities except for one patient, who presented with a tongue lesion. Immunohistochemical staining of the atypical lymphoid cells demonstrated a T-cell phenotype in all cases. In one of four frozen cases, the neoplastic cells were of T-helper cell phenotype (CD4 positive). Four of seven cases demonstrated a T-cytotoxic/suppressor cell phenotype (CD8 positive). The T-cell subset for the remaining two cases could not be determined. CD30 positivity and a high growth fraction as indicated by staining with Ki-67 were seen in three of seven and three of four cases, respectively. Genotypic analysis performed on three of our cases revealed T-cell receptor (gamma and/or beta) rearrangement, indicating a clonal proliferation. The clinical follow-up ranged from 15 months to 13 years. Four of seven patients are alive and free of disease after treatment with excision or local irradiation. One patient relapsed twice after treatment with radiation and photochemotherapy with 8-methoxypsoralen and UVA and was then lost to follow-up. The lesions of another patient resolved spontaneously but recurred at the same and in an additional site 5 years later. One patient recurred after electron beam therapy. The recurrent lesion improved with radiation therapy and local wound care but never resolved completely. The patient died of unrelated causes. Our findings suggest that PR is a distinct clinicopathologic entity, separate from unilesional mycosis fungoides, demonstrating a slow disease course. The disease is a clonal cutaneous T-cell lymphoma with relatively consistent clinical and histopathologic findings but a heterogeneous immunophenotypic profile.

Bartonella henselae causes the vasculoproliferative disorders bacillary angiomatosis (BA) and bacillary peliosis (BP). The pathomechanisms of these tumorous proliferations are unknown. Our results suggest a novel bacterial two-step pathogenicity strategy, in which the pathogen triggers growth factor production for subsequent proliferation of its own host cells. In fact, B. henselae induces host cell production of the angiogenic factor vascular endothelial growth factor (VEGF), leading to proliferation of endothelial cells. The presence of B. henselae pili was associated with host cell VEGF production, as a Pil− mutant of B. henselae was unable to induce VEGF production. In turn, VEGF-stimulated endothelial cells promoted the growth of B. henselae. Immunohistochemistry for VEGF in specimens from patients with BA or BP revealed increased VEGF expression in vivo. These findings suggest a novel bacteria-dependent mechanism of tumour growth.

The problem of accurately predicting protein three-dimensional structure from sequence has yet to be solved. Recently, several new and promising methods that work in one, two, or three dimensions have invigorated the field. Modeling by homology can yield fairly accurate three-dimensional structures for approximately 25% of the currently known protein sequences. Techniques for cooperatively fitting sequences into known three-dimensional folds, called threading methods, can increase this rate by detecting very remote homologies in favorable cases. Prediction of protein structure in two dimensions, i.e. prediction of interresidue contacts, is in its infancy. Prediction tools that work in one dimension are both mature and generally applicable; they predict secondary structure, residue solvent accessibility, and the location of transmembrane helices with reasonable accuracy. These and other prediction methods have gained immensely from the rapid increase of information in publicly accessible databases. Growing databases will lead to further improvements of prediction methods and, thus, to narrowing the gap between the number of known protein sequences and known protein structures.

A defined and balanced immunomodulatory response is crucial for the protection of mucosal surfaces being in contact with pathogenic microorganisms. This study examined the local host response mechanisms of epithelial cells in experimental Candida albicans, C. tropicalis, and C. glabrata infections by measuring the expression of cytokines at the mRNA and protein level. During the course of infection with active but not with heat-killed C. albicans stimulation of the gene expression levels for interleukin-1alpha, interleukin-1beta, tumor necrosis factor, Exodus-2, P-selectin ligand, granulocyte-monocyte colony-stimulating factor, and interleukin-8 was observed by standard and quantitative reverse transcription-polymerase chain reaction. This cytokine pattern may favor a chemotactic and a T helper 1 response. Initial moderate or weak upregulation of these cytokine genes by reverse transcription-polymerase chain reaction was also observed in epithelial infection with the less virulent species C. tropicalis and C. glabrata. Heat-killed C. albicans failed to induce an epithelial immune response. At the protein level, expression of interleukin-8 protein was strongly enhanced during the course of C. albicans infection, whereas lower levels were seen with C. tropicalis and C. glabrata. The different expression patterns of cytokines were associated with differences in virulence of the Candida strains. This study's data, therefore, show a correlation between the virulence potential of pathogenic fungi, possibly mediated by specific virulence factors (such as proteinases), and the secretion of epithelial cytokines and chemokines, which may initiate in vivo a protective T helper 1 immunologic response and contribute to the recruitment of activated leukocytes and lymphocytes to the site of mucosal infection.

Mycosis fungoides (MF) can present with purpuric lesions, and rare patients who seemed to have persistent pigmented purpuric dermatitis (PPPD) have developed MF. We recently encountered two patients referred to our cutaneous lymphoma clinic who had PPPD rather than MF and two others who appeared to have both conditions, leading us to explore the histologic similarities of these diseases. We examined specimens from 56 patients with PPPD to determine the frequency of MF-like histologic configurations, namely, the psoriasiform lichenoid, psoriasiform spongiotic lichenoid, and atrophic lichenoid patterns. We also noted the degree of spongiosis, epidermotropism, papillary dermal fibrosis, lymphocytic atypia, and epidermal hyperplasia, the number of extravasated erythrocytes and siderophages, and the distribution of lymphocytic infiltrate within the epidermis. In 29 of 56 patients, there were patterns typically seen in MF. PPPD can feature lymphocytes aligned along the epidermal side of the dermoepidermal junction, with few necrotic keratinocytes, as can MF. Papillary dermal edema occurred frequently in PPPD but not in MF, while lymphocytes in MF but not PPPD had markedly atypical nuclei and had ascended into the upper spinous layer. Given these similarities, we tested for clonality of the T-cell population using a polymerase chain reaction assay for γ-chain rearrangements. Clonal populations were present in three of three and one of two specimens from patients with both PPPD and MF, but also in 8 of 12 specimens typical of lichenoid patterns of PPPD. These findings raise the possibility that the lichenoid variants of PPPD are biologically related to MF.

We reviewed our experience with 30 nodal and extra-nodal lymphoid lesions from 17 patients with common variable immunodeficiency (CVID). Immunohistochemical studies were performed on biopsies from 15 patients, in situ hybridization for Epstein-Barr virus in nine cases, and gene rearrangement analysis on seven lesions. The biopsies were classified into four groups: malignant lymphoma (two cases); atypical lymphoid hyperplasia (eight cases); reactive lymphoid hyperplasia (14 cases); and chronic granulomatous inflammation (six cases). The two malignant lymphomas were diagnosed using histologic criteria; tissue was not available for the assessment of clonality. In one neoplasm, Epstein-Barr virus was identified in the tumor cells by in situ hybridization. The cases of reactive lymphoid hyperplasia and chronic granulomatous inflammation had no atypical architectural, cytologic, or immunohistochemical features. The cases of atypical lymphoid hyperplasia were of particular interest, as these patients had either widespread involvement or massive disease. The diagnosis of lymphoma was considered likely by the clinicians and, in three cases, the histologic slides were originally interpreted as malignant lymphoma by the referring pathologists. Although the architecture of these lesions appeared to be effaced on hematoxylin and eosin-stained sections, immunohistochemical analysis demonstrated preserved architecture with florid expansion of B-cell and T-cell compartments. In addition, clinical follow-up of these patients was benign, and gene rearrangement analysis in three lesions revealed no evidence of clonality. We conclude that the majority of lymphoid lesions in patients with CVID are benign. Immunohistochemical and gene rearrangement studies are particularly helpful in the assessment of cases of atypical lymphoid hyperplasia.

Six patients with malignant lymphoma of lymphoblastic type involving cutaneous sites at time of diagnosis are presented. Skin sites of the head and neck were involved in all patients and included the scalp (three patients), forehead (two patients), and malar region of the face (one patient). Two patients also had additional sites of skin disease (neck, breast, and anterior trunk). In two patients the skin was the predominant site of disease, whereas in the remaining patients staging workup revealed generalized lymphoma. The histologic findings in each patient were typical of lymphoblastic lymphoma; the neoplastic cells were small with blastic nuclear chromatin. In three patients the neoplastic cells were convoluted, and in three they were nonconvoluted. Immunophenotypically, four lymphomas were of pre-B cell type, and two lymphomas were of T cell type. There was no correlation between histologic features and the immunophenotype. Since the majority of lymphoblastic lymphomas are of T cell type, the predominance of pre-B cell tumors involving the skin may suggest that pre-B cell neoplasms have a predilection for cutaneous involvement. In further support of this hypothesis, both lymphomas that appear to have arisen in the skin had a pre-B cell immunophenotype.

The frequency of occurrence of nearest neighbour residue pairs on adjacent antiparallel (βA) and parallel (βP) strands is obtained from 30 known protein structures. The specificity of interstrand recognition due to such pairing as a factor in the folding of β-sheets is studied by statistical methods. Residues of sufficiently high count for statistical analysis are treated individually while the rest are combined into small groups of similar size, polarity, and/or genetic exchangeability. The hypothesis of specific recognition between individuals and small groups is contrasted with the alternative hypothesis of non-specific recognition between broad classes (hydrophobia, neutral, polar) of residues. A χ2 test of pair correlations favours specific recognition against non-specific recognition with a high level of confidence. The largest and most significant correlations are: Ser/Thr (1.9 ± 0.3), Ile/Val (1.7 ± 0.3) and Lys-Arg/Asp-Gln (1.8 ± 0.3) in βA, and Ile/Leu (1.9 ± 0.4) in βP. The pair Gly/Gly never occurs in any β-sheet. The specific residue-pair correlations derived here may be useful in statistical prediction methods of protein tertiary structure.

Background: Merkel cell polyomavirus (MCPyV) is the likely causative agent of Merkel cell carcinoma (MCC). However, the prevalence of MCPyV in non‐MCC population and its possible role in the pathogenesis of other skin cancers are not known yet. Methods: A molecular pathology study was performed in 33 MCC samples and 33 age‐ and sex‐matched samples of sun exposed non‐MCC tumors [12 seborrheic keratoses (SK), 11 basal cell carcinomas (BCC) and 10 lentigo maligna melanomas (LMM)]. All tumors were analyzed for presence of MCPyV‐DNA by polymerase chain reaction (PCR) and Southern‐Blot hybridization of PCR products. Results: MCPyV sequences were detected in 21 MCC samples (64%) and in 2 non‐MCC tumors of sun exposed skin (6%; both SK‐patients). Neither the tissue samples from BCC nor LMM proved positive for MCPyV sequences. Conclusion: We were able to confirm prior data on prevalence of MCPyV‐DNA in MCC. Furthermore, a female predominance of MCPyV‐positive MCC‐patients was detected. There was no relevant association of MCPyV with SK, BCC and LMM. Speculative, prevalence of MCPyV in an age‐ and sex‐matched non‐MCC population could average up to 6%.

Kempf W &amp; Sander C A (2010) Histopathology 56 , 57–70 Classification of cutaneous lymphomas – an update This review focuses on the evolution and conceptual aspects of classifications for cutaneous lymphomas. The World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification and the WHO classification (4th edn, 2008) represent the first widely accepted classifications for lymphomas, in which the complete spectrum of primary cutaneous lymphomas is included. These classifications for primary cutaneous lymphomas define disease entities with distinct clinical, histological, immunophenotypic and genetic features. Final diagnosis is based on a synoptic integration of these features and implies clinicopathological correlation as a pivotal element of the diagnostic approach for primary cutaneous lymphomas. The entities, their definitions and diagnostic criteria of cutaneous lymphomas listed in the WHO/EORTC and WHO classifications are presented. Recent changes in the terminology and staging, practical implications and future perspectives are discussed.

The main aim of the current study was to test the hypothesis that adult patients with attention-deficit/hyperactivity disorder (ADHD) have less stable brain arousal regulation than healthy controls. We objectively assessed brain arousal regulation using the Vigilance Algorithm Leipzig (VIGALL 2.1) to analyze 15-min resting EEG data of thirty-three ADHD patients and thirty-five matched controls. Based on automatically classified 1-s segments we computed mean EEG-vigilance (indexing arousal level) and arousal stability score (indexing arousal regulation). Adult ADHD patients showed significantly lower arousal levels and significantly less stable brain arousal regulation than controls. Multiple regression analysis indicated that arousal regulation (i.e., arousal stability score) predicted the retrospectively-assessed severity of childhood ADHD symptoms, supporting the trait aspect of brain arousal regulation. Our findings support the arousal regulation model of ADHD, which interprets hyperactivity and sensation seeking as an autoregulatory reaction to an unstable regulation of brain arousal. EEG-based arousal parameters may be candidate biomarkers for adult ADHD.

Recently, a framework has been presented that links vigilance regulation, i.e. tonic brain arousal, with clinical symptoms of affective disorders. Against this background, the aim of this study was to deepen the knowledge of vigilance regulation by (1) identifying different patterns of vigilance regulation at rest in healthy subjects (n = 141) and (2) comparing the frequency distribution of these patterns between unmedicated patients with major depression (MD; n = 30) and healthy controls (HCs; n = 30).Each 1-second segment of 15-min resting EEGs from 141 healthy subjects was classified as 1 of 7 different vigilance stages using the Vigilance Algorithm Leipzig. K-means clustering was used to distinguish different patterns of EEG vigilance regulation. The frequency distribution of these patterns was analyzed in independent data of 30 unmedicated MD patients and 30 matched HCs using a χ² test.The 3-cluster solution with a stable, a slowly declining and an unstable vigilance regulation pattern yielded the highest mathematical quality and performed best for separation of MD patients and HCs (χ² = 13.34; p < 0.001). Patterns with stable vigilance regulation were found significantly more often in patients with MD than in HCs.A stable vigilance regulation pattern, derived from a large sample of HCs, characterizes most patients with MD and separates them from matched HCs with a sensitivity between 67 and 73% and a specificity between 67 and 80%. The pattern of vigilance regulation might be a useful biomarker for delineating MD subgroups, e.g. for treatment prediction.

Summary The genetic basis of sleep is still poorly understood. Despite the moderate to high heritability of sleep‐related phenotypes, known genetic variants explain only a small proportion of the phenotypical variance. However, most previous studies were based solely upon self‐report measures. The present study aimed to conduct the first genome‐wide association (GWA) of actigraphic sleep phenotypes. The analyses included 956 middle‐ to older‐aged subjects (40–79 years) from the LIFE Adult Study. The SenseWear Pro 3 Armband was used to collect 11 actigraphic parameters of night‐ and daytime sleep and three parameters of rest (lying down). The parameters comprised measures of sleep timing, quantity and quality. A total of 7 141 204 single nucleotide polymorphisms ( SNP s) were analysed after imputation and quality control. We identified several variants below the significance threshold of P ≤ 5× 10 −8 (not corrected for analysis of multiple traits). The most significant was a hit near UFL 1 associated with sleep efficiency on weekdays ( P = 1.39 × 10 −8 ). Further SNP s were close to significance, including an association between sleep latency and a variant in CSNK 2A1 ( P = 8.20 × 10 −8 ), a gene known to be involved in the regulation of circadian rhythm. In summary, our GWAS identified novel candidate genes with biological plausibility being promising candidates for replication and further follow‐up studies.

To clarify findings of elevated cytokine levels in major depression (MD), this study aimed to investigate the relationship between serum levels of cytokines, symptoms of MD and antidepressant treatment outcome. At baseline (T0) and 4 weeks following initiation of antidepressant treatment (T1), levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage-colony-stimulating-factor (GM-CSF), CRP and depression ratings HAMD-17 and BDI-II were assessed in 30 patients with MD and 30 age-and sex-matched controls. At T0, in the patient group, cytokines, but not CRP, negatively correlated with individual BDI-II-items, factors and severities and showed both negative and positive correlations with HAMD-17 items. At T1 and within the controls, no such relationships were observed. At T0 and T1, levels of both pro- and anti-inflammatory cytokines were significantly higher in treatment responders (ΔHAMD-17T0-T1≥50%,n=15) compared to non-responders. When controlled for baseline BDI, differences between groups were only found significant for IL-2 at T0. The results suggest cytokines are not generally pro-depressive but rather relate to more specific regulation of symptoms and severities in MD. Together with the association between cytokines and treatment responder status, these data support cytokines as a promising but still controversial biomarker of depression.

Summary Accepted by the WHO and EORTC as a variant of classic mycosis fungoides, folliculotropic (syn.: follicular or pilotropic) mycosis fungoides (FMF) is characterized by a broad clinical and histological spectrum with numerous differential diagnoses. Recent studies have shown that FMF can be divided into two prognostically different subgroups, both marked by histological as well as clinical differences. Treatment should therefore be tailored to the various subtypes and clinical courses. The present review highlights the clinical and histological manifestations of FMF as well as the new subclassification. Moreover, important differential diagnoses and therapeutic options are discussed.

Large efforts have been made to erase the stigma of mental illness, but it is unclear whether they have succeeded on a population level. We examine how attitudes toward people with depression or schizophrenia have evolved in Germany since 1990, and whether there are different developments for both disorders.Using data from the three decades, four wave repeated cross-sectional representative population study in the "old" (western) states in Germany with surveys in 1990 (n = 2,044), 2001 (n = 4,005), 2011 (n = 1,984), and 2020 (n = 2,449), we calculate time-trends for social distance and emotional reactions toward someone with major depression or acute schizophrenia.Social distance worsened in six out of seven situations for schizophrenia, whereas improving in two out of seven situations for depression. Emotions related to fear and uneasiness increased for schizophrenia, whereas tending to decrease for depression. Pro-social reactions like the desire to help increased for depression, but decreased for schizophrenia. Initially observed differences, favoring depression over schizophrenia, widened over the 30-year study period. For schizophrenia, the biggest negative changes occurred between 1990 and 2001, whereas some improvements with regard to depression occurred more recently.Contrary to expectations, stigma has become more severe regarding acute schizophrenia in Germany over the last 30 years, whereas only slightly improving for depression. The apparent normalization of mental health problems seems not to directly translate into improving attitudes toward people with severe mental illness. Re-focusing of anti-stigma efforts on people with severe mental illness seems necessary.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is commonly regarded an angioproliferative process characterized by the presence of prominent, bizarrely shaped blood vessels. These vessels are accompanied by an inflammatory infiltrate that is thought to be a reactive component. Both the cell of origin and the pathogenesis of ALHE remain controversial. To define the histogenesis of this disorder, we analyzed the phenotypic and genotypic profile of the inflammatory infiltrate in ALHE by immunohistochemistry and T-cell receptor gene rearrangement by polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis, as well as automated high-resolution PCR fragment analysis. Five of 7 ALHE patients displayed a clonal T-cell population and proliferative T-cell activity in lesional tissue. Most of these cases followed a protracted and therapy-reluctant course with recurrences. These data suggest that ALHE or a subset of ALHE cases harboring a clonal T-cell population may represent a T-cell lymphoproliferative disorder of a benign or low-grade malignant nature.

We report on a 37-year-old man without history of previous allergic disease who developed an aseptic intolerance reaction to a chromium-cobalt alloy, with local discomfort, loosening, and absence of fracture healing. Both in vivo and in vitro allergoimmunologic diagnostic tests were performed.Patch testing was done with a European standard series. Specific serum IgE was measured by CAP-FEIA. In addition to immunohistology (APAAP method), peri-implantar tissue was further analyzed by PCR to determine T-cell-receptor-gamma rearrangement and thus the potential clonal (antigen-driven) T-cell repertoire. The actual tissue mRNA expression for IL-4, IL-6, and IFN-gamma was visualized by RT-PCR.Skin testing gave a delayed-type reaction to dichromate. Specific serum IgE to natural rubber latex and grass pollen was found--but without clinical symptoms. Immunohistology revealed a monocytic and dense T-cell infiltrate. The latter, instead of being random, showed an oligoclonal T-cell receptor rearrangement. In addition, there was TH1-type mediator expression (IL-6 and IFN-gamma, but not IL-4).Skin test, examination of peri-implantar tissue, and the prompt healing after replacement of the osteosynthesis material suggest an allergic reaction. PCR analysis of peri-implantar tissue can further help to identify and understand allergy-mediated implant intolerance reactions.

The product of the p16/INK4a/CDKN2/MTS1 tumor‐suppressor gene acts as a negative cell cycle regulator by inhibiting G 1 cyclin‐dependent kinases that phosphorylate the retinoblastoma protein. p16 is inactivated in a wide range of human malignancies, including familial melanoma. However, its expression and function in sporadic melanoma has not been extensively investigated. We studied p16 expression in 62 archival melanomas and 30 archival nevi and lentigines by immunohistochemistry. Eighteen of 26 (69%) superficial spreading melanomas, 17 of 28 (61%) nodular melanomas, all of three lentigo maligna melanomas, and all of five melanoma metastases were found to harbor less than 10% p16 ‐positive tumor cells. In contrast, only six of 24 (25%) nevi had less than 10% positive cells. No correlation between tumor thickness and loss of p16 expression was found. Using DNA from micro‐dissected tumor and matched normal tissues, five of seven (71%) p16 ‐negative melanoma cases had 9p21 loss of heterozygosity (LOH), and one of these 9p21 LOH cases had promoter region hypermethylation of the remaining p16 allele. These data demonstrate that partial or complete loss of p16 expression is prevalent in sporadic melanoma and is frequently associated with 9p21 LOH.

The spectrum of mycosis fungoides is exceedingly broad. Many different variants have been described, based on both clinical appearance and histological pattern. A rare form which shows preferential infiltration of hair follicles by malignant lymphocytes is follicular mycosis fungoides.We reviewed our experience with nine cases of follicular mycosis fungoides.The unifying feature was infiltration of the hair follicle epithelium by atypical lymphocytes causing varying degrees of damage to the hair follicles. In some specimens the lymphocytes displayed only minor atypia leading to a misinterpretation as pseudolymphoma. Gene rearrangement studies were particularly helpful for establishing a diagnosis of malignant lymphoma. Additionally, epidermotropism of lymphocytes, eosinophils and mucin deposition were present to varying degrees. Mucin makes the distinction from mycosis fungoides-associated follicular mucinosis difficult. We found both dermal mucin and a follicular mucinosis pattern present at different stages of disease in the same patient.We suggest the term mycosis fungoides-associated follicular mucinosis should be replaced by follicular mycosis fungoides in future lymphoma classification schemes.

Polypeptides expressed on the surface of merozoites, the invasive stage of the asexual blood cycle, are good candidates for the development of malaria vaccines. Five synthetic peptides with predetermined specificity deduced from a genomic DNA clone coding for the NH2-terminal portion of the main merozoite surface polypeptide of Plasmodium falciparum were evaluated for their capability to raise antibodies that react with the P. falciparum merozoites. Antibodies induced by two of the peptides (3 and 5) reacted with the membrane surfaces of seven of seven isolates of P. falciparum from different geographic areas. Antibodies against peptide 4, which contains a repeated amino acid sequence (Gly-Gly-Ser and Val-Ala-Ser), reacted with six of seven isolates. Structural analysis of the deduced polypeptides suggests that peptide 3 is exposed at the surface of merozoites. When it was used to immunize monkeys, three of the four animals were partially protected from a challenge infection that induced a fulminant infection in control animals.

Independent component analysis (ICA)-based muscle artefact correction has become a popular tool within electroencephalographic (EEG) research. As a comment on the article by McMenamin et al. (2010), we want to address three issues concerning the claimed lack of sensitivity and specificity of this method. The under- or overestimation of myogenic and neurogenic signals after ICA-based muscle artefact correction reported by McMenamin et al. might be explainable in part by a) insufficient temporal independence of myogenic and neurogenic components when exploring more than one condition, b) wrong classification of myogenic or neurogenic components by human raters and c) differences of neuronal mass activity during tensed or relaxed-muscle conditions. Our own data show only significant differences regarding intracortical alpha band EEG-source estimates for contrasts between clean EEG data and artificially contaminated EEG data at group-analysis level but not between clean data and data after ICA-based correction. ICA-based artefact correction already provides a powerful tool for muscle artefact rejection. More research is needed for determining reliable criteria to delineate myogenic from neurogenic components.

During the last few decades, much knowledge has been gained about sleep being a heterogeneous condition with several distinct sleep stages that represent fundamentally different physiological states. The same applies for the wake state which also comprises distinct global functional states (called vigilance stages). However, various terms and concepts have been introduced describing different aspects of wakefulness, and accordingly several methods of assessment exist, e.g. sleep laboratory assessments (Multiple Sleep Latency Test, Maintenance of Wakefulness Test), questionnaires (Epworth Sleepiness Scale, Karolinska Sleepiness Scale), behavioural tasks (Psychomotor Vigilance Test) or electroencephalography (EEG)-based assessments (Alpha Attenuation Test, Karolinska Drowsiness Test). Furthermore, several theoretical concepts about the regulation of sleep and wakefulness have been put forward, and physiological correlates have been identified. Most relevant for healthy functioning is the regulation of brain arousal and the adaption of wakefulness to the environmental and situational needs so that the optimal balance between energy conservation and responsiveness can be obtained. Since one approach to the assessment of brain arousal regulation is the classification of EEG vigilance stages, a computer-based algorithm (Vigilance Algorithm Leipzig) has been introduced, allowing classification of EEG vigilance stages in EEG recordings under resting conditions. The time course of EEG vigilance stages in EEGs of 15-20 min duration allows estimation of the individual arousal regulation (hyperstable, adaptive, or unstable vigilance pattern). The vigilance model of affective disorders and attention-deficit/hyperactivity disorder links a disturbed arousal regulation to the pathogenesis of psychiatric disorders and accordingly helps to explain and possibly also predict treatment effects of pharmacological and non-pharmacological interventions for these conditions.

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 11, Issue 6 p. 563-602 Guidelines S3-Guideline “Diagnosis, therapy and follow-up of melanoma” – short version Annette Pflugfelder, Annette Pflugfelder Department of Dermatology, University Hospital Tübingen, Germany shared first authorship,Search for more papers by this authorCorinna Kochs, Corinna Kochs Department of Dermatology, University Hospital Essen, Germany shared first authorship,Search for more papers by this authorAndreas Blum, Andreas Blum Public, Private and Teaching Practice of Dermatology, Konstanz, GermanySearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorChristina Czeschik, Christina Czeschik Department of Dermatology, University Hospital Essen, GermanySearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik Lüdenscheidt, GermanySearch for more papers by this authorEdgar Dippel, Edgar Dippel Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorThomas Eigentler, Thomas Eigentler Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPetra Feyer, Petra Feyer Clinic of radiotherapy and radiooncology, Vivantes Clinics Neukölln – Berlin, GermanySearch for more papers by this authorMarkus Follmann, Markus Follmann The German Cancer Society Berlin, GermanySearch for more papers by this authorBernhard Frerich, Bernhard Frerich Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Rostock, GermanySearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorJan Gärtner, Jan Gärtner Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorJessica Hassel, Jessica Hassel German Cancer Research Center, Heidelberg, GermanySearch for more papers by this authorAxel Hauschild, Axel Hauschild Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, GermanySearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe University, Frankfurt am Main, GermanySearch for more papers by this authorMartin Kaatz, Martin Kaatz Department of Dermatology and Allergology, SRH Waldklinikum Gera Gmbh, GermanySearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisch-onkologische Praxis Altona (HOPA), Struensee-Haus, Hamburg, GermanySearch for more papers by this authorOliver Kölbl, Oliver Kölbl Department of Radiotherapy, University Hospital Regensburg, GermanySearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Department of Radiation Therapy, University of Leipzig, GermanySearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorPeter Kurschat, Peter Kurschat Department of Dermatology and Venereology, University Hospital of Cologne, GermanySearch for more papers by this authorUlrike Leiter, Ulrike Leiter Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorHartmut Link, Hartmut Link Medical Clinic I, Westpfalz Klinikum, Kaiserslautern, GermanySearch for more papers by this authorCarmen Loquai, Carmen Loquai Department of Dermatology, University of Mainz, GermanySearch for more papers by this authorChristoph Löser, Christoph Löser Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Dept. of Internal Medicine 5 – Hematology/Oncology, University of Erlangen, GermanySearch for more papers by this authorFriedegund Meier, Friedegund Meier Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPeter Mohr, Peter Mohr Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Department of Dermatology, University Hospital Tübingen, Germany Praxisklinik Tübingen – Haut und Venen, GermanySearch for more papers by this authorDorothee Nashan, Dorothee Nashan Department of Dermatology, Klinikum Dortmund gGmbH, GermanySearch for more papers by this authorSven Reske, Sven Reske Department of Nuclear Medicine, University Clinic, Ulm, GermanySearch for more papers by this authorChristian Rose, Christian Rose Lübeck, GermanySearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. Georg, GermanySearch for more papers by this authorImke Satzger, Imke Satzger Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Department of Psychosocial Oncology, Fachklinik Hornheide, Münster, GermanySearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorLothar Swoboda, Lothar Swoboda German Society of Thoracic Surgery, Berlin, GermanySearch for more papers by this authorUwe Trefzer, Uwe Trefzer Department of Dermatology, University Hospital Charité Berlin, GermanySearch for more papers by this authorRaymond Voltz, Raymond Voltz Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorDirk Vordermark, Dirk Vordermark Department of Radiooncology, Universitätsklinikum Halle, Halle/Saale, GermanySearch for more papers by this authorMichael Weichenthal, Michael Weichenthal Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorAndreas Werner, Andreas Werner Tumor Center Rhineland Palatinate, Mainz, GermanySearch for more papers by this authorSimone Wesselmann, Simone Wesselmann The German Cancer Society Berlin, GermanySearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Bad Bentheim Hospital, Department of Dermatology and Allergy, Bad Bentheim, GermanySearch for more papers by this authorWolfgang Wick, Wolfgang Wick Dep. of Neurooncology, University Clinic, Heidelberg, GermanySearch for more papers by this authorClaus Garbe, Claus Garbe Department of Dermatology, University Hospital Tübingen, Germany shared last authorshipSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Department of Dermatology, University Hospital Essen, Germany shared last authorshipSearch for more papers by this author Annette Pflugfelder, Annette Pflugfelder Department of Dermatology, University Hospital Tübingen, Germany shared first authorship,Search for more papers by this authorCorinna Kochs, Corinna Kochs Department of Dermatology, University Hospital Essen, Germany shared first authorship,Search for more papers by this authorAndreas Blum, Andreas Blum Public, Private and Teaching Practice of Dermatology, Konstanz, GermanySearch for more papers by this authorMarcus Capellaro, Marcus Capellaro Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorChristina Czeschik, Christina Czeschik Department of Dermatology, University Hospital Essen, GermanySearch for more papers by this authorTherese Dettenborn, Therese Dettenborn Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorDorothee Dill, Dorothee Dill Hautklinik Lüdenscheidt, GermanySearch for more papers by this authorEdgar Dippel, Edgar Dippel Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorThomas Eigentler, Thomas Eigentler Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPetra Feyer, Petra Feyer Clinic of radiotherapy and radiooncology, Vivantes Clinics Neukölln – Berlin, GermanySearch for more papers by this authorMarkus Follmann, Markus Follmann The German Cancer Society Berlin, GermanySearch for more papers by this authorBernhard Frerich, Bernhard Frerich Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, University of Rostock, GermanySearch for more papers by this authorMaria-Katharina Ganten, Maria-Katharina Ganten German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorJan Gärtner, Jan Gärtner Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorRalf Gutzmer, Ralf Gutzmer Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorJessica Hassel, Jessica Hassel German Cancer Research Center, Heidelberg, GermanySearch for more papers by this authorAxel Hauschild, Axel Hauschild Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorPeter Hohenberger, Peter Hohenberger Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, GermanySearch for more papers by this authorJutta Hübner, Jutta Hübner Johann Wolfgang Goethe University, Frankfurt am Main, GermanySearch for more papers by this authorMartin Kaatz, Martin Kaatz Department of Dermatology and Allergology, SRH Waldklinikum Gera Gmbh, GermanySearch for more papers by this authorUlrich R. Kleeberg, Ulrich R. Kleeberg Hämatologisch-onkologische Praxis Altona (HOPA), Struensee-Haus, Hamburg, GermanySearch for more papers by this authorOliver Kölbl, Oliver Kölbl Department of Radiotherapy, University Hospital Regensburg, GermanySearch for more papers by this authorRolf-Dieter Kortmann, Rolf-Dieter Kortmann Department of Radiation Therapy, University of Leipzig, GermanySearch for more papers by this authorAlbrecht Krause-Bergmann, Albrecht Krause-Bergmann Plastische und Ästhetische Chirurgie, Fachklinik Hornheide, GermanySearch for more papers by this authorPeter Kurschat, Peter Kurschat Department of Dermatology and Venereology, University Hospital of Cologne, GermanySearch for more papers by this authorUlrike Leiter, Ulrike Leiter Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorHartmut Link, Hartmut Link Medical Clinic I, Westpfalz Klinikum, Kaiserslautern, GermanySearch for more papers by this authorCarmen Loquai, Carmen Loquai Department of Dermatology, University of Mainz, GermanySearch for more papers by this authorChristoph Löser, Christoph Löser Department of Dermatology, Skin Cancer Center, Ludwigshafen Hospital, GermanySearch for more papers by this authorAndreas Mackensen, Andreas Mackensen Dept. of Internal Medicine 5 – Hematology/Oncology, University of Erlangen, GermanySearch for more papers by this authorFriedegund Meier, Friedegund Meier Department of Dermatology, University Hospital Tübingen, GermanySearch for more papers by this authorPeter Mohr, Peter Mohr Association of Dermatological Prevention, Buxtehude, GermanySearch for more papers by this authorMatthias Möhrle, Matthias Möhrle Department of Dermatology, University Hospital Tübingen, Germany Praxisklinik Tübingen – Haut und Venen, GermanySearch for more papers by this authorDorothee Nashan, Dorothee Nashan Department of Dermatology, Klinikum Dortmund gGmbH, GermanySearch for more papers by this authorSven Reske, Sven Reske Department of Nuclear Medicine, University Clinic, Ulm, GermanySearch for more papers by this authorChristian Rose, Christian Rose Lübeck, GermanySearch for more papers by this authorChristian Sander, Christian Sander Klinik für Dermatologie und Allergologie, Asklepios Klinik St. Georg, GermanySearch for more papers by this authorImke Satzger, Imke Satzger Department of Dermatology and Allergy, Hannover Medical School, GermanySearch for more papers by this authorMeinhard Schiller, Meinhard Schiller Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorHeinz-Peter Schlemmer, Heinz-Peter Schlemmer German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg, GermanySearch for more papers by this authorGerhard Strittmatter, Gerhard Strittmatter Department of Psychosocial Oncology, Fachklinik Hornheide, Münster, GermanySearch for more papers by this authorCord Sunderkötter, Cord Sunderkötter Department of Dermatology, University Hospital of Münster, Münster, GermanySearch for more papers by this authorLothar Swoboda, Lothar Swoboda German Society of Thoracic Surgery, Berlin, GermanySearch for more papers by this authorUwe Trefzer, Uwe Trefzer Department of Dermatology, University Hospital Charité Berlin, GermanySearch for more papers by this authorRaymond Voltz, Raymond Voltz Department of Palliative Medicine, University Hospital Cologne, GermanySearch for more papers by this authorDirk Vordermark, Dirk Vordermark Department of Radiooncology, Universitätsklinikum Halle, Halle/Saale, GermanySearch for more papers by this authorMichael Weichenthal, Michael Weichenthal Department of Dermatology, University of Kiel, GermanySearch for more papers by this authorAndreas Werner, Andreas Werner Tumor Center Rhineland Palatinate, Mainz, GermanySearch for more papers by this authorSimone Wesselmann, Simone Wesselmann The German Cancer Society Berlin, GermanySearch for more papers by this authorAnsgar J. Weyergraf, Ansgar J. Weyergraf Bad Bentheim Hospital, Department of Dermatology and Allergy, Bad Bentheim, GermanySearch for more papers by this authorWolfgang Wick, Wolfgang Wick Dep. of Neurooncology, University Clinic, Heidelberg, GermanySearch for more papers by this authorClaus Garbe, Claus Garbe Department of Dermatology, University Hospital Tübingen, Germany shared last authorshipSearch for more papers by this authorDirk Schadendorf, Dirk Schadendorf Department of Dermatology, University Hospital Essen, Germany shared last authorshipSearch for more papers by this author First published: 30 May 2013 https://doi.org/10.1111/ddg.12044Citations: 21 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Robert Koch-Institut. http://www.rki.de 2012. 2Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC, Jr., Morton DL, Ross MI, Sober AJ, Sondak VK. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27: 6199–206. 3Azzola MF, Shaw HM, Thompson JF, Soong SJ, Scolyer RA, Watson GF, Colman MH, Zhang Y. Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center. Cancer 2003; 97: 1488–98. 4 The Cancer Council Australia and Australian Cancer Network SaNZGGW. Australian Cancer Network Melanoma Guidelines Revision Working Party. Clinical Practice Guidelines for the Management of Melanoma in Australia and New Zealand. 2008. 5Martin RC, Scoggins CR, Ross MI, Reintgen DS, Noyes RD, Edwards MJ, McMasters KM. Is incisional biopsy of melanoma harmful? Am J Surg 2005; 190: 913–7. 6Pflugfelder A, Weide B, Eigentler TK, Forschner A, Leiter U, Held L, Meier F, Garbe C. Incisional biopsy and melanoma prognosis: Facts and controversies. Clin Dermatol 2010; 28: 316–8. 7Ng JC, Swain S, Dowling JP, Wolfe R, Simpson P, Kelly JW. The impact of partial biopsy on histopathologic diagnosis of cutaneous melanoma: experience of an Australian tertiary referral service. Arch.Dermatol 2010; 146: 234–9. 8Sladden MJ, Balch C, Barzilai DA, Berg D, Freiman A, Handiside T, Hollis S, Lens MB, Thompson JF. Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst Rev 2009; 4: CD004835. 9Kenady DE, Brown BW, McBride CM. Excision of underlying fascia with a primary malignant melanoma: effect on recurrence and survival rates. Surgery 1982; 92: 615–8. 10McLeod M, Choudhary S, Giannakakis G, Nouri K. Surgical Treatments for Lentigo Maligna: A Review Dermatol Surg 2011; 10–4725. 11Stevenson O, Ahmed I. Lentigo maligna: prognosis and treatment options. Am J Clin Dermatol 2005; 6: 151–64. 12Mohrle M. [Micrographic controlled surgery (3D-histology) in cutaneous melanoma]. J Dtsch Dermatol Ges 2003; 1: 869–75. 13Loser C, Rompel R, Breuninger H, Mohrle M, Hafner HM, Kunte C, Hassel J, Hohenleutner U, Podda M, Sebastian G, Hafner J, Konz B, Kaufmann R. Microscopically controlled surgery (MCS). J Dtsch Dermatol Ges 2010; 8: 920–5. 14Lichte V, Breuninger H, Metzler G, Haefner HM, Moehrle M. Acral lentiginous melanoma: conventional histology vs. three-dimensional histology. Br J Dermatol 2009; 160: 591–9. 15Moehrle M, Metzger S, Schippert W, Garbe C, Rassner G, Breuninger H. ìFunctionalî surgery in subungual melanoma. Dermatol Surg 2003; 29: 366–74. 16Moehrle M, Dietz K, Garbe C, Breuninger H. Conventional histology vs. three-dimensional histology in lentigo maligna melanoma. The British journal of dermatology 2006; 154: 453–9. 17Farshad A, Burg G, Panizzon R, Dummer R. A retrospective study of 150 patients with lentigo maligna and lentigo ≠maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays. Br J Dermatol 2002; 146: 1042–6. 18Schmid-Wendtner MH, Brunner B, Konz B, Kaudewitz P, Wendtner CM, Peter RU, Plewig G, Volkenandt M. Fractionated radiotherapy of lentigo maligna and lentigo maligna melanoma in 64 patients. Journal of the American Academy of Dermatology 2000; 43: 477–82. 19Harwood AR. Conventional fractionated radiotherapy for 51 patients with lentigo maligna and lentigo maligna melanoma. International journal of radiation oncology, biology, physics 1983; 9: 1019–21. 20Stevens G, Thompson JF, Firth I, OíBrien CJ, McCarthy WH, Quinn MJ. Locally advanced melanoma: results of postoperative hypofractionated radiation therapy. Cancer 2000; 88: 88–94. 21Storper IS, Lee SP, Abemayor E, Juillard G. The role of radiation therapy in the treatment of head and neck cutaneous melanoma. Am J Otolaryngol 1993; 14: 426–31. 22Ang KK, Peters LJ, Weber RS, Morrison WH, Frankenthaler RA, Garden AS, Goepfert H, Ha CS, Byers RM. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. International journal of radiation oncology, biology, physics 1994; 30: 795–8. 23Foote MC, Burmeister B, Burmeister E, Bayley G, Smithers BM. Desmoplastic melanoma: the role of radiotherapy in improving local control. ANZ J Surg 2008; 78: 273–6. 24Vongtama R, Safa A, Gallardo D, Calcaterra T, Juillard G. Efficacy of radiation therapy in the local control of desmoplastic malignant melanoma. Head Neck 2003; 25: 423–8. 25Wasif N, Gray RJ, Pockaj BA. Desmoplastic melanoma – the step-child in the melanoma family? J Surg Oncol 2011; 103: 158–62. 26Sawyer A, McGoldrick RB, Mackey SP, Allan R, Powell B. Does staging computered tomography change management in thick malignant melanoma? J Plast Reconstr Aesthet Surg 2009; 62: 453–6. 27Yancovitz M, Finelt N, Warycha MA, Christos PJ, Mazumdar M, Shapiro RL, Pavlick AC, Osman I, Polsky D, Berman RS. Role of radiologic imaging at the time of initial diagnosis of stage T1b-T3b melanoma. Cancer 2007; 110: 1107–14. 28Vereecken P, Laporte M, Petein M, Steels E, Heenen M. Evaluation of extensive initial staging procedure in intermediate/high-risk melanoma patients. J Eur Acad Dermatol Venereol 2005; 19: 66–73. 29Xing Y, Bronstein Y, Ross MI, Askew RL, Lee JE, Gershenwald JE, Royal R, Cormier JN. Contemporary diagnostic imaging modalities for the staging and surveillance of melanoma patients: a meta-analysis. J Natl Cancer Inst 2011; 103: 129–42. 30Schlamann M, Loquai C, Goericke S, Forsting M, Wanke I. Cerebral MRI in neurological asymptomatic patients with ≠malignant melanoma. Rofo 2008; 180: 143–7. 31Fogarty GB, Tartaglia C. The utility of magnetic resonance imaging in the detection of brain metastases in the staging of cutaneous melanoma. Clin Oncol (R.Coll.Radiol) 2006; 18: 360–2. 32Wang TS, Johnson TM, Cascade PN, Redman BG, Sondak VK, Schwartz JL. Evaluation of staging chest radiographs and serum lactate dehydrogenase for localized melanoma. J Am Acad Dermatol 2004; 51: 399–405. 33Hafner J, Schmid MH, Kempf W, Burg G, Kunzi W, Meuli-Simmen C, Neff P, Meyer V, Mihic D, Garzoli E, Jungius KP, Seifert B, Dummer R, Steinert H. Baseline staging in cutaneous malignant melanoma. Br J Dermatol 2004; 150: 677–86. 34Hofmann U, Szedlak M, Rittgen W, Jung EG, Schadendorf D. Primary staging and follow-up in melanoma patients–monocenter evaluation of methods, costs and patient survival. Br J Cancer 2002; 87: 151–7. 35Terhune MH, Swanson N, Johnson TM. Use of chest radiography in the initial evaluation of patients with localized melanoma. Arch Dermatol 1998; 134: 569–72. 36Tsao H, Feldman M, Fullerton JE, Sober AJ, Rosenthal D, Goggins W. Early detection of asymptomatic pulmonary melanoma metastases by routine chest radiographs is not associated with improved survival. Arch Dermatol 2004; 140: 67–70. 37Bafounta ML, Beauchet A, Chagnon S, Saiag P. Ultrasonography or palpation for detection of melanoma nodal invasion: a meta-analysis. Lancet Oncol 2004; 5: 673–80. 38Garbe C, Paul A, Kohler-Spath H, Ellwanger U, Stroebel W, Schwarz M, Schlagenhauff B, Meier F, Schittek B, Blaheta HJ, Blum A, Rassner G. Prospective evaluation of a follow-up schedule in cutaneous melanoma patients: recommendations for an effective follow-up strategy. J Clin Oncol 2003; 21: 520–9. 39Ardizzoni A, Grimaldi A, Repetto L, Bruzzone M, Sertoli MR, Rosso R. Stage I-II melanoma: the value of metastatic work-up. Oncology 1987; 44: 87–9. 40Goerz G, Schulte-Beerbuhl R, Roder K, Schoppe WD, Munchhoff C, Jungblut RM. Malignant melanoma: which examinations are useful in staging and follow-up? Dtsch Med Wochenschr 1986; 111: 1230–3. 41Mocellin S, Zavagno G, Nitti D. The prognostic value of serum S100B in patients with cutaneous melanoma: a meta-analysis. Int J Cancer 2008; 123: 2370–6. 42Hofmann MA, Gussmann F, Fritsche A, Biesold S, Schicke B, Kuchler I, Voit C, Trefzer U. Diagnostic value of melanoma inhibitory activity serum marker in the follow-up of patients with stage I or II cutaneous melanoma. Melanoma Res 2009; 19: 17–23. 43Garbe C, Leiter U, Ellwanger U, Blaheta HJ, Meier F, Rassner G, Schittek B. Diagnostic value and prognostic significance of protein S-100beta, melanoma-inhibitory activity, and tyrosinase/MART-1 reverse transcription-polymerase chain reaction in the follow-up of high-risk melanoma patients. Cancer 2003; 97: 1737–45. 44Krahn G, Kaskel P, Sander S, Waizenhofer PJ, Wortmann S, Leiter U, Peter RU. S100 beta is a more reliable tumor marker in peripheral blood for patients with newly occurred melanoma metastases compared with MIA, albumin and lactate-dehydrogenase. Anticancer Res 2001; 21: 1311–6. 45Bosserhoff AK, Kaufmann M, Kaluza B, Bartke I, Zirngibl H, Hein R, Stolz W, Buettner R. Melanoma-inhibiting activity, a novel serum marker for progression of malignant melanoma. Cancer Res 1997; 57: 3149–53. 46Veit-Haibach P, Vogt FM, Jablonka R, Kuehl H, Bockisch A, Beyer T, Dahmen G, Rosenbaum S, Antoch G. Diagnostic accuracy of contrast-enhanced FDG-PET/CT in primary staging of cutaneous malignant melanoma. Eur J Nucl Med Mol Imaging 2009; 36: 910–8. 47Khansur T, Sanders J, Das SK. Evaluation of staging workup in malignant melanoma. Arch Surg 1989; 124: 847–9. 48Zartman GM, Thomas MR, Robinson WA. Metastatic disease in patients with newly diagnosed malignant melanoma. J Surg Oncol 1987; 35: 163–4. 49Kersey PA, Iscoe NA, Gapski JA, Osoba D, From L, DeBoer G, Quirt IC. The value of staging and serial follow-up investigations in patients with completely resected, primary, cutaneous malignant melanoma. Br J Surg 1985; 72: 614–7. 50Valsecchi ME, Silbermins D, de Rosa N, Wong SL, Lyman GH. Lymphatic Mapping and Sentinel Lymph Node Biopsy in Patients With Melanoma: A Meta-Analysis. J Clin Oncol 2011. 51Warycha MA, Zakrzewski J, Ni Q, Shapiro RL, Berman RS, Pavlick AC, Polsky D, Mazumdar M, Osman I. Meta-analysis of sentinel lymph node positivity in thin melanoma (<or = 1 mm). Cancer 2009; 115: 869–79. 52Kunte C, Geimer T, Baumert J, Konz B, Volkenandt M, Flaig M, Ruzicka T, Berking C, Schmid-Wendtner MH. Prognostic factors associated with sentinel lymph node positivity and effect of sentinel status on survival: an analysis of 1049 patients with cutaneous melanoma. Melanoma Res 2010; 20: 330–7. 53Mays MP, Martin RC, Burton A, Ginter B, Edwards MJ, Reintgen DS, Ross MI, Urist MM, Stromberg AJ, McMasters KM, Scoggins CR. Should all patients with melanoma between 1 and 2 mm Breslow thickness undergo sentinel lymph node biopsy? Cancer 2010; 116: 1535–44. 54Testori A, De Salvo GL, Montesco MC, Trifiro G, Mocellin S, Landi G, Macripo G, Carcoforo P, Ricotti G, Giudice G, Picciotto F, Donner D, Di Filippo F, Soteldo J, Casara D, Schiavon M, Vecchiato A, Pasquali S, Baldini F, Mazzarol G, Rossi CR, Italian M, I. Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI). Ann Surg Oncol 2009; 16: 2018–27. 55Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, Nieweg OE, Roses DF, Hoekstra HJ, Karakousis CP, Reintgen DS, Coventry BJ, Glass EC, Wang HJ, MSLT Group. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006; 355: 1307–17. 56McMasters KM, Wong SL, Edwards MJ, Ross MI, Chao C, Noyes RD, Viar V, Cerrito PB, Reintgen DS. Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma. Surgery 2001; 130: 151–6. 57Puleo CA, Messina JL, Riker AI, Glass LF, Nelson C, Cruse CW, Johnson TM, Sondak VK. Sentinel node biopsy for thin melanomas: which patients should be considered? Cancer Control 2005; 12: 230–5. 58Socrier Y, Lauwers-Cances V, Lamant L, Garrido I, Lauwers F, Lopez R, Rochaix P, Chevreau C, Payoux P, Viraben R, Paul C, Meyer N. Histological regression in primary melanoma: not a predictor of sentinel lymph node metastasis in a cohort of 397 patients. Br J Dermatol 2010; 162: 830–4. 59Kaur MR, Colloby PS, Martin-Clavijo A, Marsden JR. Melanoma histopathology reporting: are we complying with the National Minimum Dataset? J Clin Pathol 2007; 60: 1121–3. 60Even-Sapir E, Lerman H, Lievshitz G, Khafif A, Fliss DM, Schwartz A, Gur E, Skornick Y, Schneebaum S. Lymphoscintigraphy for sentinel node mapping using a hybrid SPECT/CT system. J Nucl Med 2003; 44: 1413–20. 61Mar MV, Miller SA, Kim EE, Macapinlac HA. Evaluation and localization of lymphatic drainage and sentinel lymph nodes in patients with head and neck melanomas by hybrid SPECT/CT lymphoscintigraphic imaging. J Nucl Med Technol 2007; 35: 10–6. 62Dengel LT, More MJ, Judy PG, Petroni GR, Smolkin ME, Rehm PK, Majewski S, Williams MB, Slingluff CL, Jr. Intraoperative imaging guidance for sentinel node biopsy in melanoma ≠using a mobile gamma camera. Ann Surg 2010. 63Vidal-Sicart S, Paredes P, Zanon G, Pahisa J, Martinez-Roman S, Caparros X, Vilalta A, Rull R, Pons F. Added value of intraoperative real-time imaging in searches for difficult-to-locate sentinel nodes. J Nucl Med 2010; 51: 1219–25. 64Wendler T, Herrmann K, Schnelzer A, Lasser T, Traub J, ≠Kutter O, Ehlerding A, Scheidhauer K, Schuster T, Kiechle M, Schwaiger M, Navab N, Ziegler SI,

A tonically high level of brain arousal and its hyperstable regulation is supposed to be a pathogenic factor in major depression. Preclinical studies indicate that most antidepressants may counteract this dysregulation. Therefore, it was hypothesized that responders to antidepressants show a) a high level of EEG-vigilance (an indicator of brain arousal) and b) a more stable EEG-vigilance regulation than non-responders. In 65 unmedicated depressed patients 15-min resting-state EEGs were recorded off medication (baseline). In 57 patients an additional EEG was recorded 14 ± 1 days following onset of antidepressant treatment (T1). Response was defined as a ≥50% HAMD-17-improvement after 28 ± 1 days of treatment (T2), resulting in 29 responders and 36 non-responders. Brain arousal was assessed using the Vigilance Algorithm Leipzig (VIGALL 2.1). At baseline responders and non-responders differed in distribution of overall EEG-vigilance stages (F2,133 = 4.780, p = 0.009), with responders showing significantly more high vigilance stage A and less low vigilance stage B. The 15-minutes Time-course of EEG-vigilance did not differ significantly between groups. Exploratory analyses revealed that responders showed a stronger decline in EEG-vigilance levels from baseline to T1 than non-responders (F2,130 = 4.978, p = 0.005). Higher brain arousal level in responders to antidepressants supports the concept that dysregulation of brain arousal is a possible predictor of treatment response in affective disorders.

Background: The histopathologic diagnosis of mycosis fungoides (MF) may be difficult. Objective: Our purpose was to evaluate the role of immunophenotyping and T-cell receptor (TCR) gene rearrangement studies as an adjunct to the histopathologic diagnosis of MF. Methods: Immunohistochemical studies with antibodies to CD4, CD5, CD7, and CD8 and TCR γ gene rearrangement analysis with a polymerase chain reaction were performed on fresh-frozen material of patients with “classic” histology of MF, “inconclusive” histology, and benign inflammatory dermatoses. Results: Clonal TCR γ gene rearrangements were found in 11 of 16 (69%) of classic MF cases, in 3 of 19 (16%) of inconclusive cases, and in none of the 12 inflammatory dermatoses cases (P < .05 and P < .001, respectively). Only the mean CD7 counts were statistically significantly different between these 3 groups (MF < inconclusive < inflammatory). Conclusion: Inconclusive histology is probably a heterogeneous group in which CD7 counts and TCR γ gene rearrangement studies might help to differentiate the MF cases from the benign cases. (J Am Acad Dermatol 1998;39:554-9.)

Delayed-type hypersensitivity reactions (DTHR) are mediated by IFN-gamma-producing CD4+ (Th1) or CD8+ T cells (Tc1) and can be prevented by steering T cells toward an IL-4-producing Th2 or Tc2 phenotype. It is currently accepted that T cells can be directed toward a Th2 or Tc2 phenotype only during the initiation of an immune response. Once established, the cytokine pattern of immune reactions is believed to be stable. Therefore, inhibition of DTHR by the induction of Th2/Tc2 responses, termed immune deviation, is considered only as a prevention but not as a therapy of harmful DTHR. Here we demonstrate that therapeutic immune deviation can reverse established contact hypersensitivity (CHS), a Th1/Tc1-mediated DTHR. One or two weeks after induction of CHS, mice received either a single cycle of IL-4 therapy or adoptive transfer of antigen-specific Th2 cells. This treatment generated a novel state of immunity that provided long-lasting protection against tissue destruction and neutrophil recruitment during subsequent antigen exposures. Therapeutic immune deviation of established CHS was dependent on CD4+ T cells and the induction of endogenous IL-4 synthesis. Thus, a population of immunoregulatory Th2 cells persists during advanced inflammatory responses that can be used for therapeutic deviation of established DTHR.

Disseminated actinic keratoses are a therapeutic problem.Our purpose was to evaluate the efficacy of a combination of topical 5-fluorouracil twice a day and 20 mg of oral isotretinoin daily for disseminated actinic keratoses.Twenty-seven patients who had disseminated actinic keratoses (3 women, 24 men) were treated with 5-fluorouracil (5%) twice a day applied to the photodamaged area bearing actinic keratoses along with oral isotretinoin, 20 mg daily. The median treatment time was 21 days.Actinic keratoses disappeared and signs of photodamaged skin improved in all patients. Side effects were burning and itching as well as painful erosions during the final stage of treatment.The combination of topical 5-fluorouracil and isotretinoin is highly effective in the treatment of disseminated actinic keratoses on photodamaged skin.

Abstract Lymphomatoid papulosis (LyP) represents an intriguing cutaneous T-cell lymphoproliferative disorder with a histologic appearance resembling malignant lymphoma. This finding strongly contrasts with the benign clinical course of the disease. However, in 10% to 20% of cases, LyP can precede, coexist with, or follow malignant lymphoma. In these cases, the same T-cell population has been shown to be present in the LyP as well as in the associated lymphoma. In most LyP cases, there is—despite the sometimes extremely long course of the disease—no evolution of a secondary lymphoma. The investigation of these uncomplicated LyP cases for the presence of clonal T-cell receptor rearrangements has produced heterogeneous results. This might be explained by biologic or technical reasons arising from analyzing whole tissue DNA extracts. To definitively clarify whether the large atypical CD30+ cells in LyP without associated lymphoma all belong to the same clone or represent individually rearranged T cells, we analyzed the T-cell receptor–γ rearrangements of single CD30+ as well as of single CD30− cells isolated from 14 LyP lesions of 11 patients. By using this approach we could demonstrate that the CD30+ cells represent members of a single T-cell clone in all LyP cases. Moreover, in 3 patients the same CD30+ cell clone was found in anatomically and temporally separate lesions. In contrast, with only a few exceptions, the CD30− cells were polyclonal in all instances and unrelated to the CD30+ cell clone. Our results demonstrate that LyP unequivocally represents a monoclonal T-cell disorder of CD30+ cells in all instances.

Differing classification schemes for malignant lymphomas have been used in Europe and the United States. Attempts to translate between the principle classifications have been unsuccessful and historically it has been difficult to arrive at an unified approach. In addition, many new lymphoma entities have been recognized in recent years that are not delineated in any of the existing classification schemes. To provide a unified international basis for clinical and investigative work in this field, in 1994 the International Lymphoma Study Group (ILSG) proposed a new classification termed Revised European‐American Classification of Lymphoid Neoplasms (REAL). This review discusses the REAL classification, especially as it pertains to cutaneous lymphomas, and provides insight into the clinicopathologic features of lymphoproliferative disease involving the skin. The premise of the REAL classification is that a classification scheme should be based on the delineation of disease entities, utilizing pathologic, immunophenotypic, genetic, and clinical features. Therefore, if cutaneous involvement is an integral aspect of any lymphoma subtype, this clinical information is included in the definition of that neoplasm. We conclude that the principles of the REAL classification are applicable to cutaneous lymphomas, as well as lymphomas involving other anatomic sites.

Analysis of data of 6931 patients with cutaneous melanoma seen at the Department of Dermatology and Allergology at the Ludwig-Maximilians-University of Munich between 1977 and 1998 identified 36 patients in whom cutaneous melanomas developed during childhood or adolescence (age <18 years). Clinical courses of all patients and histopathologic characteristics of the lesions were reviewed. Seventeen patients were boys and 19 patients were girls. The median ages of the boys and girls were 15 and 16 years, respectively (range, 2-17 years). Thirty-one patients presented with nonmetastatic primary melanomas and 5 patients presented with metastatic melanoma. Forty-seven percent of the primary lesions were associated with a nevus (22% with congenital nevi and 25% with acquired nevi). Tumor thickness ranged from 0.24 to 7.0 mm, with a median of 1.29 mm (mean, 1.67 mm). All patients with primary melanomas received surgical therapy; patients with metastatic disease received chemotherapy, radiation therapy, or both. Relative 5-year survival was 87.5% for the group of patients younger than 18 years. Similar to experience in adult patients, survival strongly correlated with tumor thickness and clinical stage at the time of diagnosis. The data emphasize that a high index of suspicion for cutaneous melanoma is needed by clinicians assessing melanocytic lesions in children and adolescents for early diagnosis. Reduction of the melanoma mortality rate in children and adolescents will be achieved through identification of patients at increased risk.

BRAF, a serine/threonine kinase, is a component of the retrovirus-associated sequence (RAS)-RAF-extracellular-regulated protein kinase (ERK)-MAP kinase signal transduction pathway mediating signals from RAS to ERK. The T1796A single point mutation in exon 15 of the BRAF gene has recently been reported in a high percentage of malignant melanomas and benign melanocytic lesions such as congenital nevi, compound nevi, intradermal nevi and dysplastic nevi. The T1796A mutation has been shown to promote cell proliferation.We screened 21 Spitz nevi and six spitzoid malignant melanomas for the presence of the T1796A BRAF mutation.The T1796A BRAF mutation could not be detected in any of the 21 Spitz nevi but was present in two of the six spitzoid malignant melanomas.Our results, in conjunction with data from a previous investigation, suggest that the melanocytic proliferation of Spitz nevi might be induced by components of the RAS-RAF-ERK-MAP kinase pathway different from BRAF, possibly combined with other genetic aberrations. The lack of the T1796A BRAF mutation might be of practical importance in distinguishing Spitz nevi from other melanocytic lesions simulating Spitz nevi as a part of a future complex diagnostic assay.

Important properties of globular proteins, such as the stability of its folded state, depend sensitively on interactions with solvent molecules.Existing methods for estimating these interactions, such as the geometrical surface model, are either physically misleading or too time consuming to be applied routinely in energy calculations.As an alternative, we derive here a simple model for the interactions between protein atoms and solvent atoms in the first hydration layer, the solvent contact model, based on the conservation of the total number of atomic contacts, a consequence of the excluded-volume effect.The model has the conceptual advantage that protein-protein contacts and proteinsolvent contacts same language advantage that are treated in the and the technical the solvent term becomes a particularly simple function of interatomic distances.The model allows rapid calculation of any physical property that depends only on the num- ber and type of protein-solvent near- est-neighbor contacts.We propose use of the method in the calculation of protein solvation energies, conformational energy calculations, and molecu- lar dynamics simulations.

In a pilot study it was investigated whether assessment of EEG-vigilance is useful for the prediction of treatment outcome in ADHD patients. Resting EEG recordings of 49 unmedicated ADHD patients and 49 age-matched controls were analyzed. Vigilance level was determined for 1-s segments with a computer-based algorithm, distinguishing six stages from higher vigilance stages A1, A2 and A3 with dominant alpha activity to lower stages B1 and B2/3 with low amplitude non-alpha and increasing theta and delta activity and further onto stage C characterizing sleep onset. Treatment outcome was measured as changes in continuous performance test (CPT) results from baseline after at least 4 weeks of medication. ADHD patients spend less time in higher A1-stages (ADHD = 66%, controls = 81%) and showed more switching between vigilance stages (ADHD = 26.02%, controls = 19.09%), indicating a more unstable vigilance regulation. Patients with less stable vigilance showed a worse pre-treatment CPT performance but achieved a better post-treatment result compared to patients with more stable vigilance regulation. These differences did not reach statistical significance. Signs of vigilance instability where found in ADHD patients compared to controls. Those patients with a higher degree of vigilance instability seemed to benefit more from stimulant medication. This is the first investigation of EEG-vigilance in ADHD-patients. Results are limited by a short recording time but the results strongly suggest further investigation of the vigilance regulation in ADHD patients.

International Journal of Quantum ChemistryVolume 24, Issue S10 p. 181-199 Article The normal modes of a protein: Native bovine pancreatic trypsin inhibitor Michael Levitt, Michael Levitt Chemical Physics Department, Weizmann Institute of Science, 76100 Rehovot, IsraelSearch for more papers by this authorChristian Sander, Christian Sander Chemical Physics Department, Weizmann Institute of Science, 76100 Rehovot, IsraelSearch for more papers by this authorPeter S. Stern, Peter S. Stern Chemical Physics Department, Weizmann Institute of Science, 76100 Rehovot, IsraelSearch for more papers by this author Michael Levitt, Michael Levitt Chemical Physics Department, Weizmann Institute of Science, 76100 Rehovot, IsraelSearch for more papers by this authorChristian Sander, Christian Sander Chemical Physics Department, Weizmann Institute of Science, 76100 Rehovot, IsraelSearch for more papers by this authorPeter S. Stern, Peter S. Stern Chemical Physics Department, Weizmann Institute of Science, 76100 Rehovot, IsraelSearch for more papers by this author First published: 14/16 March 1983 https://doi.org/10.1002/qua.560240721Citations: 26AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract A completely general treatment of normal mode analysis is developed that can be used with any potential energy function and any set of generalized coordinates. The method is applied to the calculation of the normal modes of the small protein bovine pancreatic trypsin inhibitor that has been the subject of many previous theoretical studies. The potential energy function used comprises a torsion angle potential, a van der Waals potential between nonbonded pairs of atoms, and a hydrogen bond potential. Therefore, the generalized coordinates used are the 208 Φ, ϕ, and χ torsion angles about single bonds. This eliminates the difficulties inherent in using internal or Cartesian coordinates for a large molecule. Many dynamic properties of the protein may now be calculated in the normal mode description. In particular, the rms magnitudes and pair correlations of the fluctuations in positions and velocities of the α-carbon atoms and various classes of torsion angles, such as backbone, side chain, β-sheet, and α-helix, are calculated and analyzed to identify the most correlated modes. In addition, the ir intensities are calculated. Citing Literature Volume24, IssueS10Supplement: Proceedings of the International Symposium on Quantum Biology and Quantum Pharmacology14/16 March 1983Pages 181-199 RelatedInformation

Signaling through tumor necrosis factor receptor 1 (TNFR1) controls bacterial infections and the induction of inflammatory Th1 cell-mediated autoimmune diseases. By dissecting Th1 cell-mediated delayed-type hypersensitivity responses (DTHRs) into single steps, we localized a central defect to the missing TNFR1 expression by endothelial cells (ECs). Adoptive transfer and mast cell knockin experiments into Kit(W)/Kit(W-v), TNF(-/-), and TNFR1(-/-) mice showed that the signaling defect exclusively affects mast cell-EC interactions but not T cells or antigen-presenting cells. As a consequence, TNFR1(-/-) mice had strongly reduced mRNA and protein expression of P-selectin, E-selectin, ICAM-1, and VCAM-1 during DTHR elicitation. In consequence, intravital fluorescence microscopy revealed up to 80% reduction of leukocyte rolling and firm adhesion in TNFR1(-/-) mice. As substitution of TNF(-/-) mice with TNF-producing mast cells fully restored DTHR in these mice, signaling of mast cell-derived TNF through TNFR1-expressing ECs is essential for the recruitment of leukocytes into sites of inflammation.

Mania and attention-deficit hyperactivity disorder (ADHD) show a high degree of symptom overlap and comorbidity. Clinical trials and case reports indicate that psychostimulants do not or only rarely trigger or aggravate manic episodes but can even produce rapid and pronounced antimanic effects. An explanatory model is presented here in which the sensation seeking, hyperactive behaviour observed in mania and ADHD is interpreted as an autoregulatory attempt to stabilize vigilance by increasing external stimulation. Accordingly, patients with both mania and ADHD show rapid declines to lower vigilance levels (e.g., sleep spindles in EEG) under resting conditions with low external stimulation. The "paradoxical" antimanic effect of psychostimulants possibly results from their vigilance stabilizing properties.

Azide (10-3 M, solution buffered at pH 3) is more effective in inducing mutations in embryonic shoots of seeds germinated between 8 and 16 h than in non-germinated seeds and in seeds germinated between 0 and 8 h and 16 to 28 h. This peak of chlorophyll-deficient seedling mutation frequency coincides with maximum frequencies of seeding lethals and DNA replication in the cells of the embryonic shoot. The mutation data suggest azide may only act on replicating DNA. Azide induced no chromosome-aberration frequencies significantly above controls in (1) embryonic shoots of barley seeds germinated for 8--12 h, (2) microspores of barley and (3) human leukocytes. It appears to be a point-mutation mutagen.

[18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) is a well-established method for the examination of the cerebral glucose metabolism of patients with affective disorder or memory impairment. An understudied question is how far results are influenced by interindividual differences in central nervous arousal as assessed with electroencephalogram (EEG-vigilance) during the PET recording. Building upon previous neuroimaging studies, we supposed an association between EEG-vigilance and normalized brain [18F]FDG-uptake (nFDGu) as measured by [18F]FDG-PET. For the first time, the present study exploratively investigated this association in a routine diagnostic work-up. Simultaneous 31-channel EEG and [18F]FDG-PET under resting conditions were acquired from 14 patients with depressive episode or mild cognitive impairment (MCI). EEG-vigilance was automatically classified by using the VIGALL algorithm (Vigilance Algorithm Leipzig). A nonparametric voxelwise simple linear regression with vigilance measure as predictor and nFDGu as criterion was performed using the Statistical nonParametric Mapping toolbox. The main finding was a significant negative correlation between vigilance measure and nFDGu in bilateral frontal and temporal regions, bilateral cingulate gyrus and right thalamus with vigilance-related changes of nFDGu between 17.1 and 44.4%. Simultaneous EEG and [18F]FDG-PET under resting conditions revealed that brain regions associated with EEG-vigilance partly overlapped with regions of impaired nFDGu in depression and MCI, as reported by previous studies. Vigilance-related changes of nFDGu were about the same magnitude as disease-related metabolic changes in patients with affective disorder or memory impairment as reported in previous studies. Therefore, our data suggest that differences in EEG-vigilance might influence alterations of nFDGu in disorders such as depression or MCI. Whether this possible impact of vigilance on nFDGu should be taken into account during the routine diagnostic application of [18F]FDG-PET has to be explored in future studies with larger patient groups.

The temporal dynamics of electroencephalogram (EEG)-vigilance as a measure of tonic cortical arousal are discussed as pathogenetic factors in neuropsychiatric disorders. Although there is broad knowledge about the interaction of cortical arousal and activity of the autonomous nervous system (ANS) during different sleep stages, the association and temporal interaction between fine-graded EEG-vigilance stages and markers of sympathetic and parasympathetic activity during the transition from wakefulness to sleep onset warrants more detailed exploration and was focus of the presented study. A 15-min resting-EEG, electrocardiogram (ECG), and skin conductance level (SCL) were recorded from 54 healthy subjects. Using an EEG-algorithm (VIGALL), 1-s segments were classified into seven different vigilance stages. Associations and temporal interactions between EEG-vigilance stages and heart rate variability (HRV), heart rate (HR), and SCL were computed using correlation analysis, regression analysis, and cross-correlations of EEG-vigilance and ANS time series. EEG-vigilance stages and ANS activity showed a significant association between increased HRV parameters including total and (normalized) very low frequency power and low vigilance stages. Regression analysis revealed significantly increased values of SCL and HR for high vigilance stages in comparison to lower ones. In these relationships, for SCL but not HR most of the covariance was explained by the effect of time. Phasic increases in EEG-vigilance were paralleled by significant increases of HR but not of SCL. Cross-correlations between EEG-vigilance and ANS time series yielded highest correlations when there was no or only a minimal temporal lag. ANS activity during the transition from wakefulness to sleep onset gradually changes along with different fine-graded EEG-vigilance stages. Associations between cortical and autonomic activity are better reflected by HR than by SCL.

Different levels of brain arousal can be delineated not only during sleep but also during wakefulness. Electroencephalography (EEG) is the gold standard to assess different levels of brain arousal. A novel EEG- and electrooculography (EOG)-based tool, the Vigilance Algorithm Leipzig (VIGALL 2.0), allows determining the level of EEG-vigilance (indicating brain arousal). Considering the frequency patterns and LORETA-based cortical distribution of electroencephalic activity, VIGALL 2.0 automatically attributes one out of seven vigilance stages to each EEG segment (1-sec EEG segments by default), ranging from high alertness (stage 0), to relaxed wakefulness (stage A1 to A3), to drowsiness (stage B1 to B2/3) up to sleep onset (stage C). Building on the time series of these seven vigilance stages across 20 min, two parameterizations of the temporal dynamic (brain arousal regulation) are calculated: the lability score and the slope index. 27 healthy participants (age = 22.93 ± 3.44 years, 18 females) underwent two sessions (7 days apart) of a twenty-minute eyes-closed resting EEG paradigm. The test-retest reliability coefficients for the EEG-vigilance stages were between rho = .53 and .86 (all p < .01). For the temporal dynamic of the stages across 20 min, the test-retest reliability coefficients were rho = .70 (lability score, p < .001) and .71 (slope index, p < .001). This study demonstrated some trait aspects of brain arousal regulation by confirming the stability of temporal dynamic of EEG-vigilance stages as assessed with VIGALL 2.0. Considering the “first day in lab” effect identified in the present study, more adaptation to the lab surrounding and a stricter control of other state factors should be taken into account, which might improve reliability. Additionally, in a clinical context, a broader range of brain arousal regulation patterns might be found, possibly leading to higher test-retest reliability than was found in this homogenous healthy sample. This would be desirable, as parameters of brain arousal regulation are promising diagnostic and prognostic biomarkers for diseases with arousal disturbances, such as affective disorders, ADHD and fatigue.

Previous studies compared evoked potentials (EPs) between several sleep stages but only one uniform wake state. However, using electroencephalography (EEG), several arousal states can be distinguished before sleep onset. Recently, the Vigilance Algorithm Leipzig (VIGALL 2.0) has been developed, which automatically attributes one out of seven EEG-vigilance stages to each 1-s EEG segment, ranging from stage 0 (associated with cognitively active wakefulness), to stages A1, A2 and A3 (associated with relaxed wakefulness), to stages B1 and B2/3 (associated with drowsiness) up to stage C (indicating sleep onset). Applying VIGALL, we specified the effects of these finely differentiated EEG-vigilance stages (indicating arousal states) on EPs (P1, N1, P2, N300, MMN and P3) and behavioral performance. Subjects underwent an ignored and attended condition of a 2-h eyes-closed oddball-task. Final analysis included 43 subjects in the ignored and 51 subjects in the attended condition. First, the effect of brain arousal states on EPs and performance parameters were analyzed between EEG-vigilance stages A (i.e. A1, A2 and A3 combined), B1 and B2/3&C (i.e. B2/3 and C combined). Then, in a second step, the effects of the finely differentiated EEG-vigilance stages were further specified. Comparing stages A versus B1 versus B2/3&C, a significant effect of EEG-vigilance stages on all behavioral parameters and all EPs, with exception of MMN and P3, was found. By applying VIGALL, a more detailed view of arousal effects on EP and performance was possible, such as the finding that the P2 showed no further significant increase in stages deeper than B1. Stage 0 did not differ from any of the A-stages. Within more fine-graded stages, such as the A-substages, EPs and performance only partially differed. However, these analyses were partly based on small sample sizes and future studies should take effort to get enough epochs of rare stages (such as A3 and C). A clear impact of arousal on EPs and behavioral performance was obtained, which emphasize the necessity to consider arousal effects when interpreting EPs.

Abstract Sleep impairments are a hallmark of acute bipolar disorder (BD) episodes and are present even in the euthymic state. Studying healthy subjects who are vulnerable to BD can improve our understanding of whether sleep impairment is a predisposing factor. Therefore, we investigated whether vulnerability to BD, dimensionally assessed by the hypomanic personality scale (HPS), is associated with sleep disturbances in healthy subjects. We analyzed participants from a population-based cohort who had completed the HPS and had either a 7-day actigraphy recording or a Pittsburgh sleep quality index (PSQI) assessment. In addition, subjects had to be free of confounding diseases or medications. This resulted in 771 subjects for actigraphy and 1766 for PSQI analyses. We found strong evidence that higher HPS scores are associated with greater intraindividual sleep variability, more disturbed sleep and more daytime sleepiness. In addition, factor analyses revealed that core hypomanic features were especially associated with self-reported sleep impairments. Results support the assumption of disturbed sleep as a possibly predisposing factor for BD and suggest sleep improvement as a potential early prevention target.

Abstract Background and purpose The ENIGMA‐EEG working group was established to enable large‐scale international collaborations among cohorts that investigate the genetics of brain function measured with electroencephalography (EEG). In this perspective, we will discuss why analyzing the genetics of functional brain activity may be crucial for understanding how neurological and psychiatric liability genes affect the brain. Methods We summarize how we have performed our currently largest genome‐wide association study of oscillatory brain activity in EEG recordings by meta‐analyzing the results across five participating cohorts, resulting in the first genome‐wide significant hits for oscillatory brain function located in/near genes that were previously associated with psychiatric disorders. We describe how we have tackled methodological issues surrounding genetic meta‐analysis of EEG features. We discuss the importance of harmonizing EEG signal processing, cleaning, and feature extraction. Finally, we explain our selection of EEG features currently being investigated, including the temporal dynamics of oscillations and the connectivity network based on synchronization of oscillations. Results We present data that show how to perform systematic quality control and evaluate how choices in reference electrode and montage affect individual differences in EEG parameters. Conclusion The long list of potential challenges to our large‐scale meta‐analytic approach requires extensive effort and organization between participating cohorts; however, our perspective shows that these challenges are surmountable. Our perspective argues that elucidating the genetic of EEG oscillatory activity is a worthwhile effort in order to elucidate the pathway from gene to disease liability.

A markedly elevated serum level of mast cell tryptase (77.6 microg/L; 95th percentile in normals 13.5 microg/L) was detected in a patient treated for 5 years with wasp venom immunotherapy because of severe anaphylaxis following a wasp sting. Retrospective analysis of stored serum samples taken during the course of immunotherapy revealed that the tryptase level had been elevated for at least 3 years. Despite several dermatological examinations, skin changes of mastocytosis had been missed. Re-examination of the patient revealed sparse macules on the thorax and thighs; Darier's sign was negative. Histologically, mast cell accumulation in these lesions was demonstrable. No signs of systemic mastocytosis were detected. The most appropriate diagnosis was telangiectasia macularis eruptiva perstans. Even in patients with highly elevated tryptase levels, mastocytosis may go undiagnosed. As mastocytosis predisposes to severe anaphylaxis, the condition should be looked for in patients with such reactions by clinical examination and measurement of serum tryptase levels.

Journal Article Predicting local structural changes that result from point mutations Get access V. De Filippis, V. De Filippis Search for other works by this author on: Oxford Academic PubMed Google Scholar C. Sander, C. Sander 1Protein Design Group, EMBLMeyerhofstrasse 1, 69117 Heidelberg, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar G. Vriend G. Vriend 2 1Protein Design Group, EMBLMeyerhofstrasse 1, 69117 Heidelberg, Germany 2To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Protein Engineering, Design and Selection, Volume 7, Issue 10, October 1994, Pages 1203–1208, https://doi.org/10.1093/protein/7.10.1203 Published: 01 October 1994 Article history Received: 11 April 1994 Revision received: 18 July 1994 Accepted: 27 July 1994 Published: 01 October 1994

Although patients with depression often suffer from sleep disturbances, most of them are not sleepy. Upregulation of brain arousal has been proposed as pathophysiological mechanism explaining sleep disturbances, inner tension, autonomic hyperarousal and anhedonia in depression. The aim of the current study was to examine the association between night-time sleep disturbances and brain arousal regulation the next day in depressed versus non-depressed subjects.Twenty-eight elderly subjects (21 female; age = 70.5 ± 4.4 years) with depressive syndromes without psychotropic medication, and 28 controls (22 female; age = 70.9 ± 4.5 years), underwent a 15-min resting electroencephalogram; the Vigilance Algorithm Leipzig (VIGALL 2.1) provided an objective measure of brain arousal regulation. Sleep disturbances were assessed by a validated and self-rated sleep questionnaire.In the depressive group, but not in controls, more sleep disturbances were associated with a higher brain arousal stability score (high score corresponds to upregulation) the next day (sleep onset latency: rs = 0.69, P < .0001; sleep quality: rs = -0.59, P < .001).The data confirm the hypothesis that in persons with depressive syndromes sleep disturbances are related to upregulation of brain arousal the next day. This finding is in line with the concept that dysregulation of brain arousal is a central pathophysiological aspect in depression.

Daytime sleepiness is a significant public health concern. Early evidence points toward the computerized VIGALL (Vigilance Algorithm Leipzig) as time-efficient tool to assess sleepiness objectively. In the present study, we investigated the association between VIGALL variables of EEG vigilance (indicating brain arousal in resting state) and subjective daytime sleepiness in the LIFE cohort study. Additionally, we validated VIGALL against the self-rated likelihood of having fallen asleep during the conducted resting EEG and against heart periods. Participants of the primary sample LIFE 60+ (N = 1927, 60–79 years) and replication sample LIFE 40+ (N = 293, 40–56 years) completed the Epworth Sleepiness Scale (ESS). After an average interval of 3 weeks (LIFE 60+) and 65 weeks (LIFE 40+), respectively, participants underwent a single 20-minute resting EEG, analyzed using VIGALL 2.1. Analyses revealed significant associations between ESS and EEG vigilance in LIFE 60+ (rho = −0.17, p = 1E–14) and LIFE 40+ (rho = −0.24, p = 2E-5). Correlations between EEG vigilance and self-rated sleep likelihood reached rho = −0.43 (p = 2E-91) in LIFE 60+ and rho = −0.50 (p = 5E–20) in LIFE 40+. Overall, strongest correlations were obtained for EEG vigilance variable “slope index.” Furthermore, lower EEG vigilance was consistently associated with longer heart periods. The present study contributes to the validation of VIGALL. Despite the considerable interval between ESS and EEG assessment dates, the strength of ESS-VIGALL association approximates prior ESS–Multiple Sleep Latency Test results. In this light, VIGALL might constitute an economical choice for the objective assessment of daytime sleepiness in large cohort studies. The discriminative power to identify disorders of hypersomnolence, however, remains to be addressed.

Several studies have found upregulated brain arousal during 15-minute EEG recordings at rest in depressed patients. However, studies based on shorter EEG recording intervals are lacking. Here we aimed to compare measures of brain arousal obtained from 2-minute EEGs at rest under eyes-closed condition in depressed patients and healthy controls in a multisite project-Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). We expected that depressed patients would show stable and elevated brain arousal relative to controls. Eighty-seven depressed patients and 36 healthy controls from four research sites in the United States were included in the analyses. The Vigilance Algorithm Leipzig (VIGALL) was used for the fully automatic classification of EEG-vigilance stages (indicating arousal states) of 1-second EEG segments; VIGALL-derived measures of brain arousal were calculated. We found that depressed patients scored higher on arousal stability ( Z = -2.163, P = .015) and A stages (dominant alpha activity; P = .027) but lower on B1 stages (low-voltage non-alpha activity, P = .008) compared with healthy controls. No significant group differences were observed in Stage B2/3. In summary, we were able to demonstrate stable and elevated brain arousal during brief 2-minute recordings at rest in depressed patients. Results set the stage for examining the value of these measures for predicting clinical response to antidepressants in the entire EMBARC sample and evaluating whether an upregulated brain arousal is particularly characteristic for responders to antidepressants.

Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p < 5E-8), although seven loci were suggestive (p < 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.

Background: The personality trait neuroticism has been implicated in a poor response to stress, may relate to increased concentrations of cytokines and the development of depression. Inflammatory mechanisms may also be associated with the onset, severity and symptoms of depression. Both are related to poor antidepressant treatment outcome. Therefore, mediators of inflammation may bridge the relationship between neuroticism and depression. Methods: To disentangle these interrelationships, the associations between neuroticism (according to NEO-PIR-N), depressive symptoms (BDI-II scores) and serum levels of hsCRP, TNF-α, IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, GM-CSF were investigated in 212 depressed (n=37) and non-depressed (n=175) participants. A mediation model was used to investigate whether the impact of neuroticism on depressive symptoms may be mediated by cytokines. Results: Regression analyses revealed that IFN-γ, IL-5, and IL-12-levels, but none of the anti-inflammatory cytokines, were associated with the overall neuroticism score and several of the cytokines were related to the different facets of neuroticism. TNF-α, IFN-γ, IL-5, IL-12, and IL-13 were further related to the severity of depressive symptoms, as well as the somatic-affective and the cognitive dimensions of depression. Pro-inflammatory IFN-γ, IL-5 and IL-12 were identified as mediators of the positive prediction of depression severity by the degree of neuroticism. Conclusions: The current findings demonstrate that conditions related to long-term stress, such as depression and high neuroticism, are related to an up-regulation of inflammatory agents. Neuroticism may increase stress perception and, thus, increase the production of pro-inflammatory messenger molecules which are invloved in the development of depression. This evidence may contribute to future anti-inflammatory interventions, particularly in subjects with high neuroticism who are at risk for developing depression. Furthermore, depressed patients may require early escalations in the intensity of treatment, along with additional therapeutic elements to increase the rate of treatment success.

There is a wide clinicopathologic spectrum of vascular proliferations characterized by the presence of epithelioid endothelial cells, comprising epithelioid hemangioma (EH)—pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma (PM-HAE), epithelioid hemangioendothelioma, and epithelioid angiosarcoma. Immunohistochemical FOS-B expression as well as FOS-B rearrangement (fluorescent in situ hybridization [FISH]) have recently been described as diagnostically relevant underpinnings of EH (restricted to osseous lesions) and PM-HAE. The aim of this study was to clinicopathologically characterize and to elucidate FOS-B expression in patients with eruptive lesions of the cellular variant of cutaneous EH. All cases of cutaneous cellular EH (n=16) showed strong diffuse immunohistochemical expression of FOS-B, in conjunction with positivity for ERG and nestin. Expression of MYC, CAMTA-1, AE1/3, and MNF116 was negative in all cases. FISH investigations did not show any sign of rearrangements for CAMTA-1 or MYC amplification. Negative-control cases included 15 lobular hemangiomas, 5 epithelioid angiosarcomas, and 5 nodular Kaposi sarcomas, all of which were negative for FOS-B. Positive-control cases included 15 angiolymphoid hyperplasia with eosinophilia cases, all of them being positive. In contrast with what has been published so far, cutaneous variants of cellular EH exhibit positive immunostaining for FOS-B. Remarkably, FOS-B expression is not restricted to the intraosseous subset of EH. For differential diagnosis of epithelioid vascular tumors, we therefore suggest a helpful panel of antibodies including CAMTA-1, TFE-3, FOS-B, and AE1/AE3. We point out the telltale immunophenotypes: angiolymphoid hyperplasia with eosinophilia and EH (FOS-B + /others negative), PM-HAE (FOS-B + /AE1/AE3 + /others negative), epithelioid hemangioendothelioma (CAMTA-1 + or TFE-3 + /others negative). Remarkably, MYC is not expressed in these tumors, neither is there an MYC amplification by FISH. We suggest the term multiple eruptive EHs for this subset of cutaneous vascular tumors.

Background Internet- and mobile-based interventions are most efficacious in the treatment of depression when they involve some form of guidance, but providing guidance requires resources such as trained personnel, who might not always be available (eg, during lockdowns to contain the COVID-19 pandemic). Objective The current analysis focuses on changes in symptoms of depression in a guided sample of patients with depression who registered for an internet-based intervention, the iFightDepression tool, as well as the extent of intervention use, compared to an unguided sample. The objective is to further understand the effects of guidance and adherence on the intervention’s potential to induce symptom change. Methods Log data from two convenience samples in German routine care were used to assess symptom change after 6-9 weeks of intervention as well as minimal dose (finishing at least two workshops). A linear regression model with changes in Patient Health Questionnaire (PHQ-9) score as a dependent variable and guidance and minimal dose as well as their interaction as independent variables was specified. Results Data from 1423 people with symptoms of depression (n=940 unguided, 66.1%) were included in the current analysis. In the linear regression model predicting symptom change, a significant interaction of guidance and minimal dose revealed a specifically greater improvement for patients who received guidance and also worked with the intervention content (β=–1.75, t=–2.37, P=.02), while there was little difference in symptom change due to guidance in the group that did not use the intervention. In this model, the main effect of guidance was only marginally significant (β=–.53, t=–1.78, P=.08). Conclusions Guidance in internet-based interventions for depression is not only an important factor to facilitate adherence, but also seems to further improve results for patients adhering to the intervention compared to those who do the same but without guidance.

Aging is associated with increased white matter hyperintensities (WMHs) and with alterations of alpha oscillations (7-13 Hz). However, a crucial question remains, whether changes in alpha oscillations relate to aging per se or whether this relationship is mediated by age-related neuropathology like WMHs. Using a large cohort of cognitively healthy older adults (N = 907, 60-80 years), we assessed relative alpha power, alpha peak frequency, and long-range temporal correlations from resting-state EEG. We further associated these parameters with voxel-wise WMHs from 3T MRI. We found that a higher prevalence of WMHs in the superior and posterior corona radiata as well as in the thalamic radiation was related to elevated alpha power, with the strongest association in the bilateral occipital cortex. In contrast, we observed no significant relation of the WMHs probability with alpha peak frequency and long-range temporal correlations. Finally, higher age was associated with elevated alpha power via total WMH volume. We suggest that an elevated alpha power is a consequence of WMHs affecting a spatial organization of alpha sources.

The heartbeat-evoked potential (HEP) is a brain response to each heartbeat, which is thought to reflect cardiac signaling to central autonomic areas and suggested to be a marker of internal body awareness (eg, interoception).Because cardiac communication with central autonomic circuits has been shown to be impaired in patients with atrial fibrillation (AF), we hypothesized that HEPs are attenuated in these patients.By simultaneous electroencephalography and electrocardiography recordings, HEP was investigated in 56 individuals with persistent AF and 56 control subjects matched for age, sex, and body mass index.HEP in control subjects was characterized by right frontotemporal negativity peaking around 300 to 550 ms after the R-peak, consistent with previous studies. In comparison with control subjects, HEP amplitudes were attenuated, and HEP amplitude differences remained significant when matching the samples for heart frequency, stroke volume (assessed by echocardiography), systolic blood pressure, and the amplitude of the T-wave. Effect sizes for the group differences were medium to large (Cohen's d between 0.6 and 0.9). EEG source analysis on HEP amplitude differences pointed to a neural representation within the right insular cortex, an area known as a hub for central autonomic control.The heartbeat-evoked potential is reduced in AF, particularly in the right insula. We speculate that the attenuated HEP in AF may be a marker of impaired heart-brain interactions. Attenuated interoception might furthermore underlie the frequent occurrence of silent AF.

Diagnosis of scabies infection can be difficult as in many cases only few mites are present on an infected person, and in some cases the skin manifestations can be subtle or atypical. We describe the use of polymerase chain reaction (PCR) to amplify Sarcoptes scabiei DNA in a patient presenting with clinically atypical eczema. Cutaneous scales were PCR positive for S. scabiei DNA before, and negative 2 weeks after, therapy. This method facilitates fast and very sensitive diagnosis of clinically atypical or inapparent scabies infection and therapy control in severely affected patients and may help to identify previously unrecognized scabies cases.

We reviewed our experience with six T-cell-rich B-cell lymphomas (TRBL) presenting in skin. Immunohistochemical studies were performed on all biopsies. The lymphoid population consisted mainly of CD3 and/or UCHL-1 (CD45RO) positive T cells. 5 to 15% of the lymphoid cells stained for the B-cell marker L26 (CD20). Monoclonality of the B-cell component was demonstrated in all cases, utilizing either light chain restriction (5 cases) or clonal immunoglobulin heavy chain gene rearrangement by polymerase chain reaction (PCR) (2 cases). One case was confirmed to be monoclonal by both techniques. Additionally, no clonal rearrangements of the T-cell receptor gamma gene were observed. There was considerable morphological variety in these cases. In H&E stained sections, the differential diagnosis included pseudolymphoma, peripheral T-cell lymphoma, Hodgkin's disease, Lennert's lymphoma and a MALT lymphoma. A significant component of monoclonal plasma cells was present in 3 of 6 cases, suggesting a possible origin from cutaneous immunocytoma. In fact, one of our cases was a biphasic lymphoma displaying TRBL with a small focus of immunocytoma. We conclude that immunophenotypic analysis is necessary for the diagnosis of TRBL. Pathologists should be aware of this type of cutaneous B-cell lymphoma to avoid misinterpretation as a pseudolymphoma.

Cutaneous lymphomas are a heterogeneous group of lymphomas that show variations in histology, immunophenotype, and prognosis. At the time of presentation, cutaneous lymphomas may be primary or may involve the skin as a secondary site of involvement. Primary cutaneous lymphomas, in many instances, are distinct from morphologically similar lymphomas arising in lymph nodes. Their natural history is often more indolent than nodal lymphomas, and for that reason, they often require different therapeutic approaches. A classification scheme should recognize those lymphomas that are unique to the skin, as well as those arising in other sites. The mode of presentation of a lymphoma is often an indication of underlying biological distinctions. However, organ-specific classification systems undermine communication among medical specialists. The World Health Organization classification of hematopoietic and lymphoid malignancies offers a comprehensive approach and proposes that lymphomas should be viewed as a list of individual diseases and that each disease can be defined by a constellation of morphological, biological, and clinical features. The current review will focus on the spectrum of primary and secondary cutaneous lymphomas, emphasizing those features of importance to the clinical oncologist.

Dermatoscopy and high frequency sonography have recently been combined to increase diagnostic preoperative accuracy in the treatment of pigmented skin lesions. In this monocentric study 80 patients with pigmented skin lesions were evaluated clinically, by dermatoscopy, and 20 MHz‐sonography followed by dermatohistopathological evaluation; 39 malignant melanomas, 37 common nevi, 3 dysplastic nevi, and 1 nevus Spitz were diagnosed histologically. In 72 of the 80 cases (91.3%) dermatoscopical diagnoses were confirmed by histopathology, compared to only 79% correct clinical diagnoses. For the mere clinical diagnosis of melanoma sensitivity was 79%, specificity was 78% and diagnostic accuracy was 65%. All diagnostic values increased by dermatoscopy: sensitivity reached 90%, specificity was 93%, and diagnostic accuracy was 83%. In order to determine tumor thickness preoperatively tumor thickness was measured by 20 MHz sonography. The correlation of tumor thickness between histometric and sonographic results was determined for nevi (r = 0.93) and melanoma (r = 0.95); 74.3% of melanomas were diagnosed correctly within an 0.2 mm range. Regarding the clinical important limit of 1 mm tumor thickness, 87.2% were diagnosed in accordance with histometric evaluation. An increase of 18% in diagnostic accuracy by dermatoscopy and 87.2% of correctly diagnosed cases of tumor thickness of malignant melanoma by high frequency sonography clearly demonstrate that these methods should be considered standard procedures in the diagnosis of pigmented skin lesions and will facilitate the decision on necessary surgical treatment.