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Purpose: The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer.
Methods: The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure.
Recommendations: Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.
Ziele: Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) und der Deutschen Krebsgesellschaft (DKG) publiziert und koordiniert wurde, ist es, die Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms zu optimieren.
Methoden: Der Aktualisierungsprozess der S3-Leitlinie aus 2012 basierte zum einen auf der Adaptation identifizierter Quellleitlinien und zum anderen auf Evidenzübersichten, die nach Entwicklung von PICO-(Patients/Interventions/Control/Outcome-)Fragen, systematischer Recherche in Literaturdatenbanken sowie Selektion und Bewertung der gefundenen Literatur angefertigt wurden. In den interdisziplinären Arbeitsgruppen wurden auf dieser Grundlage Vorschläge für Empfehlungen und Statements erarbeitet, die im Rahmen von strukturierten Konsensusverfahren modifiziert und graduiert wurden.
Empfehlungen: Der Teil 1 dieser Kurzversion der Leitlinie zeigt Empfehlungen zur Früherkennung, Diagnostik und Nachsorge des Mammakarzinoms: Der Stellenwert des Mammografie-Screenings wird in der aktualisierten Leitlinienversion bestätigt und bildet damit die Grundlage der Früherkennung. Neben den konventionellen Methoden der Karzinomdiagnostik wird die Computertomografie (CT) zum Staging bei höherem Rückfallrisiko empfohlen. Die Nachsorgekonzepte beinhalten Untersuchungsintervalle für die körperliche Untersuchung, Ultraschall und Mammografie, während weiterführende Gerätediagnostik und Tumormarkerbestimmungen bei der metastasierten Erkrankung Anwendung finden.
The large conductance voltage- and Ca2+-activated potassium (BK) channel has been suggested to play an important role in the signal transduction process of cochlear inner hair cells. BK channels have been shown to be composed of the pore-forming alpha-subunit coexpressed with the auxiliary beta-1-subunit. Analyzing the hearing function and cochlear phenotype of BK channel alpha-(BKalpha–/–) and beta-1-subunit (BKbeta-1–/–) knockout mice, we demonstrate normal hearing function and cochlear structure of BKbeta-1–/– mice. During the first 4 postnatal weeks also, BKalpha–/– mice most surprisingly did not show any obvious hearing deficits. High-frequency hearing loss developed in BKalpha–/– mice only from ca. 8 weeks postnatally onward and was accompanied by a lack of distortion product otoacoustic emissions, suggesting outer hair cell (OHC) dysfunction. Hearing loss was linked to a loss of the KCNQ4 potassium channel in membranes of OHCs in the basal and midbasal cochlear turn, preceding hair cell degeneration and leading to a similar phenotype as elicited by pharmacologic blockade of KCNQ4 channels. Although the actual link between BK gene deletion, loss of KCNQ4 in OHCs, and OHC degeneration requires further investigation, data already suggest human BK-coding slo1 gene mutation as a susceptibility factor for progressive deafness, similar to KCNQ4 potassium channel mutations. © 2004, The National Academy of Sciences. Freely available online through the PNAS open access option.
Oligonucleotides suppress PKB/Akt and act as superinductors of apoptosis in human keratinocytes
(2009)
DNA oligonucleotides (ODN) applied to an organism are known to modulate the innate and adaptive immune system. Previous studies showed that a CpG-containing ODN (CpG-1-PTO) and interestingly, also a non-CpG-containing ODN (nCpG- 5-PTO) suppress inflammatory markers in skin. In the present study it was investigated whether these molecules also influence cell apoptosis. Here we show that CpG-1-PTO, nCpG-5-PTO, and also natural DNA suppress the phosphorylation of PKB/Akt in a cell-type-specific manner. Interestingly, only epithelial cells of the skin (normal human keratinocytes, HaCaT and A-431) show a suppression of PKB/Akt. This suppressive effect depends from ODN lengths, sequence and backbone. Moreover, it was found that TGFa-induced levels of PKB/Akt and EGFR were suppressed by the ODN tested. We hypothesize that this suppression might facilitate programmed cell death. By testing this hypothesis we found an increase of apoptosis markers (caspase 3/7, 8, 9, cytosolic cytochrome c, histone associated DNA fragments, apoptotic bodies) when cells were treated with ODN in combination with low doses of staurosporin, a wellknown pro-apoptotic stimulus. In summary the present data demonstrate DNA as a modulator of apoptosis which specifically targets skin epithelial cells.
Mit einiger Berechtigung könnte man das 19. Jahrhundert nicht nur als Jahrhundert nationaler Einheitstendenzen, sondern auch als Jahrhundert der Diversität beschreiben: einerseits der biologischen Diversität, insofern die Anzahl der bekannten Arten exponentiell zunimmt und die Evolutionslehre den Naturprozess selbst als Entstehung organischer Diversität bestimmt, andererseits aber auch als Jahrhundert der kulturellen und sozialen Diversifizierung: Unübersehbarkeit des empirischen Wissens, Differenzierung der Disziplinen, Vervielfältigung der kulturellen Tendenzen, Pluralisierung der Lebensformen und Weltanschauungen, die - mit Nietzsches Formulierung - "unkräftige Vielseitigkeit des modernen Lebens", all das gehört jedenfalls zu den gängigen Selbstbeschreibungen der Zeit. Dabei taucht Diversität in den Gegenwartsdiagnosen um 1900 weniger als Wert oder gar Forderung auf, sondern vor allem als krisenhaft oder ambivalent wahrgenommenes Phänomen
Biodiversity is a cornerstone of human health and well-being. However, while evidence of the contributions of nature to human health is rapidly building, research into how biodiversity relates to human health remains limited in important respects. In particular, a better mechanistic understanding of the range of pathways through which biodiversity can influence human health is needed. These pathways relate to both psychological and social processes as well as biophysical processes. Building on evidence from across the natural, social and health sciences, we present a conceptual framework organizing the pathways linking biodiversity to human health. Four domains of pathways—both beneficial as well as harmful—link biodiversity with human health: (i) reducing harm (e.g. provision of medicines, decreasing exposure to air and noise pollution); (ii) restoring capacities (e.g. attention restoration, stress reduction); (iii) building capacities (e.g. promoting physical activity, transcendent experiences); and (iv) causing harm (e.g. dangerous wildlife, zoonotic diseases, allergens). We discuss how to test components of the biodiversity-health framework with available analytical approaches and existing datasets. In a world with accelerating declines in biodiversity, profound land-use change, and an increase in non-communicable and zoonotic diseases globally, greater understanding of these pathways can reinforce biodiversity conservation as a strategy for the promotion of health for both people and nature. We conclude by identifying research avenues and recommendations for policy and practice to foster biodiversity-focused public health actions.
Background In melanoma, preclinical data suggest a possible role of polyunsaturated fatty acids inhibiting cell growth. A new target molecule for free fatty acids, the G protein-coupled receptor GPR40, was identified in melanoma cells.
Objectives The aim of this study was to investigate GPR40 expression in human melanocytic tissues and to evaluate its potential as a prognostic marker.
Methods and Results A total of 114 tissue sections of naevi, primary melanoma and melanoma metastasis were immunohistochemically stained with anti-GPR40. The staining was evaluated, using the immunoreactivity scoring system. Compared to naevi, primary melanoma and melanoma metastasis showed significantly higher levels of GPR40 (P < 0.05). In primary melanoma, GPR40 expression positively correlated with tumour thickness (P = 0.044) and AJCC level (P = 0.017) and in melanoma metastasis with AJCC level (P = 0.035). Primary melanoma patients with high levels of GPR40 had a significantly poorer overall survival (P = 0.004) and shorter disease-free survival (0.040).
Conclusion The present study identified GPR40 as a novel target molecule in melanoma. First evidence for a potential role of the receptor in tumour progression and metastases was found, and it could be demonstrated that GPR40 expression is negatively correlated with patient’s survival.
[Nachruf] Willy Hilgenberg
(2013)
Kleidung verweist im Märchen auf bestimmte Eigenschaften der Protagonisten. Innere und äußere Schönheit stimmen überein. Die entsprechende Kleidung bewirkt, dass im Märchen auch immer das Gute, der/die edelmütige Held/in siegt. Es zeigt aber auch, dass nur die 'Guten' die ihnen zustehenden schönen Kleidungsstücke verdienen. Oft ist es so, dass die Helden zu Beginn des Märchens als von der Umwelt verachtete, in armseligen Kleidern und auf der niedrigsten sozialen Stufe stehende Figuren beschrieben werden. Held und Heldin machen ihr Glück, was stets auch mit einem sozialen Aufstieg verbunden ist. Aber auch die Realität zeigt, dass Menschen oft den Wunsch hatten und noch haben, eine andere Identität anzunehmen, um ihre Lebenssituation bzw. ihre Lebensumstände zu verbessern. Als wichtiges Medium solch eines Identitätswandels dient die Kleidung. Ein prägnantes Beispiel dafür ist der 'Hauptmann von Köpenick'.
In zwei bemerkenswerten Feuilletons hat der österreichische Expressionist Robert Müller eine Gesamtcharakteristik des Schriftstellers Gustav Meyrink entworfen. Sie liest sich, als solle bewiesen werden, daß die - erst später und am historischen Gegenstand des barocken Trauerspiels entfaltete - Benjaminsche Kategorie des Allegorischen auf die zeitgenössische Literatur anwendbar sei. Geschrieben zu eben der Zeit, in der Benjamin, nicht zuletzt unter dem Eindruck des Expressionismus, sein Buch 'Über das deutsche Trauerspiel' zu konzipieren begann, umkreisen Müllers Aufsätze den melancholischen Blick eines Autors, dem die Welt insgesamt zum Gegenstand einer allegorischen Lektüre gerät: Meyrink versuche "Chiffren (alles Leben ist Bild) in Sprache umzusetzen", so Müller in seiner Rezension des 1916 veröffentlichten Romans 'Das grüne Gesicht', den er als Fortsetzung des ein Jahr zuvor erschienen Erfolgsbuchs 'Der Golem' begreift. In seinen "Grenzmenschen" gehe "das Tote um, Erstarrtes", sie seien "unverwendbar für das Leben des Lesers".
Die Prinzipien der Meyrinkschen Darstellungsweise erläutert Müller eingehender: "Es fehlt seinem Geschriebenen an Einmaligkeit und Präzision. Er hat keinen Humor, denn er ist ein Pathetiker bis zum Unerträglichen, aber er hat Komik, sein Witz eben ist pathetisch, es ist eine Komik, die ganz aus den Worten kommt wie seine Melancholie, sein verzehrender Pessimismus, seine Mystik, die oft zu den tiefsten Dingen geht. Wo er chaotisch ist, an den Wurzeln des Denkens, im Fegefeuer der Sprache, wird er symptomatisch für das Zeiterlebnis, das einen wissenschaftlichen Nihilismus, eine Aufklärung wider das Gelehrtendogma kennt. Das Leben erscheint als Kreislauf von Motiven, Worte, nein Wörter stehen pflanzenhaft, als Fetische des Geschehens, im Mittelpunkt. Er denkt in Sprachprämien, das Phonetische einer Prägung ist nichts Zufälliges, sondern eine Verwandtschaft, die Lautanalogie sozusagen zum Urgrunde alles Seins. [...] Meyrinks Schreibeakt chiffriert das Leben, in diesen Kürzungen und Kraftworten kommen die sonderbaren Leitmotive, die das Weltgeschehen ins Kreisen bringen, in einer Art Nebelplastik, wie Wolken, die über das Bewußtsein ziehen, zum Ausdruck."
Since the domestication of the urus, 10.000 years ago, mankind utilizes bovine milk for different purposes. Besides usage as a nutrient also the external application of milk on skin has a long tradition going back to at least the ancient Aegypt with Cleopatra VII as a great exponent. In order to test whether milk has impact on skin physiology, cultures of human skin fibroblasts were exposed to commercial bovine milk. Our data show significant induction of proliferation by milk (max. 2,3-fold, EC50: 2,5% milk) without toxic effects. Surprisingly, bovine milk was identified as strong inducer of collagen 1A1 synthesis at both, the protein (4-fold, EC50: 0,09% milk) and promoter level. Regarding the underlying molecular pathways, we show functional activation of STAT6 in a p44/42 and p38-dependent manner. More upstream, we identified IGF-1 and insulin as key factors responsible for milk-induced collagen synthesis. These findings show that bovine milk contains bioactive molecules that act on human skin cells. Therefore, it is tempting to test the herein introduced concept in treatment of atrophic skin conditions induced e.g. by UV light or corticosteroids.
Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.
Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).
Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
Background: It has been demonstrated that cognitive behavioural therapy (CBT) has a moderate effect on symptom reduction and on general well being of patients suffering from psychosis. However, questions regarding the specific efficacy of CBT, the treatment safety, the cost-effectiveness, and the moderators and mediators of treatment effects are still a major issue. The major objective of this trial is to investigate whether CBT is specifically efficacious in reducing positive symptoms when compared with non-specific supportive therapy (ST) which does not implement CBT-techniques but provides comparable therapeutic attention. Methods: The POSITIVE study is a multicenter, prospective, single-blind, parallel group, randomised clinical trial, comparing CBT and ST with respect to the efficacy in reducing positive symptoms in psychotic disorders. CBT as well as ST consist of 20 sessions altogether, 165 participants receiving CBT and 165 participants receiving ST. Major methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, analysis by intention to treat, data management using remote data entry, measures of quality assurance (e.g. on-site monitoring with source data verification, regular query process), advanced statistical analysis, manualized treatment, checks of adherence and competence of therapists. Research relating the psychotherapy process with outcome, neurobiological research addressing basic questions of delusion formation using fMRI and neuropsychological assessment and treatment research investigating adaptations of CBT for adolescents is combined in this network. Problems of transfer into routine clinical care will be identified and addressed by a project focusing on cost efficiency. Discussion: This clinical trial is part of efforts to intensify psychotherapy research in the field of psychosis in Germany, to contribute to the international discussion on psychotherapy in psychotic disorders, and to help implement psychotherapy in routine care. Furthermore, the study will allow drawing conclusions about the mediators of treatment effects of CBT of psychotic disorders. Trial Registration Current Controlled Trials ISRCTN29242879
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
The project focuses on the efficiency of combined technologies to reduce the release of micropollutants and bacteria into surface waters via sewage treatment plants of different size and via stormwater overflow basins of different types. As a model river in a highly populated catchment area, the river Schussen and, as a control, the river Argen, two tributaries of Lake Constance, Southern Germany, are under investigation in this project. The efficiency of the different cleaning technologies is monitored by a wide range of exposure and effect analyses including chemical and microbiological techniques as well as effect studies ranging from molecules to communities.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
Mechanical stress is known to modulate fundamental events such as cell life and death. Mechanical stretch in particular has been identified as a positive regulator of proliferation in skin keratinocytes and other cell systems. In the present study it was investigated whether antiapoptotic signaling is also stimulated by mechanical stretch. It was demonstrated that mechanical stretch rapidly induced the phosphorylation of the proto-oncogene protein kinase B (PKB)/Akt at both phosphorylation sites (serine 473/threonine 308) in different epithelial cells (HaCaT, A-431, and human embryonic kidney-293). Blocking of phosphoinositide 3-OH kinase by selective inhibitors (LY-294002 and wortmannin) abrogated the stretch-induced PKB/Akt phosphorylation. Furthermore mechanical stretch stimulated phosphorylation of epidermal growth factor receptor (EGFR) and the formation of EGFR membrane clusters. Functional blocking of EGFR phosphorylation by either selective inhibitors (AG1478 and PD168393) or dominant-negative expression suppressed stretch-induced PKB/Akt phosphorylation. Finally, the angiotensin II type 1 receptor (AT1-R) was shown to induce positive transactivation of EGFR in response to cell stretch. These findings define a novel signaling pathway of mechanical stretch, namely the activation of PKB/Akt by transactivation of EGFR via angiotensin II type 1 receptor. Evidence is provided that stretch-induced activation of PKB/Akt protects cells against induced apoptosis.