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The Charité – Universitätsmedizin Berlin is the oldest and most prominent hospital and medical school in Berlin. Acting today as the medical school for both the Humboldt University and Freie Universität Berlin, Charité is one of the largest university hospitals in Europe. With numerous Collaborative Research Centers of the Deutsche Forschungsgemeinschaft, Charité is one of Germany's most research-intensive medical institutions. Wikipedia.


Reshetnik A.,Charite - Medical University of Berlin
Blood Pressure Monitoring | Year: 2016

OBJECTIVE: Hypertension is a major cardiovascular risk factor. Therefore, the accuracy of blood pressure (BP) measurement with self-measuring devices is of fundamental importance. Consequently, emerging BP devices should be evaluated against the gold standard according to an established and proven protocol. METHODS: Tel-O-GRAPH, a new oscillometric self-measuring device of brachial BP, was evaluated against auscultatory sphygmomanometry according to the BHS protocol. Bland–Altman plots were completed for systolic (SBP) and diastolic blood pressures (DBP), and the mean differences and SDs between the test device and the reference device were computed for all BP values. RESULTS: A total of 85 individuals (mean age 48.11±18.0 years; 61% men) were included after they provided informed consent. Overall, 510 measurements were performed. The mean device–observer difference was −0.2±6.6 for SBP and 0.2±6.6 for DBP. The device achieved grade A for SBP and DBP for both observers. Examination of the different BP ranges indicated grade B for SBP more than 160 mmHg and grade A for all BP ranges. CONCLUSION: Tel-O-GRAPH fulfilled the accuracy requirements of the BHS with the highest accuracy level (A) and can thus be used reliably in the oscillometric measurement of the brachial BP. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Lichtner G.,Charite - Medical University of Berlin
Clinical Journal of Pain | Year: 2015

OBJECTIVE:: To reanalyze scoring criteria for automatic detection of nociceptive flexion reflexes (NFR) in electromyography (EMG) recordings and to improve detection accuracy by accounting for multiple characteristics of the recordings, such as baseline noise level or sampling rate. METHODS:: Single scoring criteria for the NFR were re-analyzed and validated against an independent dataset. To account for influences on the single scoring criteria, such as the baseline noise, multivariate classification models were derived. RESULTS:: Re-analysis of single scoring criteria yielded significantly lower threshold values than previously reported. The threshold value of the best performing single scoring criterion, the NFR Interval Peak z-score, was found to be strongly dependent on the level of baseline noise and the EMG sampling rate. Multivariate classification models could reduce the number of incorrectly classified recordings in an independent dataset by 25-37% compared to the best performing single scoring criterion. DISCUSSION:: The automatic detection of reflex responses in electromyograms can be significantly improved by including multiple reflex, baseline and EMG characteristics into a classification model. These findings should help to improve the accuracy of currently used standard measurement algorithms and algorithms engineered towards specific properties, such as short measurements or less induced pain for the subjects. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Numerous interventions such as avoidance of food allergens, prolonged breast feeding and supplementation of proand/or prebiotics have been tried as primary prevention of atopic dermatitis. Recent data suggest that prevention of infantile eczema is possible in a subgroup of children by feeding bacterial lysates early in life. Bacterial lysates of Escherichia coli and Enterococcus faecalis were found to impair allergic immune responses in rats. An interventional trial in 606 infants at risk for atopy showed a reduction of atopic dermatitis at the end of the treatment phase (month 2 until month 7) of 50% in a subgroup of children with single heredity for atopy. This was even more pronounced in the group of children with paternal heredity for atopy. This effect was still seen at age 1 year. There was no effect on food sensitisation. In conclusion, an immune modulation in terms of prevention of atopic dermatitis in infancy if single atopic family history is present seems to be possible by feeding bacterial lysates early in life. © 2013 Wageningen Academic Publishers.


Liepe J.,Charite - Medical University of Berlin
PLoS computational biology | Year: 2010

The identification of proteasome-generated spliced peptides (PSP) revealed a new unpredicted activity of the major cellular protease. However, so far characterization of PSP was entirely dependent on the availability of patient-derived cytotoxic CD8+ T lymphocytes (CTL) thus preventing a systematic investigation of proteasome-catalyzed peptide splicing (PCPS). For an unrestricted PSP identification we here developed SpliceMet, combining the computer-based algorithm ProteaJ with in vitro proteasomal degradation assays and mass spectrometry. By applying SpliceMet for the analysis of proteasomal processing products of four different substrate polypeptides, derived from human tumor as well as viral antigens, we identified fifteen new spliced peptides generated by PCPS either by cis or from two separate substrate molecules, i.e., by trans splicing. Our data suggest that 20S proteasomes represent a molecular machine that, due to its catalytic and structural properties, facilitates the generation of spliced peptides, thereby providing a pool of qualitatively new peptides from which functionally relevant products may be selected.


Winkelmann A.,Charite - Medical University of Berlin
Annals of Anatomy | Year: 2015

Heinrich von Eggeling (1869-1954), professor of anatomy in Breslau from 1922, was secretary of the Anatomische Gesellschaft (AG) from 1919 until 1949 and also editor of the Anatomischer Anzeiger, today's Annals of Anatomy. His ". Wissenschaftlicher Nachlass [scientific estate]" could recently be located in private hands and has now been made available at the archive of the AG held by the current secretary. It consists of 45 folders, mainly containing von Eggeling's national and international correspondence from 1919 to 1953. It thus covers the times of the Weimar republic and of the "Third Reich" as well as the post-war period, when the AG had been officially closed down by the Allied Control Council and was eventually re-founded in 1949. Von Eggeling preserved this material despite war destruction of his Berlin home, where he lived after his retirement in 1935, and his cramped post-war confines in a small town near Hannover. The estate also includes autobiographical manuscripts of von Eggeling and some material from his predecessor, the first secretary of the AG since 1886, Karl von Bardeleben (1849-1918). There is evidence that the correspondence is not complete, even if there are no significant time gaps. The contents suggest that letters deemed insignificant, like fee reminders or editorial decisions, were discarded at some point, but it remains unclear by whom. This estate fills a significant gap in the historical material related to the AG and will be an important source for any future historical investigation regarding the society. © 2015 Elsevier GmbH.


Kringelbach M.L.,University of Oxford | Kringelbach M.L.,University of Aarhus | McIntosh A.R.,Rotman Research Institute | Ritter P.,Max Planck Institute for Human Cognitive and Brain Sciences | And 3 more authors.
Trends in Cognitive Sciences | Year: 2015

Slowness of thought is not necessarily a handicap but could be a signature of optimal brain function. Emerging evidence shows that neuroanatomical and dynamical constraints of the human brain shape its functionality in optimal ways, characterized by slowness during task-based cognition in the context of spontaneous resting-state activity. This activity can be described mechanistically by whole-brain computational modeling that relates directly to optimality in the context of theories arguing for metastability in the brain. We discuss the role for optimal processing of information in the context of cognitive, task-related activity, and propose that combining multi-modal neuroimaging and explicit whole-brain models focused on the timing of functional dynamics can help to uncover fundamental rules of brain function in health and disease. The dynamics of the human brain exhibits 'slowness' during spontaneous activity and task-based cognition.Whole-brain computational modeling can account for the mechanisms underlying this slowness in terms of maximal metastability of the dynamical system.A better understanding of the balance between fast and slow brain processing could lead to fundamental new insights into the brain in health and disease. © 2015 Elsevier Ltd.


Turpie A.G.G.,McMaster University | Kreutz R.,Charite - Medical University of Berlin | Llau J.,Hospital Clinico | Norrving B.,Lund University | Haas S.,TU Munich
Thrombosis and Haemostasis | Year: 2012

A number of novel oral anticoagulants that directly target factor Xa or thrombin have been developed in recent years. Rivaroxaban and apixa-ban (direct factor Xa inhibitors) and dabigatran etexilate (a direct throm-bin inhibitor) have shown considerable promise in large-scale, random -ised clinical studies for the management of thromboembolic disorders, and have been approved for clinical use in specific indications. Rivar-oxaban is licensed for the prevention of venous thromboembolism in patients undergoing elective hip or knee replacement surgery, the treatment of deep-vein thrombosis and prevention of recurrent venous thromboem-bolism, and for stroke prevention in patients with non-valvular atrial fibrillation. Based on the clinical trial data for rivaroxaban, feedback on its use in clinical practice and the authors' experience with the use of riva -roxaban, practical guidance for the use of rivaroxaban in special patient populations and specific clinical situations is provided. Although most recommendations are in line with the European summary of product characteristics for the approved indications, additional and, in several areas, different recommendations are given based on review of the literature and the authors' clinical experience. © Schattauer 2012.


Holzhauer S.,Charite - Medical University of Berlin | Zieger B.,Albert Ludwigs University of Freiburg
Seminars in Fetal and Neonatal Medicine | Year: 2011

Thrombocytopenia is the most common haematological abnormality in newborns admitted to neonatal care units and serves as an important indicator of underlying pathological processes of mother or child. In most cases thrombocytopenia is mild to moderate and resolves within the first weeks of life without any intervention. However, in some neonates thrombocytopenia is severe or may reflect an inborn platelet disorder. As clinical course and outcome of thrombocytopenia depend on the aetiology of thrombocytopenia, an appropriate work-up is essential to guide therapy in neonates with thrombocytopenia and to avoid severe bleeding. © 2011.


Denkert C.,Charite - Medical University of Berlin
Seminars in immunopathology | Year: 2011

Several studies suggest that the progression of malignant tumors as well as the response to chemotherapy and targeted therapy is critically dependent on the immunological parameters that are derived from the host immune system as well as a modulation of the immune system by therapeutic antibodies. It has been shown for many tumor types that the presence of a lymphocytic infiltrate in different types of cancers is a positive factor for clinical outcome and that the response to neoadjuvant chemotherapy is increased in a tumor with a prominent pretherapeutic infiltrate. Furthermore, new targeted therapies in breast cancer, such as trastuzumab, as well as in hematological malignancies, such as rituximab and alemtuzumab, have been shown to interact with immunological pathways, and this interaction is critical for response and clinical outcome. In neoplasms of lymphoid and hematopoietic tissues, targeted therapies not only reduce toxic effects on normal tissues but also lead to modulations of the immune system depending on the target molecule, its physiological function and cellular distribution. This review gives an overview on clinical data on response to classical chemotherapy as well as molecular targeted therapy and its interaction with the immune system.


Sander L.E.,Charite - Medical University of Berlin
BioEssays | Year: 2012

Recent advances have highlighted the outstanding role of the innate immune system for instructing adaptive immunity. Translating this knowledge into successful immunotherapies like vaccines, however, has proven to be a difficult task. This essay is based on the hypothesis that immune responses are tightly scaled to the infectious threat posed by a given microbial stimulus. A meticulous immunological risk-assessment process is therefore instrumental for eliciting well-balanced responses and maintaining immune homeostasis. The immune system makes fine distinctions, for example, between live and dead bacteria, or pathogenic and non-pathogenic microorganisms. Here, I discuss recent evidence for some of the mechanisms underlying these distinctions and speculate on strategies for therapeutically targeting the immunological risk-assessment machinery. © 2012 WILEY Periodicals, Inc.


Akabane S.,Tokyo Medical University | Ueda T.,Tokyo Medical University | Nierhaus K.H.,Charite - Medical University of Berlin | Takeuchi N.,Tokyo Medical University
PLoS Genetics | Year: 2014

Release factors (RFs) govern the termination phase of protein synthesis. Human mitochondria harbor four different members of the class 1 RF family: RF1Lmt/mtRF1a, RF1mt, C12orf65 and ICT1. The homolog of the essential ICT1 factor is widely distributed in bacteria and organelles and has the peculiar feature in human mitochondria to be part of the ribosome as a ribosomal protein of the large subunit. The factor has been suggested to rescue stalled ribosomes in a codon-independent manner. The mechanism of action of this factor was obscure and is addressed here. Using a homologous mitochondria system of purified components, we demonstrate that the integrated ICT1 has no rescue activity. Rather, purified ICT1 binds stoichiometrically to mitochondrial ribosomes in addition to the integrated copy and functions as a general rescue factor, i.e. it releases the polypeptide from the peptidyl tRNA from ribosomes stalled at the end or in the middle of an mRNA or even from non-programmed ribosomes. The data suggest that the unusual termination at a sense codon (AGA/G) of the oxidative-phosphorylation enzymes CO1 and ND6 is also performed by ICT1 challenging a previous model, according to which RF1Lmt/mtRF1a is responsible for the translation termination at non-standard stop codons. We also demonstrate by mutational analyses that the unique insertion sequence present in the N-terminal domain of ICT1 is essential for peptide release rather than for ribosome binding. The function of RF1mt, another member of the class1 RFs in mammalian mitochondria, was also examined and is discussed. © 2014 Akabane et al.


BROCKMANN C.,Charite - Medical University of Berlin
Retina | Year: 2016

PURPOSE:: To identify predictors of treatment response by evaluating long-term outcomes of vasoproliferative retinal tumors after ruthenium-106 brachytherapy. METHODS:: In a retrospective case series, 39 eyes of 38 patients with vasoproliferative retinal tumors received ruthenium-106 brachytherapy between 2001 and 2013. Baseline clinical and morphologic parameters were analyzed regarding posttreatment tumor activity status. RESULTS:: Within a median follow-up period of 2.9 ± 2.9 years, overall, a tumor inactivation was achieved in 72% of cases and visual acuity remained stable in 69%. The mean apex dose was 90 ± 23 Gy (range, 51–140 Gy). Mean tumor thickness decreased significantly, from 2.9 ± 0.9 mm to 1.5 ± 1.0 mm (P < 0.001; paired t-test). Persistence or recurrence of tumor activity occurred in 28% of cases, requiring secondary intervention with intravitreal drug injections, vitrectomy, cryotherapy, or repeated brachytherapy. Comparison of inactive and active vasoproliferative retinal tumors revealed significant correlation between both initial basal tumour diameter and area and subsequent tumour activity status. In particular, a diameter >7.5 mm was associated with an 8-fold risk of persistent or recurrent activity, whereas basal area >40 mm demonstrated a 6-fold risk (P = 0.009 and 0.021, respectively; Fisherʼs exact-test). In contrast, tumor thickness was not found to be of prognostic relevance. CONCLUSION:: Ruthenium-106 brachytherapy is an effective and safe therapeutic option for vasoproliferative retinal tumors. Additionally, tumor diameter and area are efficient predictors of persistence or recurrence of tumor activity. © 2016 by Ophthalmic Communications Society, Inc.


Vogtmann T.,Charite - Medical University of Berlin
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | Year: 2013

Automated, daily Home Monitoring (HM) of pacemaker and implantable cardioverter-defibrillator (ICD) patients can improve patient care. Yet, HM introduction to routine clinical practice is challenged by resource allocation for regular HM data review. We tested the feasibility, safety, workload, and clinical usefulness of a centralized HM model consisting of one monitor centre and nine satellite clinics. Having no knowledge about patients' clinical data, a telemonitoring nurse (TN) and a supporting physician at the monitor centre screened and filtered HM data in 62 pacemaker and 59 ICD patients from nine satellite clinics for over 1 year. Basic screening of arrhythmic and technical events required 25.7 min (TN) and 0.7 min (physician) per working day, normalized for 100 patients monitored. Communication of relevant events to satellite clinics per email or phone required additional 4.3 min (TN) and 0.4 min (physician). Telemonitoring nurse also screened for abnormal developments in longitudinal data trends weekly for 3 months after implantation, and then monthly; one patient session lasted 4.0 ± 2.9 min. To handle transmission-gap notifications, TN needed additional 2.8 min daily. Satellite clinics received 231.3 observations from the monitor centre per 100 patients/year, which prompted 86.3 patient contacts or intensive HM screening periods by the satellite clinic itself (37.3% response rate), 51.7 extra follow-up controls (22.3%), and 30.1 clinical interventions (13.0%). Centralized HM was feasible, reliable, safe, and clinically useful. Basic screening and communication of relevant arrhythmic and technical events required a total of 30 min (TN) and 1.1 min (physician) daily per 100 patients monitored.


de Grahl C.,Charite - Medical University of Berlin
German medical science : GMS e-journal | Year: 2012

To date there are only a few studies published, dealing with delirium in critically ill patients. The problem with these studies is that prevalence rates of delirium could only be estimated because of the lack of validated delirium assessment tools for the paediatric intensive care unit (PICU). The paediatric Confusion Assessment Method for the Intensive Care Unit (pCAM-ICU) was specifically developed and validated for the detection of delirium in PICU patients. The purpose of this study was the translation of the English pCAM-ICU into German according to international validated guidelines. The translation process was performed according to the principles of good practice for the translation and cultural adaptation process for patient reported outcomes measures: From three independently created German forward-translation versions one preliminary German version was developed, which was then retranslated to English by a certified, state-approved translator. The back-translated version was submitted to the original author for evaluation. The German translation was evaluated by clinicians and specialists anonymously (German grades) in regards to language and content of the translation. The results of the cognitive debriefing revealed good to very good results. After that the translation process was successfully completed and the final version of the German pCAM-ICU was adopted by the expert committee. The German version of the pCAM-ICU is a result of a translation process in accordance with internationally acknowledged guidelines. Particularly, with respect to the excellent results of the cognitive debriefing, we could finalise the translation and cultural adaptation process for the German pCAM-ICU.


Dirnagl U.,Charite - Medical University of Berlin
Stroke | Year: 2016

Based on research, mainly in rodents, tremendous progress has been made in our basic understanding of the pathophysiology of stroke. After many failures, however, few scientists today deny that bench-to-bedside translation in stroke has a disappointing track record. I here summarize many measures to improve the predictiveness of preclinical stroke research, some of which are currently in various stages of implementation: We must reduce preventable (detrimental) attrition. Key measures for this revolve around improving preclinical study design. Internal validity must be improved by reducing bias; external validity will improve by including aged, comorbid rodents of both sexes in our modeling. False-positives and inflated effect sizes can be reduced by increasing statistical power, which necessitates increasing group sizes. Compliance to reporting guidelines and checklists needs to be enforced by journals and funders. Customizing study designs to exploratory and confirmatory studies will leverage the complementary strengths of both modes of investigation. All studies should publish their full data sets. On the other hand, we should embrace inevitable NULL results. This entails planning experiments in such a way that they produce high-quality evidence when NULL results are obtained and making these available to the community. A collaborative effort is needed to implement some of these recommendations. Just as in clinical medicine, multicenter approaches help to obtain sufficient group sizes and robust results. Translational stroke research is not broken, but its engine needs an overhauling to render more predictive results. © 2016 American Heart Association, Inc.


Wolf S.,Charite - Medical University of Berlin
Current Opinion in Critical Care | Year: 2015

Purpose of review The amount of blood in the basal cisterns is predictive for the final outcome after aneurysmal subarachnoid hemorrhage (SAH) and clinical problems such as delayed cerebral ischemia and angiographic vasospasm. A lumbar drainage presents an additional, physiologically appealing treatment. In contrast to an external ventricular drain, stasis of clots is thought to be prevented and clearance of the basal cisterns accelerated. In theory, patients with higher clinical grades and dense layers of subarachnoid blood should benefit most. Recent findings A positive signal but so far no conclusive evidence for lumbar drains in SAH is available from retrospective data. Two large series exist, one after clipping and one after endovascular coiling of the aneurysm leading to the index hemorrhage. The only high-quality large prospective trial failed to prove a better neurologic outcome at 6 months, but investigated predominantly good grade patients with less severe hemorrhage. Further data from another phase III trial is still pending. A concern on the safety of lumbar drains is not supported. Summary At present, no definite conclusions and recommendations on lumbar drains in patients after aneurysmal SAH are warranted. © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Baur X.,Charite - Medical University of Berlin | Bakehe P.,Institute For Arbeitsmedizin Und Maritime Medizin
International Archives of Occupational and Environmental Health | Year: 2014

Purpose: The aim of this work is to provide an evidence-based evaluation and overview of causative substances in order to improve disease management. Methods: We conducted a database search with MEDLINE via PubMed, screened reference lists of relevant reviews and matched our findings with a list of agents denoted as "may cause sensitisation by inhalation" by the phrase H334 (till 2011 R42). After exclusion of inappropriate publications, quality of the selected studies was rated with the Scottish Intercollegiate Guideline Network (SIGN) grading system. The evidence level for each causative agent was graded using the modified Royal College of General Practitioners (RCGP) three-star system. Results: A total of 865 relevant papers were identified, which covered 372 different causes of allergic work-related asthma. The highest level achieved using the SIGN grading system was 2++ indicating a high-quality study with a very low risk of confounding or bias and a high probability of a causal relationship. According to the modified RCGP three-star grading system, the strongest evidence of association with an individual agent, profession or worksite was found to be the co-exposure to various laboratory animals. An association with moderate evidence level was obtained for α-amylase from Aspergillus oryzae, various enzymes from Bacillus subtilis, papain, bakery (flour, amylase, storage mites), western red cedar, latex, psyllium, farming (animals, cereal, hay, straw and storage mites), storage mites, rat, carmine, egg proteins, atlantic salmon, fishmeal, norway lobster, prawn, snow crab, seafood, trout and turbot, reactive dyes, toluene diisocyanates and platinum salts. Conclusion: This work comprises the largest list of occupational agents and worksites causing allergic asthma. For the first time, these agents are assessed in an evidence-based manner. The identified respiratory allergic agents or worksites with at least moderate evidence for causing work-related asthma may help primary care physicians and occupational physicians in diagnostics and management of cases suffering from work-related asthma. Furthermore, this work may possibly provide a major contribution to prevention and may also initiate more detailed investigations for broadening and updating these evidence-based evaluations. © 2013 Springer-Verlag Berlin Heidelberg.


Poddubnyy D.,Charite - Medical University of Berlin
Therapeutic Advances in Musculoskeletal Disease | Year: 2013

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease predominantly affecting the axial skeleton (sacroiliac joints and spine). Nonradiographic axSpA (axSpA without radiographic sacroiliitis) and ankylosing spondylitis (AS; radiographic form of axSpA) are considered nowadays as two consecutive stages of one disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective against the major symptoms of axSpA (pain and stiffness) and may have disease-modifying properties including retarding progression of structural damage in the spine. Therefore, NSAIDs, unless contraindicated, are the treatment of choice for the majority of patients with axSpA. Beyond NSAIDs, only tumour necrosis factor (TNF) α blockers are effective and approved for the treatment of active axSpA. Several novel drugs (i.e. monoclonal antibodies targeting interleukin-17, interleukin-12/23, inhibitors of phosphodiesterase-4 and kinases), which might be effective in axSpA, are currently under investigation. Pharmacological therapy of axSpA should always be combined with nonpharmacological treatment including education and regular exercise/physiotherapy. © The Author(s) 2012.


Parson W.,Innsbruck Medical University | Roewer L.,Charite - Medical University of Berlin
International Journal of Legal Medicine | Year: 2010

This manuscript extends on earlier recommendations of the editor of the International Journal of Legal Medicine on short tandem repeat population data and provides details on specific criteria relevant for the analysis and publication of population studies on haploid DNA markers, i.e. Y-chromosomal polymorphisms and mitochondrial DNA. The proposed concept is based on review experience with the two forensic haploid markers databases YHRD and EMPOP, which are both endorsed by the International Society for Forensic Genetics. The intention is to provide guidance with the preparation of population studies and their results to improve the reviewing process and the quality of published data. We also suggest a minimal set of required information to be presented in the publication to increase understanding and use of the data. The outlined procedure has in part been elaborated with the editors of the journal Forensic Science International Genetics. © The Author(s) 2010.


Tschoppe P.,Charite - Medical University of Berlin
Quintessence international (Berlin, Germany : 1985) | Year: 2010

Hyposalivation is represented by a reduced salivary flow rate and can be caused by etiologic factors such as systemic diseases and intake of various medications or by radiotherapy following head and neck cancer. The aim of this review was to compile data about the qualitative and quantitative changes of salivary components during hyposalivation, and to summarize their consequences for oral health. A Medline/PubMed/Scopus search was conducted to identify and summarize articles published in English and German that reported on etiology of hyposalivation and changes in the salivary composition due to hyposalivation of different origins. The search revealed 94 articles, 71 of which were original articles. Apart from the reduction of the salivary flow rate, the quality of saliva is strongly altered because of systemic diseases, medications, and radiotherapy, including increased viscosity and pH shift to more acidic values and changes in salivary protein compositions. Furthermore, hyposalivation may be accompanied by pronounced shifts in specific microbial components, in particular toward a highly acidogenic microflora. Moreover, therapy of hyposalivation is often restricted to palliative treatment (ie, saliva substitutes or gels). To prevent tooth tissue demineralization, clinicians should consider saliva substitutes that are supersaturated with calcium and phosphates and contain fluoride.


Hassan B.A.,Center for the Biology of Disease | Hiesinger P.R.,Free University of Berlin | Hiesinger P.R.,Charite - Medical University of Berlin
Cell | Year: 2015

Molecular codes, like postal zip codes, are generally considered a robust way to ensure the specificity of neuronal target selection. However, a code capable of unambiguously generating complex neural circuits is difficult to conceive. Here, we re-examine the notion of molecular codes in the light of developmental algorithms. We explore how molecules and mechanisms that have been considered part of a code may alternatively implement simple pattern formation rules sufficient to ensure wiring specificity in neural circuits. This analysis delineates a pattern-based framework for circuit construction that may contribute to our understanding of brain wiring. © 2015 Elsevier Inc.


Francis R.C.,Charite - Medical University of Berlin
Emergency medicine journal : EMJ | Year: 2010

To evaluate the effect of standard operating procedures (SOPs) to improve the completion of patient care documentation items on patient care reports (PCRs) in a physician-staffed, 4500-calls-per-year preclinical ground emergency medical service (EMS) base. Two series of PCRs were analysed before (n=505) and after (n=520) the introduction of SOPs. PCR forms were analysed for the rate of completion of documentation comparing prompted data in check boxes and non-prompted data written in blank spaces at the discretion of the emergency physician. The chi2 test for independence was used to assess the effect of SOPs and prompting on data completion rate. SOPs improved the documentation rate of numerous prompted and non-prompted items, independent of whether these items had a high (eg, Glasgow Coma Score: 91.5% vs 95.7%) or a low documentation rate during the pre-SOP period (eg, allergies: 6.2% vs 18.7%). Prompted items were more frequently documented than non-prompted items, both before and after the introduction of SOPs. Lowest rates were found among non-prompted items (eg, 'last meal' 3.6%). In this EMS base, developing SOPs is an effective tool to improve the quality of PCRs and the rate of completion of documentation items. Check boxes on PCR forms seem to have an important impact as they prompt the initial assessment, treatment and documentation of the actions taken during an EMS call. Consequently, SOPs and check boxes may serve to improve the transition of important information to emergency department staff, and thus contribute to improved patient care.


The new S3 guideline on prostate cancer Includes Imaging modalities applied for early detection, primary diagnosis, and staging of prostate cancer. Detection and primary diagnosis are based on digital rectal examination, serum PSA levels, and prostate biopsy. Among the imaging modalities, MRI shows the highest test quality parameters. Although MRI cannot replace biopsy to prove prostate cancer, its high negative predictive value can help to reduce the number of subsequent biopsies after negative prostate biopsy. For Tstaglng, MRI also demonstrates the highest test quality parameters. Its clinical appllca-tion is limited, since therapeutic consequences are restricted. Due to its high specificity, MRI can save unnecessary pelvic lymph node dissections In patients at high risk for lymph node metastasis (N-staging). Risk-adjusted bone scans, complemented by additional radiological examinations if necessary, remain the standard to assess hematogenous metastasis (M staging). © 2010 Springer-Verlag.


Emery P.,University of Leeds | Emery P.,NIHR Leeds Musculoskeletal Biomedical Research Unit | Dorner T.,Charite - Medical University of Berlin
Annals of the Rheumatic Diseases | Year: 2011

Following a greater understanding of the pathogenesis of rheumatoid arthritis (RA), the treatment of this chronic disease has improved with the availability of biological agents targeting key molecules. Despite this, initial treatment produces an inadequate response in many patients and guidance on the optimal treatment for these patients is needed. Research in specific patient populations aims to define predictive biomarkers of response to identify those patients most likely to benefit from treatment with specific agents. Although there have been conflicting results from studies of various genetic markers, single nucleotide polymorphisms in the tumour necrosis factor (TNF) -308 promoter region may play a role in response to specific TNF inhibitors. Microarray analysis of mRNA expression levels has identified unique sets of genes with differentially regulated expression in responders compared with non-responders to the TNF inhibitor infliximab. Of the various protein biomarkers studied, rheumatoid factor and/or anticitrullinated protein autoantibodies may have a future role in predicting response or guiding the order in which to use biological agents. Further research is needed with larger, well-designed studies to clarify the current understanding on the role of biomarkers in predicting treatment response in RA to help guide clinical decision-making. Individualised treatment has the potential to improve the therapeutic outcomes for patients.


Staubach P.,University Medicine Mainz | Metz M.,Charite - Medical University of Berlin
JDDG - Journal of the German Society of Dermatology | Year: 2013

Pruritus is a common symptom encountered by many different specialties. One must clinically differentiate between pruritus associated with skin disease or inflammation and pruritus with normal skin. Searching for possible underlying diseases is indispensable, because pruritus can be very chronic and has multiple pathogenetic mechanisms. Therapy - especially topical therapy - is difficult and often not successful. Very often systemic treatment has to be combined with topical approaches, considering both the active ingredients and appropriate vehicles. There are still open therapeutic gaps in the pharmaceutical product market, which can partially be resolved by using standard prescriptions for formulations. Due to the new pharmacy practice order, standardized compounded formulations should be given preference, since individual formulations often do not pass the plausibility check of the compounding pharmacist. Also the use of cosmetic ingredients (by example, commercial cold creams) is no longer permitted, since only ingredients with pharmaceutical quality can be used in compounding. We will show - based on practical cases - different therapeutic options for treatment with standardized magistral formulations from the NRF (New German Pharmacopoeia for compounded medications).


Rauch U.,Charite - Medical University of Berlin
Handbook of Experimental Pharmacology | Year: 2012

Cardiovascular disease is the main cause of mortality and morbidity worldwide. The rate of thromboembolic events has increased in women but not in men. Large clinical studies support the use of a variety of antithrombotic drugs for the treatment of patients with different cardiovascular diseases. The heterogeneous patient population included in these trials affects the attempt to generalize the study results to subgroups, which are not sufficiently represented in the study population, such as women and other minorities. Gender-related differences in the clinical presentation and outcome seem to relate to differences in platelet biology and coagulation reactions, resulting in different rates of thromboembolic and bleeding events. The effectiveness of antithrombotic therapies and the occurrence of adverse events define the clinical benefit of the treatment for each patient. This chapter gives an overview of the currently available data on gender-differences in anticoagulation and antithrombotic therapy. © 2012 Springer-Verlag Berlin Heidelberg.


Dirnagl U.,Charite - Medical University of Berlin
Annals of the New York Academy of Sciences | Year: 2012

Throughout the history of research on stroke pathophysiology, focus has shifted from purely vascular concepts to the insight that a complex interplay of biochemical and molecular mechanisms involving practically any cell type of the brain ("neurovascular unit") partakes in either salvage or demise of the tissue after a stroke. In addition, it was realized that peripheral immune cells play important roles, not only after their invasion into the brain but also because of stroke-induced effects on the immune system that can result in infections. Indeed, outcome of stroke patients is not only dictated by nonmodifiable factors, such as severity of stroke, age, or premorbidity, but also by modifiable factors largely related to medical complications, such as infections and possibly sarcopenia. The highly successful concept of stroke units attests to the benefits of treating stroke comprehensively. Breakthroughs in improving outcome after stroke will only result from approaches that target not only the brain, but also systemic effects of stroke. © 2012 New York Academy of Sciences.


Schulze H.,Charite - Medical University of Berlin
Methods in Molecular Biology | Year: 2012

Megakaryocytes (MKs) are the largest hematopoietic cells in bone marrow. Since the mid-1990s, recombinant thrombopoietin has been commercially available. Together with the emerging knowledge of mouse models, this has provided an unprecedented contribution to the understanding of external and internal factors that orchestrate the transition as one large MK gives rise to thousands of discoid platelets that are indistinguishable from one another. Taking advantage of the murine fetal liver as a source of MKs allows for analysis at the single cell level and also serves to provide enough cells for classical biochemical analyses. Other sources of MK progenitors are adult bone marrow and spleen, although the yields are normally lower. This chapter describes methods to establish a standard culture of murine MKs from fetal liver and bone marrow along with approaches to purify MKs using bovine serum albumin gradients and magnetic-activated cell sorting. These culture systems allow investigations of MK development (ploidy, surface markers, etc.) and platelet biogenesis, including effects of external factors such as structural proteins or feeder layers. © 2012 Springer Science+Business Media, LLC.


Peters E.M.J.,Charite - Medical University of Berlin | Peters E.M.J.,Justus Liebig University
British Journal of Dermatology | Year: 2012

Summary The diagnosis of skin cancer imposes a great stress on our patients. Ultraviolet (UV) radiation-induced skin cancers are on the rise and frequently occur in younger patients and unexposed sites despite improved protective behaviour. Environmental factors and lifestyle habits have changed greatly in the last century and in addition to UV radiation exposure, psychosocial stressors and physical inactivity may play a role in the rising tumour incidence. With environmental stressors such as UV radiation they share the capacity to change the stress reaction. So far research into the interaction between stress, cancer and psychosocial intervention has generated some interesting results with respect to improvement of quality of life and the function of the hypothalamic-pituitary-adrenal axis, the sympathetic axis and natural killer cells. These results hint at a suppressive effect of chronic stress on cellular immunity and the importance of a sufficient length and intensity of any psychosocial intervention for it to be effective. Nevertheless, the evidence remains inconclusive and does not take into account the findings of current psychoneuroimmunological research. This research has demonstrated the importance of a third stress axis along which neurotrophins and neuropeptides are effective. Along this axis, regulatory mechanisms may contribute to suppress tumoricidal immune responses. This may be instrumental in the establishment of an immune response that promotes tumour progression and holds important implications for integrated therapeutic strategies. However, research into the psychoneuroimmunological benefits of psychosocial intervention is largely missing, and future interdisciplinary research is warranted for understanding and further promoting improved quality of life and psychological as well as physical well-being after psychosocial intervention. © 2012 The Author.


Gehr S.,Charite - Medical University of Berlin | Garner C.C.,German Center for Neurodegenerative Diseases
Cell | Year: 2016

The translation of medically relevant academic inventions that could transform public health has been notoriously difficult, stemming largely from cultural differences been academia and industry. New initiatives to kindle academic entrepreneurship and establish stronger public/private partnerships are helping to align these differences and accelerating the translation of promising new therapies. © 2016 Elsevier Inc.


Veauthier C.,Center Hospitalier Of Belfort Montbeliard | Paul F.,Charite University Medicine Berlin and Max Delbrueck Center for Molecular Medicine | Paul F.,Charite - Medical University of Berlin
Sleep Medicine | Year: 2014

Treatment of multiple sclerosis (MS)-related fatigue is still a challenging task, given that no proven therapies exist and its mechanisms are not known. Our review highlights the relationship between MS-related fatigue and sleep disorders (SD). Although many studies suggest a higher overall prevalence of SD in MS, there are no valid and robust data to confirm this hypothesis until now except for restless legs syndrome (RLS): the prevalence of RLS in MS patients-especially in those with severe pyramidal and sensory disability-seems to be four times higher than in controls subjects. RLS is sometimes difficult to distinguish from spasticity and in case of doubt, probatory dopaminergic therapy or polysomnographic (PSG) investigations may be helpful. Nocturia may impact MS-related fatigue and should be considered. The treatment of underlying SD led to an improvement of MS-related fatigue. From a scientific point of view, SD should be examined in all studies investigating MS-related fatigue and be considered as a relevant confounder. © 2013 Elsevier B.V.


Garcia Bartels N.,Charite - Medical University of Berlin
Journal of biomedical optics | Year: 2011

Variations in hair shaft morphology reflect ethnical diversity, but may also indicate internal diseases, nutritional deficiency, or hair and scalp disorders. The measurement and the follow-up of the hair shaft thickness over a defined period of time would be a valuable diagnostic tool in clinical practice. Standard light microscopy (LM) measurements require the epilation of hair shafts and frequently yield inaccurate values caused by the elliptic geometry of human hair shafts. Optical coherence tomography (OCT) is a noninvasive investigation method based on the principles of Michelson interferometry with a detection depth of approximately 1 mm in human skin. Two-dimensional images of the cross sections of tissue samples at a resolution of approximately 10 μm are produced, which allows convenient calculation of hair shaft thickness. To evaluate this new methodology for hair shaft thickness measurements, hair shafts taken from 28 healthy volunteers were analyzed by in vivo OCT and compared to standard in vitro LM measurements of hair shaft thickness. OCT yielded highly reproducible measurements of hair shaft thickness with a distinctly reduced variation compared to standard LM. This technique offers a unique opportunity for in vivo measurement and a follow-up of the kinetics of hair shaft thickness in humans during medical therapy.


Lode H.M.,Charite - Medical University of Berlin
International Journal of Antimicrobial Agents | Year: 2014

As antibiotic resistance is increasing worldwide, it is important to prescribe fluoroquinolone (FQ) antibiotics appropriately for a given infection to preserve class efficacy. Clinical studies reveal good efficacy and tolerability of the currently approved FQs (ciprofloxacin, levofloxacin and moxifloxacin) in a wide range of community- and hospital-acquired infections. However, certain features supporting their clinical efficacy suggest a rationale for inclusion of moxifloxacin and ciprofloxacin with complementary clinical benefit on a formulary rather than levofloxacin alone; it may also be more cost-effective. Ciprofloxacin has advantages over levofloxacin in the treatment of Gram-negative infections, whilst moxifloxacin has certain efficacy and ease of use advantages over levofloxacin in respiratory tract infections. To preserve the potential of FQs and to minimise the risk of resistance selection, agents with the highest in vitro activity and supportive pharmacokinetic/ pharmacodynamic profiles should be used first-line, as appropriate for local guidelines and prescribing information. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.


Jemec G.B.E.,Copenhagen University | Marsch W.Ch.,Martin Luther University of Halle Wittenberg | Von Laffert M.,Charite - Medical University of Berlin
British Journal of Dermatology | Year: 2013

Background The initial pathology in hidradenitis suppurativa (HS)/acne inversa takes place in the folliculopilosebaceous unit (FPSU) and its surrounding tissue. The process involves follicular hyperkeratosis, inflammation and perifolliculitis. Identification of the exact origin of inflammation may shed new light on the pathogenesis and aetiology of the disease. Objectives To study the morphology of the basement membrane zone (BMZ) in patients with HS. Methods In total, 65 operative specimens from 20 patients diagnosed with HS were cut stepwise. Within each specimen, the focus was set on heavily involved HS regions (centre) and clinically uninvolved regions (border). All specimens were stained with periodic acid-Schiff (PAS) to visualize the epithelial support structures of the FPSU (i.e. the BMZ), the sinus tracts (STs) and the interfollicular basement membrane (BM). The intensity of BMZ PAS staining was graded from 0 to 4+. Results Compared with the axillary skin of human controls, the sebofollicular junction in patients with HS was found to be almost devoid of PAS-positive material (grade 0/1+) in both the border and centre lesions of HS, whereas STs and BMs showed uniformly grade 2-3+ positivity irrespective of any inflammation present. The distribution of inflammatory cells around the sebofollicular junction occurred predominantly in areas of BMZ thinning. Conclusions The BMZ PAS positivity of clinically uninvolved FPSUs of patients with HS appears to be wispy or not present at all. It is speculated that this may explain the apparent fragility of the sebofollicular junction. There is an increased concentration of inflammatory cells adjacent to these areas, while inflammatory cells are scarce in areas where the PAS-positive material is intact. It is hypothesized that the PAS gap identifies (i) areas susceptible to leakage, trauma and rupture, leading to release of materials that trigger inflammatory mediators, and (ii) the seeding of the dermis with free-living stem cells generating benign but invasive epithelialized sinuses, spreading horizontally in and below the dermis. © 2013 The Authors. BJD © 2013 British Association of Dermatologists.


Busch N.A.,Charite - Medical University of Berlin | Busch N.A.,Humboldt University of Berlin
Brain Research | Year: 2013

Observers often fail to detect substantial changes in a visual scene. This so-called change blindness is often taken as evidence that visual representations are sparse and volatile. This notion rests on the assumption that the failure to detect a change implies that representations of the changing objects are lost all together. However, recent evidence suggests that under change blindness, object memory representations may be formed and stored, but not retrieved. This study investigated the fate of object memory representations when changes go unnoticed. Participants were presented with scenes consisting of real world objects, one of which changed on each trial, while recording event-related potentials (ERPs). Participants were first asked to localize where the change had occurred. In an additional recognition task, participants then discriminated old objects, either from the pre-change or the post-change scene, from entirely new objects. Neural traces of object memories were studied by comparing ERPs for old and novel objects. Participants performed poorly in the detection task and often failed to recognize objects from the scene, especially pre-change objects. However, a robust old/novel effect was observed in the ERP, even when participants were change blind and did not recognize the old object. This implicit memory trace was found both for pre-change and post-change objects. These findings suggest that object memories are stored even under change blindness. Thus, visual representations may not be as sparse and volatile as previously thought. Rather, change blindness may point to a failure to retrieve and use these representations for change detection. © 2013 Elsevier B.V.


Leithner C.,Charite - Medical University of Berlin | Royl G.,University of Lubeck
Journal of Cerebral Blood Flow and Metabolism | Year: 2014

The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO2). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO2. This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply. © 2014 ISCBFM. All rights reserved.


This article contributes to historical research on medical care in the GDR by using patients' written petitions to the Central Committee of the Socialist Party submitted in the 1980s. It investigates how patients experienced everyday medical care in the GDR beyond the ideals of official health policy. What were their experiences with doctors and nurses and what possibilities for managing conflicts did sick and needy people have? Starting with a critical consideration of sources and some remarks about the culture of petitioning in GDR society, the article provides insight into the lives of patients in the late GDR. An analysis of medical petitions reveals individual ways of coping with disease and indicates that patients made particular demands of the socialist state and its health system. Patients articulated their expectations quite critically, using characteristic patterns of argumentation and, at times, successfully exerting pressure on the regime to answer their demands. © Franz Steiner Verlag, Stuttgart.


Prinz M.,Albert Ludwigs University of Freiburg | Priller J.,Charite - Medical University of Berlin
Journal of Neuroimmunology | Year: 2010

Myeloid cells are mediators of central nervous system (CNS) damage and recovery in neuroinflammatory and neurodegenerative disorders. Besides endogenous myelomonocytic cell populations that reside in the brain already during development, newly migrated leukocytes are considered as important disease modulators in the adult brain. Thus, understanding of myeloid cell recruitment is pivotal for manipulating immune cell entry into the CNS and potentially reducing disease burden. Before myeloid cells engraft in the brain, they first tether to and roll on the activated brain endothelium, then they firmly adhere and eventually transmigrate into the damaged brain where they execute effector functions and differentiate into cells with microglia-like features. These steps are mainly regulated by adhesion molecules and by chemokines and their cognate receptors. Due to recent advances in our understanding of monocyte heterogeneity, the interest in chemokine receptors has significantly increased. Among others, the presence of the chemokine receptors CCR2 and CX3CR1 is considered to be critical for both myeloid cell trafficking along inflamed vessels and subsequent accumulation in the brain. Therefore, these molecules present viable targets for therapeutic manipulations of myeloid cells destined for the CNS. © 2010 Elsevier B.V.


Pries A.R.,Charite - Medical University of Berlin | Secomb T.W.,University of Arizona
Physiology | Year: 2014

The adequate and efficient functioning of the microcirculation requires not only numerous vessels providing a large surface area for transport but also a structure that provides short diffusion distances from capillaries to tissue and efficient distribution of convective blood flow. Theoretical models show how a combination of angiogenesis, remodeling, and pruning in response to hemodynamic and metabolic stimuli, termed “angioadaptation,” generates well organized, functional networks. © 2014 Int. Union Physiol. Sci./Am. Physiol. Soc.


Gastmeier P.,Charite - Medical University of Berlin | Vonberg R.-P.,Hannover Medical School
Infection | Year: 2014

Purpose: Two endoscopy-associated nosocomial outbreaks caused by carbapenemase-producing Klebsiella pneumoniae (CPKP) were recently observed in two German hospitals. In this study, we performed a systematic search of the medical literature in order to elucidate the epidemiology of Klebsiella spp. in endoscopy-associated outbreaks. Methods: Medline, the Outbreak Database (http://www.outbreak-database.com) and reference lists of articles extracted from these databases were screened for descriptions of endoscopy-associated nosocomial outbreaks. The data extracted and analysed were: (1) the type of medical department affected; (2) characterisation of pathogen to species and conspicuous resistance patterns (if applicable); (3) type of endoscope and the grade of its contamination; (4) number and the types of infections; (5) actual cause of the outbreak. Results: A total of seven nosocomial outbreaks were identified, of which six were outbreaks of endoscopic retrograde cholangiopancreatography-related infections and caused by contaminated duodenoscopes. Including our own outbreaks in the analysis, we identified one extended-spectrum beta-lactamase-producing K. pneumoniae strain and six CPKP strains. Insufficient reprocessing after the use of the endoscope was the main reason for subsequent pathogen transmission. Conclusions: There were only two reports of nosocomial outbreaks due to Klebsiella spp. in the first three decades of endoscopic procedures, but seven additional outbreaks of this kind have been reported within the last 4 years. It is very likely that many of such outbreaks have been missed in the past because this pathogen belongs to the physiological gut flora. However, with the emergence of highly resistant (carbapenemase-producing) strains, strict adherence to infection control guidelines is more important than ever. © Springer-Verlag 2013.


Weinmann S.,Charite - Medical University of Berlin
Epidemiologia e psichiatria sociale | Year: 2010

AIM: We aimed at developing a prioritized set of quality indicators for schizophrenia care to be used for continuous quality monitoring. They should be evidence-based and rely on routine data. METHODS: A systematic literature search was performed to identify papers on validated quality indicators published between 1990 to April 2008 in MEDLINE, the Cochrane databases, EMBASE and PsycINFO. Databases of relevant national and international organizations were searched. Indicators were described with respect to meaningfulness, feasibility and actionability. A workshop with relevant stakeholders evaluated the measures through a structured consensus process. RESULTS: We identified 78 indicators through literature search and selected 22 quality indicators. Furthermore, 12 structural and case-mix indicators were choosen. Only five quality indicators were rated "essential indicators" (priority 1), 14 were rated "additional first choice" (priority 2), and three were rated as "additional second choice" (priority 3). Only four indicators assessed outcome quality. In the majority of indicators the evidence base supporting the indicator recommendation was weak. None of the selected indicators was validated in experimental studies. CONCLUSIONS: Evidence and validation base played only a subordinate role for indicator prioritisation by stakeholders indicating that there are discrepancies between clinical questions and requirements in schizophrenia care and scientific research.


Over the last decade, the treatment of heart failure has seen the introduction of several novel therapeutic avenues into the guidelines; however, these were mostly devoted to device therapies. Not much has changed with regards to the pharmacological treatment of this syndrome. Serelaxin, a recombinant form of the human peptide hormone relaxin-2, is a promising treatment candidate for patients presenting with acute heart failure. The Relaxin in Acute Heart Failure (RELAX-AHF) trial has shown beneficial effects in terms of relief of dyspnea and congestion in these patients. Even beneficial effects on short-term survival were reported. Another treatment approach to acute heart failure was pursued in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial but the ultrafiltration used here lead to significantly worsened renal function as compared to standard pharmacologic care. Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) randomized patients with heart failure with a primary preventive indication for the implantation of an implantable cardioverter defibrillator to one of three algorithms for anti-tachycardia pacing (ATP) and shock. The authors found that initiation of such therapies only at higher heart rates than commonly used as threshold and longer time delays before the initiation of therapy may have two big advantages: the more conservative algorithms lead to a significant reduction in the cumulative probability of first inappropriate therapy and, even more striking, a reduced probability of death during follow-up. Biventricular versus Right Ventricular Pacing in Patients with Left Ventricular Dysfunction and Atrioventricular Block (BLOCK-HF) showed beneficial outcomes for cardiac resynchronization therapy in heart failure patients with a mere pacemaker indication. Other studies discussed here embraced the course of body wasting, particularly cachexia, and muscle wasting in patients with heart failure and the influence of eating behavior. © 2013 Informa UK, Ltd.


Roepke S.,Charite - Medical University of Berlin
Current psychiatry reports | Year: 2014

Although concepts of pathological narcissism are as old as psychology and psychiatry itself, only a small number of clinical studies are based on the criteria for narcissistic personality disorder (NPD), as defined in the Diagnostic and Statistical Manuals of Mental Disorders (DSM). As a result, NPD appears to be one of the most controversially discussed nosological entities in psychiatry. Whereas the majority of empirical studies used self or other ratings of NPD criteria to address issues of reliability and validity of the diagnostic category (i.e., internal consistency, factor structure, discriminant validity), only recent research has applied experimental designs to investigate specific features of NPD (e.g., self-esteem, empathy, shame). The aim of this review is to summarize available empirical data on NPD and relate these findings to current definitions of NPD (according to the DSM-5, [1]). In order to do so, this review follows the five steps to establishing diagnostic validity proposed by Robins and Guze [2], i.e., (1) clinical description, (2) laboratory studies, (3) delimitation from other disorders, (4) family studies, and (5) follow up studies. Finally, this review suggests pathways for future research that may assist further nosological evaluation of NPD and contribute to the overall goal, the improvement of treatment for patients.


Bader M.,Max Delbruck Center for Molecular Medicine | Bader M.,Charite - Medical University of Berlin | Bader M.,University of Lubeck | Bader M.,Federal University of Minas Gerais | And 4 more authors.
Pharmacological Reviews | Year: 2014

TheMas-relatedGprotein–coupled receptors (Mrgprs or Mas-related genes) comprise a subfamily of receptors named after the first discovered member, Mas. For most Mrgprs, pruriception seems to be the major function based on the following observations: 1) they are relatively promiscuous in their ligand specificity with best affinities for itch-inducing substances; 2) they are expressed in sensory neurons and mast cells in the skin, the main cellular components of pruriception; and 3) they appear in evolution first in tetrapods, which have arms and legs necessary for scratching to remove parasites or other noxious substances from the skin before they create harm. Because parasites coevolved with hosts, each species faced different parasitic challenges, which may explain another striking observation, the multiple independent duplication and expansion events of Mrgpr genes in different species as a consequence of parallel adaptive evolution. Their predominant expression in dorsal root ganglia anticipates additional functions of Mrgprs in nociception. Some Mrgprs have endogenous ligands, such as b-alanine, alamandine, adenine, RF-amide peptides, or salusin-b. However, because the functions of these agonists are still elusive, the physiologic role of the respective Mrgprs needs to be clarified. The best studied Mrgpr is Mas itself. It was shown to be a receptor for angiotensin-1–7 and to exert mainly protective actions in cardiovascular and metabolic diseases. This review summarizes the current knowledge about Mrgprs, their evolution, their ligands, their possible physiologic functions, and their therapeutic potential. © 2014 by The American Society for Pharmacology and Experimental Therapeutics.


Bozorgmehr K.,Charite - Medical University of Berlin
Globalization and Health | Year: 2010

Background: Current definitions of 'global health' lack specificity about the term 'global'. This debate presents and discusses existing definitions of 'global health' and a common problem inherent therein. It aims to provide a way forward towards an understanding of 'global health' while avoiding redundancy. The attention is concentrated on the dialectics of different concepts of 'global' in their application to malnutrition; HIV, tuberculosis & malaria; and maternal mortality. Further attention is payed to normative objectives attached to 'global health' definitions and to paradoxes involved in attempts to define the field.Discussion: The manuscript identifies denotations of 'global' as 'worldwide', as 'transcending national boundaries' and as 'holistic'. A fourth concept of 'global' as 'supraterritorial' is presented and defined as 'links between the social determinants of health anywhere in the world'. The rhetorical power of the denotations impacts considerably on the object of 'global health', exemplified in the context of malnutrition; HIV, tuberculosis & malaria; and maternal mortality. The 'global' as 'worldwide', as 'transcending national boundaries' and as 'holistic' house contradictions which can be overcome by the fourth concept of 'global' as 'supraterritorial'. The 'global-local-relationship' inherent in the proposed concept coheres with influential anthropological and sociological views despite the use of different terminology. At the same time, it may be assembled with other views on 'global' or amend apparently conflicting ones. The author argues for detaching normative objectives from 'global health' definitions to avoid so called 'entanglement-problems'. Instead, it is argued that the proposed concept constitutes an un-euphemistical approach to describe the inherently politicised field of 'global health'.Summary: While global-as-worldwide and global-as-transcending-national-boundaries are misleading and produce redundancy with public and international health, global-as-supraterritorial provides 'new' objects for research, education and practice while avoiding redundancy. Linked with 'health' as a human right, this concept preserves the rhetorical power of the term 'global health' for more innovative forms of study, research and practice. The dialectic approach reveals that the contradictions involved in the different notions of the term 'global' are only of apparent nature and not exclusive, but have to be seen as complementary to each other if expected to be useful in the final step. © 2010 Bozorgmehr K; licensee BioMed Central Ltd.


Boning D.,Charite - Medical University of Berlin
European Journal of Applied Physiology | Year: 2010

Since playing wind instrument impedes normal respiratory functions, its effect on expiratory and blood gases as well as on cardiac function was investigated. In 15 skilled clarinettists expiratory PO2 and PCO 2 were measured in gas drawn from a modified clarinet barrel when playing a composition (Robert Schumann's "Phantasiestücke" Op. 73 for clarinet and piano) with increasing difficulty from movement 1 to movement 3. Blood gases were measured in arterialized ear lobe blood at the end of each movement and the electrocardiogram was recorded continuously. From the expiratory gas pressures one may conclude that the most advanced players adapt their ventilation to the requirements of the composition and sustain expiration during difficult parts of the composition until hypoxic alveolar PO2 values are reached (minimum 77 mmHg). Less trained clarinettists tend to hyperventilation or shallow breathing. Oxygen saturation in arterialized blood showed a slight step-wise decrease from movement to movement [control 96.6 ± 0.5 (SD)%, end of concert 95.6 ± 1.0%]. SO2 was significantly higher because of possibly more effective ventilation in instrumentalists with practise time exceeding 2 h daily. Mean heart rate increased to values like during moderate to heavy physical exercise depending on artistic fitness and the difficulty of the movement (maximal individual value 173 beats/min). Additionally, a large variation might be caused through intrathoracic pressure changes, changing exertion, respiratory influences and emotion. The electrocardiogram showed no pathological events. In general, clarinet playing at a professional level imposes strain on ventilation and circulation but usually not on a pathophysiological level. © 2010 Springer-Verlag.


Penack O.,Charite - Medical University of Berlin | Socie G.,Hopital Saint Louis | Van Den Brink M.R.M.,Sloan Kettering Cancer Center
Blood | Year: 2011

GVHD and tumor relapse are fundamental problems in allogeneic HSCT. Recent research has linked neovascularization to GVHD, tumor growth, and graft-versus-tumor (GVT) activity. Damage of the endothelium by the conditioning regimen provides the initiation stimulus for recruitment of donor-derived endothelial cells and their progenitors. During the early inflammatory phase of GVHD there is considerable neovascularization facilitating migration of inflammatory cells to target organs. In the course of GVHD, however, the vasculature itself becomes a target of alloreactive donor T cells. As a consequence, later stages of GVHD are characterized by fibrosis and rarefaction of blood vessels. Importantly, the inhibition of tumor-neovascularization by activated donor T cells that release antiangiogenic substances contributes to GVT and may be enhanced by pharmacologic inhibition of neovascularization. Furthermore, the therapeutic inhibition of neovascularization may improve immunotherapy for cancer by enhancing leukocyte infiltration in tumor tissue because of normalization of tumor vessels and stimulation of leukocyte-vessel wall interactions. These insights identify important mechanisms underlining the importance of neovascularization for allogeneic immune responses and move therapeutic approaches targeting neovascularization into the spotlight. This perspective covers current knowledge of the role of neovascularization during GVHD as well as GVT and its implications for HSCT. © 2011 by The American Society of Hematology.


Stengel A.,Charite - Medical University of Berlin
Peptides | Year: 2015

Nesfatin-1 was discovered a decade ago and despite the fact that it represents just one of a multitude of food intake-inhibiting factors it received increasing attention. This led to a detailed characterization of NUCB2/nesfatin-1's physiological property to reduce food intake and also gave rise to an involvement in the long term regulation of body weight, especially under conditions of obesity. In addition, studies indicated the involvement of NUCB2/nesfatin-1 in other homeostatic functions as well: glucose homeostasis, water intake, gastrointestinal functions, temperature regulation, cardiovascular functions, puberty onset and sleep. These pleiotropic actions underline the physiological relevance of this peptide. Recently, the involvement of NUCB2/nesfatin-1 in psychiatric disorders such as anxiety has been investigated giving rise to the speculation that NUCB2/nesfatin-1 represents a peptidergic link between eating and anxiety/depression disorders. © 2015 Elsevier Inc. All rights reserved.


Saad F.,Center Hospitalier Of Iuniversite Of Montreal | Miller K.,Charite - Medical University of Berlin
Urology | Year: 2015

Despite advances in castration-resistant prostate cancer (CRPC) treatment, therapies that provide long-term survival are still needed. In 2010, sipuleucel-T was approved for CRPC on the basis of improved overall survival. Recently, new immunotherapeutic approaches have emerged with perhaps the most exciting being immune-checkpoint inhibition. Here, we provide an overview of immunotherapies for CRPC, with a focus on immune-checkpoint inhibition with ipilimumab. We consider how experience with ipilimumab in melanoma might inform future use in CRPC and describe ongoing phase 3 trials. Finally, we discuss the potential for improved antitumor activity when ipilimumab is combined with hormonal or bone-targeted agents. © 2015 Elsevier Inc.


Wiers C.E.,Humboldt University of Berlin | Wiers C.E.,Charite - Medical University of Berlin
European Archives of Psychiatry and Clinical Neuroscience | Year: 2012

The field of imaging genetics traditionally studies unidirectional associations between genes, brain functioning, and behavior. In a recent study by Ursini et al. (J Neurosci 31:6692-6698, 2011), imaging genetics methods are combined with epigenetic marks in living human beings. This approach may lead to a new field of imaging epigenetics, providing more mechanistic insight into causal pathways of how gene and environment interact and affect brain development. © Springer-Verlag 2011.


Kreutz R.,Charite - Medical University of Berlin
Fundamental and Clinical Pharmacology | Year: 2012

Rivaroxaban, an oral, direct factor Xa inhibitor, is a small molecule drug capable of inhibiting not only free factor Xa with high selectivity but also prothrombinase-bound and clot-associated factor Xa in a concentration-dependent manner. Clinical studies have demonstrated predictable anticoagulation and confirmed dose-proportional effects for rivaroxaban in humans with a rapid onset (within 2-4h) and a half-life of 7-11h and 11-13h for young and elderly subjects, respectively. For a 10mg dose, the oral bioavailability of rivaroxaban is high (80-100%) and is not affected by food intake. These favourable pharmacological properties underpin the use of rivaroxaban in fixed dosing regimens, with no need for dose adjustment or routine coagulation monitoring. Rivaroxaban has a dual mode of excretion with the renal route accounting for one-third of the overall elimination of unchanged active drug. Rivaroxaban is a substrate of CYP3A4 and P-glycoprotein and therefore not recommended for concomitant use with strong inhibitors of both pathways, e.g. most azole antimycotics and protease inhibitors. Rivaroxaban is currently approved for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. Studies using 10mg rivaroxaban once daily in this indication demonstrated its suitability for a wide range of patients regardless of age, gender or body weight. Further studies in the treatment of VTE, prevention of cardiovascular events in patients with acute coronary syndrome, prevention of stroke in those with atrial fibrillation and prevention of VTE in hospitalized medically ill patients have been reported or are ongoing. © 2011 The Author Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.


Sieper J.,Charite - Medical University of Berlin | Sieper J.,Franklin University
Current Opinion in Rheumatology | Year: 2012

Purpose of review: There is a major delay of several years between first symptoms and making a diagnosis in patients with axial spondyloarthritis. A strategy for earlier diagnosis is urgently needed, for which efficient referral parameters applicable in primary care are an important part. Published studies on referral programs are reviewed and their relevance for daily clinical practice is discussed. Results: Several referral investigations have been performed in several countries using the symptom of 'inflammatory back pain' (IBP) alone or in combination with other referral parameters. All studies performed resulted in a good and acceptable percentage of an axial SpA diagnosis in between 29 and 58%. A set of rather simple parameters (IBP and/or HLA-B27 positivity and/or sacroiliitis on imaging) performed better than IBP alone and is easier to use than more complicated referral strategies. Summary: Referral strategies to screen for axial SpA patients in primary care are available, are effective and should be applied more regularly. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Siegmund B.,Charite - Medical University of Berlin
Digestive Diseases | Year: 2015

Managing mild-to-moderate ulcerative colitis on the first view appears to be a simple task. However, real life often proofs the opposite and creates a challenging situation. In theory, mild-to-moderate disease should be sufficiently treated by mesalamine or alternatively by a probiotic. Insufficient treatment comprises the danger of leading to a flare, and hence, an exacerbation of the entire disease, with risk of progressing to severe disease. What are the considerations with regard to patient management in this situation? Certainly, disease distribution is the critical information, since it allows for planning the optimal route of administration, namely local versus systemic treatment. Novel pharmacological strategies might allow for reaching high local concentrations even at the left side of the colon or alternatively administer locally active budesonide throughout the entire colon frame, thus avoiding systemic side effects. Therapy planning has to involve the patient to identify how this can be included in daily life. Including the patient implies that depending on the condition, disease activity and even life quality, the individual therapy requires timely adaption. A recent study by Pedersen et al. [Inflamm Bowel Dis 2014;20:2276-2285] provides evidence that this strategy can be followed and leads to an overall better outcome. A last thought, besides the patient not taking the appropriate dose or lacking adherence to therapy, should consider that a worsening of disease could be due to infectious complications including Clostridium difficile or cytomegalovirus colitis. If all considerations fail within a reasonable time frame, therapy should be escalated. Patients in this situation often hesitate in accepting the need of immunosuppression. Future options, potentially including phosphatidylcholine, might bridge the gap between mesalamine, probiotics and immunosuppressive strategies. © 2015 S. Karger AG, Basel.


Scheibel M.,Charite - Medical University of Berlin
Unfallchirurg | Year: 2011

During the past decade the evaluation of the rotator cuff in the management of proximal humeral fractures has received increasing attention. Different studies have investigated the pathomorphology, prevalence and impact of rotator cuff lesions on the outcome of non-operative or surgical treatment of proximal humeral fractures. Tendon defects, either chronic or trauma related, are observed mainly in the anterosuperior or posterosuperior aspect of the rotator cuff and present as partial- or full-thickness tears. Structural changes of the rotator cuff muscles including atrophy and fatty infiltration in the context of proximal humeral fractures have been inadequately investigated. The prevalence of coexisting rotator cuff pathology varies between 5 and greater than 50% depending on the method of evaluation, the fracture morphology and the age of the patient. The influence of a concomitant rotator cuff tear on the clinical outcome has not been conclusively investigated. However, different studies indicate that some lesions can be a source of persistent pain and functional deficit after conservative or surgical management of proximal humeral fractures. Therefore, a simultaneous repair of the rotator cuff defect during surgical reconstruction of the proximal humerus is indicated. © 2011 Springer-Verlag.


Resistance to TRAIL (TNF-related apoptosis-inducing ligand)- induced apoptosis limits its therapeutic use. Different strategies of TRAIL sensitization and a dependency on Bax have been reported, but common principles of TRAIL resistance and the way of Bax activation remained poorly understood. Applying a melanoma model of TRAIL-sensitive and -resistant cell lines, efficient sensitization for TRAIL-induced apoptosis is demonstrated by the kinase inhibitor BMS-345541 (N-(1,8-dimethylimidazo(1,2-a)quinoxalin-4-yl)-1,2-ethanediamine hydrochloride), which targets IκB (inhibitor of κB proteins) kinase β (IKKβ). This effect was completely abrogated by Bax knockout as well as by Bcl-2 overexpression, in accordance with a Bax dependency. Early loss of the mitochondrial membrane potential, release of cytochrome c and Smac (second mitochondria-derived activator of caspases) clearly indicated the activation of mitochondrial apoptosis pathways. Of note, BMS-345541 alone resulted in an early Bax activation, seen by conformational changes and by Bax translocation. The synergistic effects can be explained by Bid activation through TRAIL, which inhibits Bcl-2, and the activation of Bax through BMS-345541. The critical roles of XIAP (X-chromosome-linked inhibitor of apoptosis protein), Smac and Bid were clearly proven by overexpression and siRNA knockdown, respectively. The way of Bax activation by BMS-345541 was unraveled by establishing new assays for Bax activation. These showed reduction of the inactivating Bax phosphorylation at serine-184, while the activating Bax phosphorylation at threonine-167 was enhanced. Thus, modulation of Bax phosphorylation appeared as tightly related to TRAIL sensitivity/resistance in melanoma cells, and therapeutic strategies may be considered.


Von Schwartzenberg R.J.,University of California at San Francisco | Von Schwartzenberg R.J.,Charite - Medical University of Berlin | Turnbaugh P.J.,University of California at San Francisco
Cell | Year: 2015

Zeevi et al. report that extensive monitoring of a human cohort for variations in dietary intake, lifestyle, host phenotype, and the gut microbiome has enabled the development of a machine-learning algorithm that accurately predicts the individual glycemic response to meals, providing an important first step toward personalized nutrition. © 2015 Elsevier Inc.


Bluthgen N.,Charite - Medical University of Berlin | Bluthgen N.,Humboldt University of Berlin | Legewie S.,Institute of Molecular Biology
Cellular and Molecular Life Sciences | Year: 2013

Signal transduction pathways transduce information about the outside of the cell to the nucleus, regulating gene expression and cell fate. To reliably inform the cell about its surroundings, information transfer has to be robust against typical perturbation that a cell experiences. Robustness of several mammalian signaling pathways has been studied recently by quantitative experimentation and using mathematical modeling. Here, we review these studies, and describe the emerging concepts of robustness and the underlying mechanisms. © 2012 Springer Basel AG.


Pavel M.,Charite - Medical University of Berlin
Neuroendocrinology | Year: 2013

Current treatment options for neuroendocrine tumors (NET) include somatostatin analogs, interferon-α, peptide receptor-targeted therapy and cytotoxic chemotherapy. Most patients undergo sequential therapies since these drugs are active only in subpopulations of patients and for a limited period of time. There is a need for novel drugs that are capable of amelioration of symptomatology (syndromic control) and/or tumor growth control. A number of diverse signaling pathways are involved in the pathogenesis of NET and tumor growth, thus many potential targets are available for drug targeting. Targeted therapies therefore represent an appropriate developmental therapeutic strategy given the multiplicity of potential targets in NET. These include but are not limited to: inhibitory or activating G protein-coupled receptors, receptor tyrosine kinases, ligands, and intracellular targets such as the mammalian target of rapamycin (mTOR). Numerous drugs that utilize single or multiple targets are currently in clinical development. Recently, two target-directed agents, the multiple tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus, have been approved for the treatment of progressive pancreatic NET. This review provides a broad overview of established and potential molecular targets in NET, summarizes data from phase II and III clinical trials with targeted drugs and outlines future therapeutic directions. Copyright © 2012 S. Karger AG, Basel.


Clark A.L.,Castle Hill Hospital | Anker S.D.,Charite - Medical University of Berlin
Journal of Heart and Lung Transplantation | Year: 2010

Cardiac cachexia, associated with excessive activation of the sympathetic nervous system together with immune activation, is an important prognostic indicator in heart failure. Anecdotally, the prevalence of cardiac cachexia appears to be falling, perhaps due to the increased use of beta-blockers. However, chronic heart failure is so common that many patients continue to lose weight and continue to deteriorate to a point where transplantation or mechanical support is considered. The origin of cachexia remains elusive and further research is needed to explore the relation between weight, sympathetic activation, and the response to cardiac surgery or transplantation. © 2010 International Society for Heart and Lung Transplantation.


Laule M.,Charite - Medical University of Berlin
Neuroendocrinology | Year: 2015

Purpose: Carcinoid heart disease (CHD) with severe valve destruction represents the major cause of high morbidity and mortality in patients with carcinoid syndrome. In this manuscript we present a novel interventional treatment approach and report the first clinical result achieved in a patient with extensive CHD. Methods and Results: A woman with an ileal neuroendocrine tumor (G2, Ki67: 5%) presented with severe CHD (NYHA IV) affecting both the pulmonary and the tricuspid valve. First, a balloon-expandable 23-mm Edwards SAPIEN was successfully implanted percutaneously into the pulmonary valve. Since no catheter-based techniques were available for the replacement of the native tricuspid valve, we implanted an Edwards SAPIEN 26-mm valve into the vena cava inferior between the right atrium and the ostium of the hepatic veins to reduce abdominal congestion. The implantation was technically successful and completely prevented regurgitation into the VCI and abdominal veins. After this procedure, the patient's clinical condition improved significantly, and she achieved near-normal exercise tolerance (VO2 max: 24.4 ml O2/kg/min, NYHA II). Conclusion: We demonstrated that percutaneous valve implantation may offer a novel, minimally invasive option in high risk patients with severe CHD. © 2015 S. Karger AG, Basel Copyright © 2015, S. Karger AG. All rights reserved.


Transcriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portraits, e.g. in cancer. However, mechanistic insights into the regulatory principles governing global transcriptional changes are lagging behind extensive compilations of deregulated genes. To identify regulators of transcriptome alterations, we used an integrated approach combining transcriptional profiling of colorectal cancer cell lines treated with inhibitors targeting the receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase pathway, computational prediction of regulatory elements in promoters of co-regulated genes, chromatin-based and functional cellular assays. We identified commonly co-regulated, proliferation-associated target genes that respond to the MAPK pathway. We recognized E2F and NFY transcription factor binding sites as prevalent motifs in those pathway-responsive genes and confirmed the predicted regulatory role of Y-box binding protein 1 (YBX1) by reporter gene, gel shift, and chromatin immunoprecipitation assays. We also validated the MAPK-dependent gene signature in colorectal cancers and provided evidence for the association of YBX1 with poor prognosis in colorectal cancer patients. This suggests that MEK/ERK-dependent, YBX1-regulated target genes are involved in executing malignant properties.


Obladen M.,Charite - Medical University of Berlin
Journal of Child Neurology | Year: 2011

Disturbed neurulation fascinated scientists of all times. In Egypt, anencephalic infants were venerated as animal-headed gods. Roman law required them to be killed. The medieval world held the mother responsible, either because of assumed imagination or "miswatching," or because of suspected intercourse with animals or devils. Modern embryology and teratology began with the use of the microscope by Malpighi in 1672. Details of neural tube closure were described by Koelliker in 1861 and by His in 1874. From 1822, genetic disease and familial recurrence due to insufficient nutrition were discerned and lower social class identified as a risk factor. It took a century to define the malnutrition as insufficient folate intake. The mandatory supplementation of folate in staple foods successfully reduced the incidence of neural tube defects in the United States, Australia, Canada, and Chile, but it was not adopted by most European countries. © SAGE Publications 2011.


Helmchen H.,Charite - Medical University of Berlin
Nervenarzt | Year: 2015

According to Luhmann conscience is understood as a value-neutral function for forming identity. Its background is biological in nature but receives its values from the normative context of family and society. In an evolutionary perspective group congruent behavior could offer a survival advantage that will be stabilized by an emotional bonding to a group. This bonding makes the individual dependent on the sociocultural context, including its normative content and its change.This influence becomes clear in different individual as well as time-dependent judgments of a specific moral problem in multicultural societies and with changes of the zeitgeist. Such influences are illustrated by numerous examples and lead to the question whether at all and by which criteria changes of conscience will be recognized by the person concerned. This article aims at a sensitization for questions of formation and vulnerability of the conscience. © 2014, Springer-Verlag Berlin Heidelberg.


Kees M.G.,Charite - Medical University of Berlin
Medizinische Klinik - Intensivmedizin und Notfallmedizin | Year: 2013

Antibiotics are used very frequently in critically ill patients as a causal and often life-saving treatment; however, the high density of use of broad spectrum antibiotics contributes to a further deterioration in resistance trends, which makes a rational prescription behavior mandatory. This particularly includes measures which lead to the reduction of antibiotic use, i.e. rigorous indications, targeted de-escalation and limited duration. For optimal efficacy of a necessary treatment the integration of pharmacokinetic and pharmacodynamic principles can be helpful. © 2013 Springer-Verlag Berlin Heidelberg.


Lorenz-Depiereux B.,Helmholtz Center for Environmental Research | Schnabel D.,Charite - Medical University of Berlin | Tiosano D.,Rambam Medical Center | Tiosano D.,Technion - Israel Institute of Technology | And 3 more authors.
American Journal of Human Genetics | Year: 2010

The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis; for example, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Here, we report presumable loss-of-function mutations in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase) in members of four families affected with hypophosphatemic rickets. We provide evidence for the conclusion that ENPP1 is the fourth gene-in addition to PHEX, FGF23, and DMP1-that, if mutated, causes hypophosphatemic rickets resulting from elevated FGF23 levels. Surprisingly, ENPP1 loss-of-function mutations have previously been described in generalized arterial calcification of infancy, suggesting an as yet elusive mechanism that balances arterial calcification with bone mineralization. © 2010 The American Society of Human Genetics.


Muller-Lissner S.,Charite - Medical University of Berlin
Internist | Year: 2015

The motility of the colon is modulated by the enteric nervous system. It is very complex, governing backward and forward movements of the feces. Primary megacolon and megarectum are clinically diverse. Megacolon refractory to laxative treatment may be subject to colectomy, while megarectum should be treated by consistent laxation. Acute colonic pseudo-obstruction may occur with severe systemic diseases and electrolyte disturbances or it may be postoperatively and/or medically induced. A small proportion of chronically constipated patients suffer from slow transit constipation, others from disordered defecation. In the remaining patients no objective cause of the complaints may be found. In slow transit constipation, propulsive colonic motility is disturbed, dietary fiber is ineffective, and the response to bisacodyl is blunted. Pelvic floor dyssynergia is characterized by a voluntary (although unconscious) contraction of the anal sphincter simultaneously with the abdominal muscles. It can be treated by avoiding straining and by sphincter training. © 2015, Springer-Verlag Berlin Heidelberg.


Klotz L.,University of Toronto | Miller K.,Charite - Medical University of Berlin | Crawford E.D.,University of Colorado at Denver | Shore N.,Urologic | And 4 more authors.
European Urology | Year: 2014

Background Studies comparing the gonadotropin-releasing hormone antagonist, degarelix, with luteinising hormone-releasing hormone (LHRH) agonists indicate differences in outcomes.Design, setting, and participants Data were pooled from five prospective, phase 3 or 3b randomised trials (n = 1925) of degarelix and leuprolide or goserelin in men requiring androgen deprivation therapy for the treatment of prostate cancer. Patients received either 3 mo (n = 467) or 12 mo (n = 1458) of treatment. Intervention Men were randomised to receive degarelix (n = 1266), leuprolide (n = 201), or goserelin (n = 458).Outcome measurements and statistical analysis Unadjusted Kaplan-Meier analyses were supported by the Cox proportional hazards model, adjusted for disease-related baseline factors, to estimate hazard ratios (HRs) of efficacy and safety outcomes. The Fisher exact test compared crude incidences of adverse events.Results and limitations Prostate-specific antigen (PSA) progression-free survival (PFS) was improved in the degarelix group (HR: 0.71; p = 0.017). For patients with baseline PSA levels >20 ng/ml, the HR for PSA PFS was 0.74 (p = 0.052). Overall survival (OS) was higher in the degarelix group (HR: 0.47; p = 0.023). OS was particularly improved with degarelix in patients with baseline testosterone levels >2 ng/ml (HR: 0.36; p = 0.006). In terms of disease-related adverse events, there were, overall, fewer joint-related signs and symptoms, musculoskeletal events, and urinary tract events in the degarelix group.Conclusions These data indicate clinical benefits with degarelix, including a significant improvement in PSA PFS and OS, as well as reduced incidence of joint, musculoskeletal, and urinary tract adverse events, compared with LHRH agonists. © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. -absp. Objective To assess differences in efficacy and safety outcomes in a pooled analysis of trials comparing degarelix with LHRH agonists.


De Punder K.,Charite - Medical University of Berlin | Pruimboom L.,Natura Foundation
Frontiers in Immunology | Year: 2015

Chronic non-communicable diseases (NCDs) are the leading causes of work absence, disability, and mortality worldwide. Most of these diseases are associated with low-grade inflammation. Here, we hypothesize that stresses (defined as homeostatic disturbances) can induce low-grade inflammation by increasing the availability of water, sodium, and energy-rich substances to meet the increased metabolic demand induced by the stressor. One way of triggering low-grade inflammation is by increasing intestinal barrier permeability through activation of various components of the stress system. Although beneficial to meet the demands necessary during stress, increased intestinal barrier permeability also raises the possibility of the translocation of bacteria and their toxins across the intestinal lumen into the blood circulation. In combination with modern life-style factors, the increase in bacteria/bacterial toxin translocation arising from a more permeable intestinal wall causes a low-grade inflammatory state. We support this hypothesis with numerous studies finding associations with NCDs and markers of endotoxemia, suggesting that this process plays a pivotal and perhaps even a causal role in the development of low-grade inflammation and its related diseases. © 2015 de Punder and Pruimboom.


Van Veldhuisen D.J.,University of Groningen | Anker S.D.,Charite - Medical University of Berlin | Ponikowski P.,Wroclaw Medical University | MacDougall I.C.,Kings College
Nature Reviews Cardiology | Year: 2011

Anemia and iron deficiency are common in patients with heart failure (HF), and are associated with worse symptoms and adverse outcomes in this population. Although the two can occur together, anemia in HF is often not caused by iron deficiency, and iron deficiency can be present without causing anemia. Erythropoiesis-stimulating agents have been investigated extensively in the past few years and might be of benefit in patients with HF and anemia. However, concerns have arisen regarding the safety of erythropoiesis-stimulating agents in patients with chronic kidney disease and so the results of a large mortality trial are eagerly awaited to provide information on safety in patients with HF. Iron supplementation or replacement is a much older treatment option for patients with HF and anemia, but questions about the safety of intravenous iron, and absorption problems with oral formulations have prevented its widespread use to date. In the past few years, however, new data on the importance of iron deficiency in HF have become available, and a number of studies with intravenous iron have shown promising results. Therefore, this treatment approach is likely to become an attractive option for patients with HF and iron deficiency, both with and without anemia. © 2011 Macmillan Publishers Limited. All rights reserved.


Kreutz R.,Charite - Medical University of Berlin
Current Clinical Pharmacology | Year: 2014

Anticoagulants have a key role in the management of venous and arterial thromboembolic disorders. Traditional anticoagulants, such as unfractionated heparin, low-molecular-weight heparins, fondaparinux, and vitamin K antagonists are effective but have limitations that make the management of thromboembolic disorders difficult. There is a clear need for new anticoagulants that are at least as effective as traditional agents but without their drawbacks. This review discusses the mechanism of action, pharmacokinetics, and pharmacodynamics of one of these newer agents - the direct Factor Xa inhibitor rivaroxaban - and provides an overview of the results of phase III clinical studies. Based on these results, rivaroxaban has gained approval for the prevention and treatment of several thromboembolic disorders in adult patients. Rivaroxaban, which has a rapid onset of action, targets free and clot-bound Factor Xa and Factor Xa in the prothrombinase complex. It reaches maximal plasma concentration 2-4 hours after administration and has a high bioavailability (80-100%). Rivaroxaban has several advantages over traditional anticoagulants. It does not require dose adjustment for age, sex, body weight, or ethnicity, and there is no requirement for routine coagulation monitoring because it has been shown to have predictable pharmacokinetics and pharmacodynamics. Furthermore, rivaroxaban has minimal food and drug interactions. The introduction of newer oral anticoagulants, such as rivaroxaban, that are convenient to administer and have predictable pharmacokinetic and pharmacodynamic profiles, could ultimately simplify patient management in clinical practice and may improve clinical outcomes across a broad range of thromboembolic disorders. © 2014 Bentham Science Publishers.


Church M.K.,Charite - Medical University of Berlin | Church M.K.,Sir Henry Wellcome Laboratories
Expert Opinion on Drug Safety | Year: 2011

New H 1-antihistamines should be effective in relieving the symptoms of allergic disease, should have a rapid onset and long duration of action and should neither cause sedation nor interact with cytochrome P450. A review of bilastine was undertaken to determine whether this newer H 1-antihistamine meets these requirements. Areas covered: A Medline search was conducted to identify preclinical and clinical studies of bilastine. This was supplemented with additional articles or abstracts cited in reference lists and/or obtained from online sources and internal reports supplied by Faes Farma. Review of these data indicated that bilastine has high selectivity for H 1-receptors, is rapidly and effectively absorbed, undergoes negligible metabolism and is a substrate for P-glycoprotein, which limits its passage across the bloodbrain barrier. At the recommended dose of 20 mg, bilastine is non-sedative, does not enhance the effects of alcohol or CNS sedatives, does not impair actual driving tests, shows no cardiotoxicity and has a similar efficacy to other second-generation H 1-antihistamines in the treatment of allergic rhinoconjunctivitis and urticaria. Expert opinion: In view of its favorable pharmacological and clinical characteristics, bilastine is likely to have particular benefit in urticaria for which guidelines recommend increasing the dosage of H 1-antihistamines up to fourfold if standard dosing is ineffective. © 2011 Informa UK, Ltd.


Preissner S.,Charite - Medical University of Berlin
Quintessence international (Berlin, Germany : 1985) | Year: 2013

Amelogenesis imperfecta is a hereditary disease affecting the quality and quantity of enamel with a prevalence of 1:700 to 1:14,000. Patients suffer from dental sensitivity and compromised esthetics. The conservative treatment of choice is based on ceramic crowns, but preparation design is unnecessarily destructive to tooth tissue. This case report describes a noninvasive technique with adhesively inserted occlusal composite resin crowns.


Schlattmann P.,Friedrich - Schiller University of Jena | Dirnagl U.,Charite - Medical University of Berlin
Journal of Cerebral Blood Flow and Metabolism | Year: 2010

A common setting in experimental cerebrovascular research is the comparison of more than two experimental groups. Often, continuous measures such as infarct volume, cerebral blood flow, or vessel diameter are the primary variables of interest. This article presents the principles of the statistical analysis of comparing more than two groups using analysis of variance (ANOVA). We will also explain post hoc comparisons, which are required to show which groups significantly differ once ANOVA has rejected the null hypothesis. Although statistical packages perform ANOVA and post hoc contrast at a key stroke, in this study, we use examples from experimental stroke research to reveal the simple math behind the calculations and the basic principles. This will enable the reader to understand and correctly interpret the readout of statistical packages and to help prevent common errors in the comparison of multiple means. © 2010 ISCBFM All rights reserved.


Kamphans T.,GeneTalk | Krawitz P.M.,Charite - Medical University of Berlin
Bioinformatics | Year: 2012

Next-generation sequencing has become a powerful tool in personalized medicine. Exomes or even whole genomes of patients suffering from rare diseases are screened for sequence variants. After filtering out common polymorphisms, the assessment and interpretation of detected personal variants in the clinical context is an often time-consuming effort. We have developed GeneTalk, a web-based platform that serves as an expert exchange network for the assessment of personal and potentially disease-relevant sequence variants. GeneTalk assists a clinical geneticist who is searching for information about specific sequence variants and connects this user to other users with expertise for the same sequence variant. © The Author 2012. Published by Oxford University Press.


Chronic heart failure is a severe disease with increasing importance and difficult prognosis. Patient education is an essential component of medical rehabilitation, which is aimed at increasing self-management abilities and reducing mental symptom load in these patients. A newly developed patient education programme for heart failure was implemented as part of a three-week cardiac rehabilitation programme. The present study dealt with patients' acceptance of this programme, changes in disease-related knowledge, perceived health- and illness-related quality of life, and mental symptoms over the treatment course. During inpatient cardiac rehabilitation, 64 patients (79.7% male) participated in this competence-focused programme for patients with chronic heart failure. Before, directly after and 6 months after participation in the programme, they filled in self-rating questionnaires on their mental wellbeing (HADS anxiety and depression), quality of life (SF-36, KCCQ), and a test of their knowledge on heart-related disease behavior. Additionally they were given an evaluation-questionnaire of the programme. Evaluation of the programme given by the patients was very good. Knowledge and perceived quality of life had increased significantly at the end and 6 months after rehabilitation. Mental symptoms of anxiety and depressivity were reduced directly and also 6 months after rehabilitation. Over the course of a multidimensional cardiac rehabilitation programme focusing on training of disease-directed competences, patients felt better and were better informed. However, special attention needs to be given to possible deterioration effects education programmes can have in patients with increased trait-anxiety or hypochondriac tendencies. © Georg Thieme Verlag KG Stuttgart · New York.


Zouboulis C.C.,Dessau Medical Center | Zouboulis C.C.,Charite - Medical University of Berlin
JDDG - Journal of the German Society of Dermatology | Year: 2010

Isotretinoin (13-cis retinoic acid) is the most potent known inhibitor of sebum production. The multiple modes of action for isotretinoin, including suppression of sebaceous gland activity, normalization of the pattern of keratinization within the sebaceous gland follicle, inhibition of inflammation, reduction of growth of Propionibacterium acnes in a secondary manner and, as currently shown, normalization of the expression of matrix tissue metalloproteinases and their inhibitors make this compound the single most effective in the treatment of severe recalcitrant nodulocystic acne, and in the prevention of acne scarring. Several generic formulations for oral use have recently been introduced, in addition to the brand formulations Roaccutane® and Accutane™ (Roche). This development, considering the high risk of teratogenicity associated with oral isotretinoin use, has led the European Commission and the European Medicines Agency (EMEA) to release a directive towards the harmonization of the Summary of Product Characteristics (SPC). This has similarities to US FDA regulations, a matter that caused the reaction of the Forum for the Improvement of Clinical Trials in Acne. Physician's experience, coupled with proper patient selection, dose adjustment or discontinuation of treatment, and routine monitoring for potential toxicity, has allowed the successful prevention and management of most adverse effects associated with isotretinoin. © Blackwell Verlag GmbH.


Lehmann A.,Charite - Medical University of Berlin
Molecular cell | Year: 2010

The proteasome, the central protease of eukaryotic cells, is composed of one core particle (CP) and one or two adjacent regulatory particles (RP), which contain multiple subunits. Several proteasome-dedicated chaperones govern the assembly of CP and RP, respectively. We sought for proteins that regulate final steps of RP-CP assembly in yeast and found Ecm29, a conserved HEAT-like repeat protein. Here, we show that Ecm29 controls the integrity of RP-CP assemblies. Ecm29 recognizes RP-CP species in which CP maturation is stalled due to the lack of distinct beta subunits. Reconstitution assays revealed that Ecm29 functions as scaffold protein during the remodeling of incompletely matured RP-CP assemblies into regular enzymes. Upon the completion of CP maturation, Ecm29 is degraded and RP-CP is dissociated. Copyright (c) 2010 Elsevier Inc. All rights reserved.


Kuhn S.,Max Planck Institute for Human Development | Gallinat J.,Charite - Medical University of Berlin | Gallinat J.,University of Hamburg
Addiction Biology | Year: 2015

In the past decades, the Internet has become one of the most important tools to gather information and communicate with other people. Excessive use is a growing concern of health practitioners. Based on the assumption that excessive Internet use bears resemblance with addictive behaviour, we hypothesized alterations of the fronto-striatal network in frequent users. On magnetic resonance imaging scans of 62 healthy male adults, we computed voxel-based morphometry to identify grey matter (GM) correlates of excessive Internet use, assessed by means of the Internet Addiction Test (IAT) and functional connectivity analysis and amplitude of low-frequency fluctuation (ALFF) measures on resting state data to explore the functional networks associated with structural alterations. We found a significant negative association between the IAT score and right frontal pole GM volume (P-<-0.001, family wise error corrected). Functional connectivity of right frontal pole to left ventral striatum was positively associated with higher IAT scores. Furthermore, the IAT score was positively correlated to ALFF in bilateral ventral striatum. The alterations in the fronto-striatal circuitry associated with growing IAT scores could reflect a reduction of top-down modulation of prefrontal areas, in particular, the ability to maintain long-term goals in face of distraction. The higher activation of ventral striatum at rest may indicate a constant activation in the context of a diminished prefrontal control. The results demonstrate that excessive Internet use may be driven by neuronal circuits relevant for addictive behaviour. The Internet has become one of the most important tools to gather information and communicate with other people. Excessive use is a growing concern of health practitioners. We examined its neural correlates and found a negative association between the internet addiction test (IAT) score and right frontal pole grey matter volume. Functional connectivity of right frontal pole to left ventral striatum was positively associated with higher IAT scores and IAT score was positively correlated to ALFF in bilateral ventral striatum. © 2014 Society for the Study of Addiction.


Hoffmann J.,Charite - Medical University of Berlin | Goadsby P.J.,University of California at San Francisco
Current Opinion in Neurology | Year: 2013

Purpose of Review: The aim of this article is to review recent findings on the pathophysiology of idiopathic changes in intracranial pressure. The review will focus on idiopathic intracranial hypertension (IIH) and spontaneous intracranial hypotension (SIH). Recent Findings: Substantial evidence indicates that IIH is associated with delayed absorption of cerebrospinal fluid (CSF). Stenoses of the transverse sinus are common in IIH, but their clinical significance has not been entirely clarified. Despite the observed efficacy of endovascular treatment in some IIH patients, a correlation between the extent of observed stenoses and the clinical course of the disease could not be demonstrated. The underlying cause of SIH is a spontaneous CSF leakage into the epidural space. Conservative treatment and the epidural blood patch remain the treatment of choice for this rare syndrome. Summary: Recent clinical evidence indicates that IIH is probably a result of CSF outflow abnormality rather than of CSF production. Further research is needed to elucidate the causes of elevated intracranial pressure and the mechanism leading to visual loss. Prospective randomized clinical trials are needed to clarify a possible therapeutic potential of endovascular treatment. Research efforts on SIH should focus further on associated connective tissue disorders predisposing to CSF leaks. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Buttgereit F.,Charite - Medical University of Berlin | Gibofsky A.,Cornell University
Expert Opinion on Pharmacotherapy | Year: 2013

Introduction: Despite the widespread use of glucocorticoid (GC) treatment for inflammatory conditions, there remains a need to optimize use by improving efficacy and/or reducing adverse consequences. The most advanced approach, already licensed for clinical use, is delayed-release prednisone. Areas covered: Delayed-release prednisone consists of an inert outer coat containing an inner core of active drug (1, 2, or 5 mg) taken at bedtime (approximately 22:00 h). After a lag time of 4-6 h, the coat opens to release prednisone, at the appropriate time to counteract elevated nocturnal levels of pro-inflammatory cytokines associated with the circadian pattern of symptoms seen in rheumatoid arthritis (RA) and other inflammatory conditions. Clinical trials in RA have demonstrated the improved efficacy of delayed-release prednisone with respect to morning stiffness compared with conventional immediate-release prednisone tablets taken in the morning and compared with placebo in patients on disease-modifying antirheumatic treatment; the incidence of adverse events was similar to the comparator. Preliminary studies in polymyalgia rheumatica and asthma suggest that delayed-release prednisone may also have benefits in these conditions. Expert opinion: Delayed-release prednisone offers an effective way to improve the benefit:risk ratio of GC treatment for inflammatory conditions with circadian features. © 2013 Informa UK, Ltd.


Zuberbier T.,Charite - Medical University of Berlin
Journal of the European Academy of Dermatology and Venereology | Year: 2012

Chronic urticaria (CU) is a long-lasting and distressing condition that impairs patient quality of life (QoL) by disrupting sleep and diminishing work/school productivity. Thus treatment should not only be safe and effective but also not add to this impairment or increase risks to health or safety. Non-sedating second-generation antihistamines, with their long duration of action, pharmacodynamic properties that allow once-daily dosing and lack of drug-drug interactions and sedative effects, are the first-line symptomatic treatment option, but some patients have no adequate response to standard doses of these medications. Other therapeutic approaches to refractory urticaria have been suggested but have been limited by sparse clinical data and/or significant adverse effect profiles. Although discouraged by treatment guidelines, sedating antihistamines are frequently prescribed for nighttime use when urticaria symptoms are severe as add-on therapy to a non-sedating antihistamine. However, their pronounced effects on rapid eye movement sleep and hangover negatively impact QoL, learning and performance, and limit their use for patients in occupations that require alertness. For patients who do not respond adequately to standard doses of non-sedating second-generation antihistamines, increasing the dose of non-sedating antihistamines thus may represent the safest therapeutic approach. Given the fact that only few controlled studies have assessed the efficacy and safety of high-dose non-sedating antihistamines in CU, patient safety should be a key consideration when choosing a specific antihistamine. © 2011 he Authors.


Walach H.,European University Viadrina | Teut M.,Charite - Medical University of Berlin
Homeopathy | Year: 2015

Background: Homeopathic drug provings or pathogenetic trials (HPTs) are the pillar of homeopathy. This review summarizes the authors' findings and interpretations derived from a series of homeopathic drug proving between 1994 and 2015. It gives an overview over a series of attempts to use modern scientific experimental methodology to answer the question, whether such HPTs produce symptoms in healthy volunteers that can be distinguished from placebo symptoms. Methods: Various experimental models were used: repeated crossover trials with categorical data collection, and a single-case, randomised study. Final models use diligent qualitative data-collection in experienced volunteers. In those, raters decide whether symptoms are typical for a remedy delivered or not. The design is triple-blind and placebo-controlled. Result: While previous attempts were inconclusive, this new model allowed to separate placebo symptoms from verum symptoms repeatedly in a series of two definitive studies following promising pilot studies. Results were statistically significant. Also, some signs of the purported non-local signature of homeopathic effects were visible, and the consequences for future methodology is discussed. Conclusion: Provided some cautionary notes are taken into account, HPTs can be used to separate out true specific symptoms from placebo symptoms. By the same token this is a road to experimental proof that homeopathic remedies are not just placebos. However, this needs to be taken forward by independent groups. © 2015 The Faculty of Homeopathy.


Singh N.B.,Charite - Medical University of Berlin
PloS one | Year: 2012

Fluctuations during isometric force production tasks occur due to the inability of musculature to generate purely constant submaximal forces and are considered to be an estimation of neuromuscular noise. The human sensori-motor system regulates complex interactions between multiple afferent and efferent systems, which results in variability during functional task performance. Since muscles are the only active component of the motor system, it therefore seems reasonable that neuromuscular noise plays a key role in governing variability during both standing and walking. Seventy elderly women (including 34 fallers) performed multiple repetitions of isometric force production, quiet standing and walking tasks. No relationship between neuromuscular noise and functional task performance was observed in either the faller or the non-faller cohorts. When classified into groups with either nominal (group NOM, 25(th) -75(th) percentile) or extreme (either too high or too low, group EXT) levels of neuromuscular noise, group NOM demonstrated a clear association (r(2)>0.23, p<0.05) between neuromuscular noise and variability during task performance. On the other hand, group EXT demonstrated no such relationship, but also tended to walk slower, and had lower stride lengths, as well as lower isometric strength. These results suggest that neuromuscular noise is related to the quality of both static and dynamic functional task performance, but also that extreme levels of neuromuscular noise constitute a key neuromuscular deficit in the elderly.


Korfel A.,Charite - Medical University of Berlin
Current Opinion in Oncology | Year: 2011

Purpose of Review: This review analyzes most recent data on the risk of central nervous system (CNS) dissemination and the efficacy of current strategies for CNS prophylaxis in diffuse large B-cell lymphoma (DLBCL). Recent Findings: CNS dissemination still remains a rare but usually fatal complication of DLBCL. Although risk models for CNS involvement in DLBCL have been postulated on the basis of clinical findings such as more than one extranodal site, Eastern Cooperative Oncology Group performance status greater than 1, lactate dehydrogenase elevation in serum, B-symptoms, high international prognostic index score and involvement of specific sites their predictive value is relatively low. The choice of drugs and time-point for prophylaxis still remain to be defined; however, there is some evidence supporting the role of systemic CNS-penetrating chemotherapy, in particular high-dose methotrexate (>1g/m2) in the early course of disease. A role for systemic rituximab has been postulated, however, with ambiguous results among studies. Summary: Better identification of risk factors and disease variables associated with CNS involvement in DLBCL including biological and molecular parameters is urgently needed to reduce CNS recurrences through a well designed prophylaxis regimen and to avoid unnecessary intensive and toxic treatments. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Zeiser R.,Albert Ludwigs University of Freiburg | Penack O.,Charite - Medical University of Berlin | Holler E.,University of Regensburg | Idzko M.,Albert Ludwigs University of Freiburg
Journal of Molecular Medicine | Year: 2011

Extensive cell death with consecutive release of danger signals can cause immune-mediated tissue destruction. The abundance of cell death is likely to determine the relevance of the danger signals as physiological mechanisms that counteract immune activation may be overruled. Such constellation is conceivable in chemo-/radiotherapy-induced tissue damage, reperfusion injury, trauma, and severe infection. Studies on graft-versus-host disease (GvHD) development have to consider the effects of chemo-/radiotherapy-related tissue damage leading to the release of exogenous and endogenous danger signals. Our previous work has demonstrated a role for adenosine-5′-triphosphate (ATP) as an endogenous danger signal in GvHD. Besides ATP, uric acid or soluble extracellular matrix components are functional danger signals that activate the NLRP3 inflammasome when released from dying cells or from extracellular matrix. In contrast to sterile inflammation, GvHD is more complex since bacterial components that leak through damaged intestinal barriers and the skin can activate pattern recognition receptors and directly contribute to GvHD pathogenesis. These exogenous danger signals transmit immune activation via toll-like receptors and NOD-like receptors of the innate immune system. This review covers both the impact of endogenous and exogenous danger signals activating innate immunity in GvHD. © 2011 Springer-Verlag.


Poddubnyy D.,Charite - Medical University of Berlin | Rudwaleit M.,Endokrinologikum Berlin and Charite University Medicine
Rheumatic Disease Clinics of North America | Year: 2012

Spondyloarthritis (SpA) is a large family of chronic inflammatory diseases characterized by inflammation of the axial skeleton, a typically asymmetric peripheral arthritis of the lower limbs, enthesitis, typical extra-articular manifestations, and shared genetic background. The prevalence in the general population is up to 2% for the entire group. SpA, particularly ankylosing spondylitis, has been associated with a diagnostic delay of up to 10 years. Important efforts toward shortening this delay have been made, including the development of new classification criteria. This article discusses the current concept of the disease, typical manifestations, advances in diagnosis, and current treatment recommendations. © 2012 Elsevier Inc.


Ocker M.,University of Marburg | Hopfner M.,Charite - Medical University of Berlin
European Surgical Research | Year: 2012

Resistance to cell death induction has been recognized as a hallmark of cancer. Increasing understanding of the underlying molecular events regulating different cell death mechanisms like apoptosis, endoplasmic reticulum stress, autophagy, necroptosis and others has opened new possibilities for targeted interference with these pathways. While conventional chemotherapeutic agents usually inhibit cell cycle progression, DNA replication or mitosis execution, novel agents like small molecule kinase inhibitors also target survival-related kinases and signaling pathways and contribute to overcome resistance to chemotherapy and apoptosis. Additionally, antibodies targeting cellular death receptors have been described to specifically target tumor cells only. This review briefly highlights the pathways involved in (apoptotic) cell death and summarizes the current state of development of specific modulators of cell death and how they can help to improve the tolerability of chemotherapy regimens and increase survival rates in patients with advanced cancer diseases. Copyright © 2012 S. Karger AG.


Sobesky J.,Charite - Medical University of Berlin
Journal of Cerebral Blood Flow and Metabolism | Year: 2012

In ischemic stroke, positron-emission tomography (PET) established the imaging-based concept of penumbra. It defines hypoperfused, but functionally impaired, tissue with preserved viability that can be rescued by timely reperfusion. Diffusion-weighted and perfusion-weighted (PW) magnetic resonance imaging (MRI) translated the concept of penumbra to the concept of mismatch. However, the use of mismatch-based patient stratification for reperfusion therapy remains a matter of debate. The equivalence of mismatch and penumbra, as well as the validity of the classical mismatch concept is questioned for several reasons. First, methodological differences between PET and MRI lead to different definitions of the tissue at risk. Second, the mismatch concept is still poorly standardized among imaging facilities causing relevant variability in stroke research. Third, relevant conceptual issues (e.g., the choice of the adequate perfusion measure, the best quantitative approach to perfusion maps, and the required size of the mismatch) need further refinement. Fourth, the use of single thresholds does not account for the physiological heterogeneity of the penumbra and probabilistic approaches may be more promising. The implementation of this current knowledge into an optimized state-of-the-art mismatch model and its validation in clinical stroke studies remains a major challenge for future stroke research. © 2012 ISCBFM All rights reserved.


Very recently, FOXP1 deficiency was shown to result in a phenotype of intellectual disability with significant speech and language impairment. Behavioral abnormalities should be considered as part of the clinical spectrum. Mild craniofacial abnormalities found in half of the described patients expand the clinical spectrum associated with FOXP1 mutations. Copyright © 2011 S. Karger AG, Basel.


Stockfleth E.,Charite - Medical University of Berlin | Kerl H.,Medical University of Graz | Zwingers T.,Estimate GmbH | Willers C.,Almirall Hermal GmbH
British Journal of Dermatology | Year: 2011

Background: Actinic keratoses (AKs) arise after chronic sun exposure. Because long-term ultraviolet (UV) damage may induce proliferation of atypical keratinocytes, treatment of AKs is recommended. Objectives: To compare 5-fluorouracil 0.5%/salicylic acid 10.0% [low-dose 5-FU/SA (Actikerall®)] with diclofenac 3% in hyaluronic acid (diclofenac HA) and vehicle for the treatment of AKs. Methods: This was a randomized, placebo-controlled, double-blind, parallel-group, multicentre trial. Patients received topical low-dose 5-FU/SA once daily, its vehicle or diclofenac HA twice daily for a maximum of 12 weeks. The final evaluation was at week 20. The primary objectives were to demonstrate the histological clearance rate of one predefined lesion. The secondary objectives were the improvement of treated lesions, tolerability and safety. Results: There were 470 patients with 4-10 AK lesions each (grade I or II) on the face/forehead or bald scalp included in the study. Low-dose 5-FU/SA was superior to diclofenac HA (P < 0.01) and vehicle (P < 0.0001) for histological clearance of one representative lesion 8 weeks post-treatment. In 72.0%, 59 *1% and 44.8% of patients in the low-dose 5-FU/SA, diclofenac HA and vehicle groups, respectively, the week-20 biopsy revealed no AKs. Significantly more lesions were cleared with low-dose 5-FU/SA (74.5%) compared with diclofenac HA (54.6%; P < 0.001) or vehicle (35.5%; P < 0.001). Low-dose 5-FU/SA was superior in terms of complete clinical clearance: 55.4%, vs. diclofenac HA (32.0%, P < 0.001) and vehicle (15.1% P < 0.001). Application-site disorders (mainly burning and inflammation) were more frequent with low-dose 5-FU/SA but mainly of mild to moderate intensity. Conclusions: Topical low-dose 5-FU/SA demonstrated higher histological and clinical clearance rates vs. diclofenac HA or vehicle. Low-dose 5-FU/SA is an effective lesion-directed treatment for AKs. © 2011 British Association of Dermatologists.


Greenblatt D.,Technion - Israel Institute of Technology | Schneider T.,Charite - Medical University of Berlin | Schule C.Y.,German Aerospace Center
Physics of Fluids | Year: 2012

The mechanism of flow separation control was investigated experimentally and computationally using pulse-modulated dielectric barrier discharge (DBD) plasma actuation on a stalled flat plate airfoil at a Reynolds number of 3000. Load measurements were complimented with two-dimensional phase-averaged particle image velocimetry performed in the flowfield above the airfoil. A parametric study was carried out where the pulse-modulation frequency, duty cycle, and peak plasma body-force were varied. The two-dimensional Navier-Stokes equations, with no turbulence modeling, were solved directly using a commercial flow solver and a simple but satisfactory heuristic DBD plasma body-force model was incorporated. The overall experimental trends were well predicted by the computations, where the frequencies that produced the largest increases in lift coefficient excited bluff-body shedding at a frequency corresponding approximately to its unforced sub-harmonic. At non-dimensional frequencies most effective for increasing lift (~0.2 to 0.5), the leading-edge shear layer was severed by the perturbations and then merged with a downstream vortex. In a time-mean sense this mechanism forced relatively high momentum fluid towards the surface with typically two re-circulating structures present on the airfoil. Although the essential flow control mechanism was captured by the computation, the idealized 2D approach was identified as a weakness due to the shedding instability not being present in the baseline experiments and the inability to account for three-dimensional structures in the shear layer. © 2012 American Institute of Physics.


Weinmann S.,Charite - Medical University of Berlin
BMC geriatrics | Year: 2010

BACKGROUND: The benefit of Ginkgo biloba has been discussed controversially. The aim of this review was to assess the effects of Ginkgo biloba in Alzheimer's disease as well as vascular and mixed dementia covering a variety of outcome domains. METHODS: We searched MEDLINE, EMBASE, the Cochrane databases, CINAHL and PsycINFO for controlled trials of ginkgo for Alzheimer's, vascular or mixed dementia. Studies had to be of a minimum of 12 weeks duration with at least ten participants per group. Clinical characteristics and outcomes were extracted. Meta-analysis results were expressed as risk ratios or standardized mean differences (SMD) in scores. RESULTS: Nine trials using the standardized extract EGb761(R) met our inclusion criteria. Trials were of 12 to 52 weeks duration and included 2372 patients in total. In the meta-analysis, the SMDs in change scores for cognition were in favor of ginkgo compared to placebo (-0.58, 95% confidence interval [CI] -1.14; -0.01, p = 0.04), but did not show a statistically significant difference from placebo for activities in daily living (ADLs) (SMD = -0.32, 95% CI -0.66; 0.03, p = 0.08). Heterogeneity among studies was high. For the Alzheimer subgroup, the SMDs for ADLs and cognition outcomes were larger than for the whole group of dementias with statistical superiority for ginkgo also for ADL outcomes (SMD = -0.44, 95% CI -0.77; -0.12, p = 0.008). Drop-out rates and side effects did not differ between ginkgo and placebo. No consistent results were available for quality of life and neuropsychiatric symptoms, possibly due to the heterogeneity of the study populations. CONCLUSIONS: Ginkgo biloba appears more effective than placebo. Effect sizes were moderate, while clinical relevance is, similar to other dementia drugs, difficult to determine.


Olze H.,Charite - Medical University of Berlin
HNO | Year: 2015

The cochlear implant became a very successful method of hearing rehabilitation for patients with profound sensorineural hearing loss. The benefits of the CI extend beyond the medical success and positively influence social and psychosocial areas, reflected by an improved HRQoL. Furthermore, variety of studies demonstrated that the tinnitus severity improves in 46–95 % of cases following the cochlear implantation. However, the parameters investigated in such studies are not always standardized or addressed by validated questionnaires, which explains the high outcome variation between the studies. The relationships between HRQoL and tinnitus distress before and after cochlear implantation have not been well studied. Nevertheless, it is believed that the improvement in HRQoL following CI affects particularly tinnitus. However, an existing tinnitus can also worsen or occur for the first time after the surgery. Since neither tinnitus frequency nor tinnitus loudness correlate with the tinnitus-induced distress, the measurement of HRQoL, distress factors, stress reactions and psychiatric comorbidities appears to be the meaningful assessment of positive or negative effects of CI on tinnitus. Initial studies demonstrated that also patients with unilateral hearing loss may benefit from CI supply, as shown by an improvement in HRQoL and reduction of tinnitus-induced distress. For those patients, who despite CI implantation experience severe tinnitus, there is an option of tinnitus-specific CI-fitting and tinnitus-specific therapy with psychosomatic and psychological approaches, and- in addition- a treatment of possible mental comorbidities. © 2015, Springer-Verlag Berlin Heidelberg.


Ricke J.,Universitatsklinikum Magdeburg | Wust P.,Charite - Medical University of Berlin
Seminars in Radiation Oncology | Year: 2011

Limitations of thermal liver cancer ablation have led to the development of percutaneous, catheter-based brachytherapy for the treatment of liver malignancies. Computed tomography (CT)-guided brachytherapy has been used to treat primary and metastatic liver cancers, including very large tumors >10 cm. Cooling effects by adjacent blood vessels are not a concern in brachytherapy, and the method may be used safely in tumors unsuitable for thermal ablation that are close to the liver hilum due to the relatively high radiation tolerance of bile duct. CT scanning is used for dosimetry planning after catheter implantation and also to guide the catheter placement itself. Major complications, including postinterventional bleeding, are rare despite frequent application of this technique in a salvage situation. Patients with liver cirrhosis have an increased risk for complications. Prospective trials of CT-guided brachytherapy have been performed with promising survival rates for liver metastases and hepatocellular carcinoma, respectively. In this article, the radiobiological and technical properties of CT-guided brachytherapy, appropriate patients for treatment, and prospective trials that have been published to date are reviewed. © 2011 Elsevier Inc.


Obladen M.,Charite - Medical University of Berlin
Neonatology | Year: 2013

Before the microbiologic era, venereal diseases were poorly distinguished. Congenital syphilis was believed to be transmitted during conception by the father's sperm, during delivery in the birth canal, or from infected milk or breasts. The most frequent maternofetal transmission was not considered because the mother's primary infection remained undiagnosed. The concept of treating infants with mercury transmitted by nurses' milk prompted the founding of a specialized infant hospital in Vaugirard in 1780: lactating syphilitic women received mercury orally and by rubbing it into the skin. Their own infant and a second infected infant from the foundling hospital were believed to be cured by their milk. Underwood described snuffles in 1789 and Bertin periosteal bone disease in 1810. Tardive congenital lues with keratitis, deafness, and notched upper incisors were described by Hutchinson in 1863. Feeding remained difficult, as wet nursing transmitted syphilis to the nurse and other infants. Specialized institutions tried goat or donkey milk. A debate between contagionists assuming exclusively maternal infection and hereditists assuming germinal transmission by the father's sperm continued throughout the 19th century. Schaudinn and Hoffmann identified Spirochaeta pallida in 1905. When Ehrlich discovered the efficacy of salvarsan in 1910, Noeggerath treated infants with the new drug, pioneering the injection into scalp veins. In 1943, Lentz and Ingraham established penicillin treatment for congenital syphilis. Whereas this drug effectively prevented maternofetal transmission, treating infants remained difficult due to the Jarisch-Herxheimer reaction. Copyright © 2013 S. Karger AG, Basel.


Gebauer B.,Charite - Medical University of Berlin
RöFo : Fortschritte auf dem Gebiete der Röntgenstrahlen und der Nuklearmedizin | Year: 2013

To review the long term clinical outcomes in the treatment of osteoid osteoma (OO) using radiofrequency ablation (RFA). Our retrospective study included 59 patients who were treated in the period from April 2001 to December 2012 due to a symptomatic OO using RFA. Here, the occurrence of complications and postoperative recurrence, as well as postoperative patient satisfaction were examined. Patients satisfaction was assessed by means of a telephone interview with the visual analogue scale (VAS). Mean follow-up was 50 months (2 - 116 months). The average size of the nidus was 6 mm (range 2 - 14 mm). After initial radiofrequency ablation 11.8 % (7/59) of patient showed a recurrence of symptoms. Symptoms could successfully be treated by a second ablation in 5 patients. Assisted success rate was therefore 96.6 % (57/59). The complication rate was 5.1 % (2 major and one minor complication). Furthermore we report a very high patient satisfaction and acceptance of therapy. RFA is a very successful therapy of symptomatic OOs with a high patient satisfaction. ▶ Osteoid osteomas (OO) are rare benign bone tumors of the childhood and adolescence. ▶ Treatment of OOs with minimal-invasive radiofrequency ablation (RFA) shows a high patient satisfaction. ▶ RFA is by now the standard therapy of symptomatic OOs. © Georg Thieme Verlag KG Stuttgart · New York.


Rao Y.,Free University of Berlin | Rao Y.,Max Planck Institute of Biochemistry | Haucke V.,Free University of Berlin | Haucke V.,Charite - Medical University of Berlin | Haucke V.,Leibniz Institute for Molecular Pharmacology
Cellular and Molecular Life Sciences | Year: 2011

BAR domain superfamily proteins have emerged as central regulators of dynamic membrane remodeling, thereby playing important roles in a wide variety of cellular processes, such as organelle biogenesis, cell division, cell migration, secretion, and endocytosis. Here, we review the mechanistic and structural basis for the membrane curvature-sensing and deforming properties of BAR domain superfamily proteins. Moreover, we summarize the present state of knowledge with respect to their regulation by autoinhibitory mechanisms or posttranslational modifications, and their interactions with other proteins, in particular with GTPases, and with membrane lipids. We postulate that BAR superfamily proteins act as membrane-deforming scaffolds that spatiotemporally orchestrate membrane remodeling. © Springer Basel AG 2011.


Danker-Hopfe H.,Charite - Medical University of Berlin
Progress in Biophysics and Molecular Biology | Year: 2011

The first two decades of life are characterised complex biological processes involving growth and maturation as well as differentiation. The Central Nervous System (CNS) where among others internal and external stimuli are integrated and responses of the body are prepared starts to evolve quite early during ontogenesis. One of the complex behaviours, which are regulated by the brain, is the sleep-wake cycle.The discussion of age-related changes in sleep comprises changes at the physiological level (e.g. changes in the frequency and amplitude of EEG signal, as well as development and distribution of sleep stages), changes in the corresponding behaviour (e.g. changes in the absolute amount of sleep and its distribution in 24. h perspective), and finally the subjective perception of sleep and sleep as a measure of well-being.Studies on the impact of a specific factor on sleep during childhood and adolescence have to consider chronological and biological age as well as sex as relevant biological parameters. Even when these factors are controlled for large interindividual differences persist, that is why prospective instead of cross-sectional approaches should be used whenever possible. Furthermore, it has to be distinguished between sleep assessed at the level of brain functioning (i.e. by polysomnography), which gives information on effects at the physiological level and at the level of self-assessment, which focuses on behaviour. Both, sleep at the subjective as well as at the objective level, can to a considerable degree be affected by life style factors, which hence have to be considered as potential confounders. © 2011 Elsevier Ltd.


Leondaritis G.,University of Ioannina | Eickholt B.J.,Charite - Medical University of Berlin
PLoS Biology | Year: 2015

The branching behaviors of both dendrites and axons are part of a neuronal maturation process initiated by the generation of small and transient membrane protrusions. These are highly dynamic, actin-enriched structures, collectively called filopodia, which can mature in neurons to form stable branches. Consequently, the generation of filopodia protrusions is crucial during the formation of neuronal circuits and involves the precise control of an interplay between the plasma membrane and actin dynamics. In this issue of PLOS Biology, Hou and colleagues identify a Ca2+/CaM-dependent molecular machinery in dendrites that ensures proper targeting of branch formation by activation of the actin nucleator Cobl. © 2015 Leondaritis, Eickholt.


Tsokos M.,Charite - Medical University of Berlin
Forensic Science, Medicine, and Pathology | Year: 2015

Physical abuse of children has many manifestations. Depending on the type of force involved, specific injury patterns are produced on the body of the child, the morphology and localization of which are forensically relevant in terms of diagnostic classification as child abuse. Typical patterned bruising includes, for example, tramline bruises resulting from blows with oblong, stick-like objects. In addition to rounded or one-sided horseshoe-shaped bite injuries, injuries of different ages, clustered injuries (e.g., three or more individual injuries in the same body region), and thermal injuries are typical results of abuse. Abusive scalds are usually characterized by a symmetrical impression and localization with sharp delineation of the scald wound edges, in contrast to accidental scalding injuries with radiating splash patterns ending in tapered points. The coloration of a hematoma can help indicate the time when the injury occurred. Lack of a coherent and comprehensible explanation for accidental injury constitutes grounds for suspecting abuse. Suspicions should be raised in cases of a delayed visit to a doctor, waiting for an unusually long period before summoning emergency medical help for serious injuries to a child, and when differing versions of a purported accident are provided. Documentation of the findings is highly relevant in later reviews of the diagnosis, for instance, when new relevant facts and investigative results come to light in subsequent criminal proceedings. © 2015, Springer Science+Business Media New York.


Kleber C.,Charite - Medical University of Berlin
American journal of disaster medicine | Year: 2013

In-hospital triage is the key factor for successful management of an overwhelming number of patients in lack of treatment capacity. The main goal of in-hospital triage is to identify casualties with life-threatening injuries and to allocate immediate medical aid. For the first time, we evaluate the quality of in-hospital triage in the German capital Berlin. In this prospective observational study of 17 unheralded external mass casualty trainings for Berlin disaster hospitals in 2010/2011, we analyzed the in-hospital triage of 601 rouged casualty actors. Evaluation was performed by structured external survey and interview of the casualty actors after the disaster training. In 93 percent (n = 558), complete data were available and suitable for statistical analysis. The primary triage category was allocated correctly to 61 percent (n = 338) of the simulated injury severity. The following measurements were performed: anamnesis in 77 percent, physical examination 71 percent, blood pressure in 68 percent, heart rate in 61 percent, and oxygen saturation in 25 percent. Additive radiological diagnostics were used: 38 percent X-ray, 16 percent computer tomography, and 7 percent ultrasound. On an average, 1.6 ± 1.2 diagnostic tools were used to allocate injury severity to rouged casualties. Of all the rouged casualties, 24 percent overtriage and 16 percent undertriage were observed. Overtriage was significantly infrequent in level I trauma centers (p = 0.03). Of the patients with life-threatening injuries, 18 percent was undertriaged. Of the 62 percent with secondary right allocation to triage category, re-triage was only used in 4 percent. The accuracy of in-hospital triage is low (61 percent). Predominately, the problem of overtriage (24 percent) due to insufficient triage training in contrast to undertriage (16 percent) occurs. The diagnostic triage adjuncts, ultrasound and re-triage, should be routinely used to lower the rate of undetected life threat in mass casualty incidents. Furthermore, a standardized training program and triage algorithm for in-hospital triage should be established.


Dorner T.,Charite - Medical University of Berlin
Nature Reviews Rheumatology | Year: 2012

From neutrophil extracellular traps to genetic networks that underlie the disease and new targeted therapies, important advances in 2011 improve our understanding of the pathogenesis of systemic lupus erythematosus and mark the beginning of our ability to treat it effectively. © 2012 Macmillan Publishers Limited. All rights reserved.


Von Roth P.,Charite - Medical University of Berlin | Abdel M.P.,Mayo Medical School | Harmsen W.S.,Mayo Medical School | Berry D.J.,Mayo Medical School
Journal of Bone and Joint Surgery - American Volume | Year: 2015

Uncemented jumbo cups are commonly used for acetabular revision because they are technically straightforward to implant and provide good intermediate-term results. Understanding long-term survival is particularly important because this method is common and because jumbo cups do not provide notable bone stock restoration. The purpose of the present study was to determine the twenty-year results of jumbo cup use during revision total hip arthroplasty. In the original publication, we reported on eighty-nine patients who underwent revision with an uncemented jumbo cup with a single design (Harris-Galante) prior to 1993. The Harris Hip Score (HHS), radiographic results, and Kaplan-Meier survivorship curves were evaluated. Mean follow-up was twenty years. The mean postoperative HHS was 71 compared with 56 preoperatively (p = 0.001). A total of five jumbo cups were revised for aseptic loosening; one, for infection; and one, for recurrent dislocation. Eight liners were revised with retention of the metal acetabular component: six during femoral component revision, one for wear, and one for recurrent dislocations. Twenty-year survivorship was 88% free from aseptic loosening of the metal acetabular component, 85% free from aseptic loosening or radiographic evidence of definite loosening of the metal acetabular component, and 83% free fromrevision of the metal acetabular component for any reason. The twenty-year results of revision with uncemented jumbo acetabular components demonstrated acceptable clinical outcomes and radiographic stability. These results justify the use of jumbo cups as a common method of acetabular revision. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. Copyright © 2015 by The Journal of Bone and Joint Surgery, Incorporated.


Seeland U.,Universitaetsmedizin Berlin Charite | Regitz-Zagrosek V.,Universitaetsmedizin Berlin Charite | Regitz-Zagrosek V.,Charite - Medical University of Berlin
Handbook of Experimental Pharmacology | Year: 2012

This chapter outlines sex differences in pharmacokinetics and pharmacodynamics of the most frequently used drugs in cardiovascular diseases, e.g., coronary artery disease, hypertension, heart failure. Retrospective analysis of previously published drug trials revealed marked sex differences in efficacy and adverse effects in a number of cardiovascular drugs. This includes a higher mortality among women taking digoxin for heart failure, more torsade de pointes arrhythmia in QT prolonging drugs and more cough with ACE inhibitors. Trends towards a greater benefit for women and/or female animals have been observed in some studies for endothelin receptor antagonists, the calcium channel blocker amlodipine, the ACE-inhibitor ramipril and the aldosterone antagonist eplerenone. However, reproduction of these results in independent studies and solid statistical evidence is still lacking. Some drugs require a particularly careful dose adaptation in women: the beta-blocker metoprolol, the calcium channel blocker verapamil, loop-, and thiazide diuretics. In conclusion, sex differences in pharmacokinetics and pharmacodynamics have to be taken into account for cardiovascular drug therapy in women. © 2012 Springer-Verlag Berlin Heidelberg.


Church M.K.,Charite - Medical University of Berlin | Church M.K.,University of Southampton
British Journal of Dermatology | Year: 2010

Summary Background European guidelines recommend increasing H 1-antihistamine doses up to fourfold in poorly responding patients with urticaria. Objectives To assess the efficacy and tolerability of high-dose rupatadine (40 mg) against platelet-activating factor (PAF)- and histamine-induced flare responses in human skin and to verify its anti-PAF activity by assessing its inhibition of PAF-induced platelet aggregation in the blood of subjects receiving rupatadine 40 mg. Methods In the flare study, six male volunteers received a single dose of rupatadine 40 mg. Flares were induced before dosing and up to 96 h afterwards by intradermal PAF and histamine. In the ex vivo study, four male volunteers received an oral dose of rupatadine 40 mg and blood samples were taken 4 h afterwards. Platelet aggregation was assessed in platelet-rich plasma by incubation for 5 min with PAF. Results Rupatadine 40 mg reached maximal plasma levels of 15·1 ± 4·4 ng mL -1 at 1 h and its metabolite, desloratadine, 5·2 ± 0·9 ng mL-1 at 2 h. Neither was detectable at 12 h. Inhibition of histamine- and PAF-induced flares was significant within 2 h, maximal at 6 h (87·8 ± 3·1% and 87·1 ± 2·5% inhibition, respectively, P < 0·0001) and still statistically significant at 72 h. Rupatadine 40 mg inhibited PAF-induced platelet aggregation ex vivo by 82 ± 9% (P = 0·023). A single oral dose of rupatadine 40 mg was well tolerated with mild transient somnolence being reported. Conclusions A single dose of rupatadine at four times the recommended dose is well tolerated, highly effective for up to 72 h against PAF- and histamine-induced dermal flares and has demonstrable PAF-receptor antagonism ex vivo. © 2010 British Association of Dermatologists.


Robinson P.N.,Charite - Medical University of Berlin
Human Mutation | Year: 2012

In medical contexts, the word "phenotype" is used to refer to some deviation from normal morphology, physiology, or behavior. The analysis of phenotype plays a key role in clinical practice and medical research, and yet phenotypic descriptions in clinical notes and medical publications are often imprecise. Deep phenotyping can be defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The emerging field of precision medicine aims to provide the best available care for each patient based on stratification into disease subclasses with a common biological basis of disease. The comprehensive discovery of such subclasses, as well as the translation of this knowledge into clinical care, will depend critically upon computational resources to capture, store, and exchange phenotypic data, and upon sophisticated algorithms to integrate it with genomic variation, omics profiles, and other clinical information. This special issue of Human Mutation offers a number of articles describing computational solutions for current challenges in deep phenotyping, including semantic and technical standards for phenotype and disease data, digital imaging for facial phenotype analysis, model organism phenotypes, and databases for correlating phenotypes with genomic variation. 2012. © 2012 Wiley Periodicals, Inc.


Manukyan M.,Albert Ludwigs University of Freiburg | Singh P.B.,Charite - Medical University of Berlin
Genes to Cells | Year: 2012

Induced pluripotent stem (iPS) cells have provided a rational means of obtaining histo-compatible tissues for 'patient-specific' regenerative therapies (Hanna 2010; Yamanaka & Blau 2010). Despite the obvious potential of iPS cell-based therapies, there are certain problems that must be overcome before these therapies can become safe and routine (Ohi 2011; Pera 2011). As an alternative, we have recently explored the possibility of using 'epigenetic rejuvenation', where the specialized functions of an old cell are rejuvenated in the absence of any change in its differentiated state (Singh & Zacouto 2010). The mechanism(s) that underpin 'epigenetic rejuvenation' are unknown and here we discuss model systems, using key epigenetic modifiers, which might shed light on the processes involved. Epigenetic rejuvenation has advantages over iPS cell techniques that are currently being pursued. First, the genetic and epigenetic abnormalities that arise through the cycle of dedifferentiation of somatic cells to iPS cells followed by redifferentiation of iPS cells into the desired cell type are avoided (Gore 2011; Hussein 2011; Pera 2011): epigenetic rejuvenation does not require passage through the de-/redifferentiation cycle. Second, because the aim of epigenetic rejuvenation is to ensure that the differentiated cell type retains its specialized function it makes redundant the question of transcriptional memory that is inimical to iPS cell-based therapies (Ohi 2011). Third, to produce unrelated cell types using the iPS technology takes a long time, around three weeks, whereas epigenetic rejuvenation of old cells will take only a matter of days. Epigenetic rejuvenation provides the most safe, rapid and cheap route to successful regenerative medicine. © 2012 The Authors. Journal compilation © 2012 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.


Strobel C.,Charite - Medical University of Berlin
Journal of controlled release : official journal of the Controlled Release Society | Year: 2011

The local application of antibiotics in combination with timely controlled growth factor delivery might be beneficial for the prevention of infections and to stimulate bone healing. Therefore, in this study a variable sequential drug delivery system with three distinctly different release profiles was developed: i) a burst release of gentamicin, ii) a burst release of IGF-I followed by a sustained release, and iii) a slow sustained release of BMP-2 out of an implant coating. Only one polymer [poly(D,L-lactide)], incorporating gentamicin, IGF-I or BMP-2, was used for two- or three-layer coatings of K-wires. To control the release kinetics, the polymer concentrations in the solvent were varied. The activity of early released gentamicin from a two-layer coating was confirmed microbiologically and BMP-2 stimulated the metabolic activity and alkaline phosphatase activity of C2C12 cells after 2 weeks. From the three-layer coated wires, IGF-I continuously stimulated the cell proliferation, whereas BMP-2 enhanced ALP between 1 and 3 weeks. The sequential release of growth factors revealed an additive effect on the metabolic activity and ALP of primary osteoblast-like cells compared to the single coated controls. The controlled delivery of different factors from one implant might prevent infections and subsequently stimulate the different phases of bone healing. Copyright © 2011 Elsevier B.V. All rights reserved.


Rodelsperger C.,Charite - Medical University of Berlin | Rodelsperger C.,Max Planck Institute for Molecular Genetics | Dieterich C.,Berlin Institute for Medical Systems Biology
PLoS ONE | Year: 2010

Whole genome gene order evolution in higher eukaryotes was initially considered as a random process. Gene order conservation or conserved synteny was seen as a feature of common descent and did not imply the existence of functional constraints. This view had to be revised in the light of results from sequencing dozens of vertebrate genomes. It became apparent that other factors exist that constrain gene order in some genomic regions over long evolutionary time periods. Outside of these regions, genomes diverge more rapidly in terms of gene content and order. We have developed CYNTENATOR, a progressive gene order alignment software, to identify genomic regions of conserved synteny over a large set of diverging species. CYNTENATOR does not depend on nucleotide-level alignments and a priori homology assignment. Our software implements an improved scoring function that utilizes the underlying phylogeny. In this manuscript, we report on our progressive gene order alignment approach, a and give a comparison to previous software and an analysis of 17 vertebrate genomes for conservation in gene order. CYNTENATOR has a runtime complexity of O(n 3) and a space complexity of O(n2) with n being the gene number in a genome. CYNTENATOR performs as good as state-of-the-art software on simulated pairwise gene order comparisons, but is the only algorithm that works in practice for aligning dozens of vertebrate-sized gene orders. Lineage-specific characterization of gene order across 17 vertebrate genomes revealed mechanisms for maintaining conserved synteny such as enhancers and coregulation by bidirectional promoters. Genes outside conserved synteny blocks show enrichments for genes involved in responses to external stimuli, stimuli such as immunity and olfactory response in primate genome comparisons. We even see significant gene ontology term enrichments for breakpoint regions of ancestral nodes close to the root of the phylogeny. Additionally, our analysis of transposable elements has revealed a significant accumulation of LINE-1 elements in mammalian breakpoint regions. In summary, CYNTENATOR is a flexible and scalable tool for the identification of conserved gene orders across multiple species over long evolutionary distances. © 2010 Rödelsperger.


von Kleist L.,Free University of Berlin | Haucke V.,Free University of Berlin | Haucke V.,Charite - Medical University of Berlin | Haucke V.,Leibniz Institute for Molecular Pharmacology
Traffic | Year: 2012

Intracellular membrane traffic regulates cell physiology at multiple levels ranging from cell growth and development to the function of the nervous and immune systems. Multiple endocytic routes are used by distinct cargoes including ligands bound to their receptors but also viruses and pathogens to gain access to the cell interior. Within the endosomal system, proteins and lipids are sorted for degradation or recycling allowing cells to dynamically respond to environmental signals and to regulate cell shape and morphology. Some receptors or toxins are sorted along the retrograde pathway from endosomes to the Golgi complex, where they intersect with secretory cargo destined for exocytosis. Genetic manipulations of these pathways frequently cause problems with regard to data interpretation as the resulting phenotypes may be indirect consequences resulting from perturbation of multiple steps or trafficking routes. Hence, novel approaches are needed to acutely and reversibly perturb intracellular membrane traffic, e.g. by small molecule inhibitors. Such drugs may also be pharmacologically important as they offer new avenues to fight human diseases. Here, we provide an overview of the small molecules available to interfere with intracellular membrane traffic and outline strategies for future research. © 2011 John Wiley & Sons A/S.


Hewing B.,New York University | Hewing B.,Charite - Medical University of Berlin | Fisher E.A.,New York University
Current Opinion in Lipidology | Year: 2012

Purpose of Review: Raising HDL cholesterol (HDL-C) has become an attractive therapeutic target to lower cardiovascular risk in addition to statins. Inhibition of the cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL to apolipoprotein B-containing particles, leads to a substantial increase in HDL-C levels. Various CETP inhibitors are currently being evaluated in phase II and phase III clinical trials. However, the beneficial effect of CETP inhibition on cardiovascular outcome remains to be established. Recent Findings: Torcetrapib, the first CETP inhibitor tested in a phase III clinical trial (ILLUMINATE), failed in 2006 because of an increase in all-cause mortality and cardiovascular events that subsequently were attributed to nonclass-related off-target effects (particularly increased blood pressure and low serum potassium) related to the stimulation of aldosterone production. Anacetrapib, another potent CETP inhibitor, raises HDL-C levels by approximately 138% and decreases LDL cholesterol (LDL-C) levels by approximately 40%, without the adverse off-targets effects of torcetrapib (DEFINE study). The CETP modulator dalcetrapib raises HDL-C levels by approximately 30% (with only minimal effect on LDL-C levels) and proved safety in the dal-VESSEL and dal-PLAQUE trials involving a total of nearly 600 patients. Evacetrapib, a relatively new CETP inhibitor, exhibited favorable changes in the lipid profile in a phase II study. Summary: The two ongoing outcome trials, dal-OUTCOMES (dalcetrapib) and REVEAL (anacetrapib), will provide more conclusive answers for the concept of reducing cardiovascular risk by raising HDL-C with CETP inhibition. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Obladen M.,Charite - Medical University of Berlin
Neonatology | Year: 2012

Wet nursing was widely practiced from antiquity. For the wealthy, it was a way to overcome the burdens of breastfeeding and increase the number of offspring. For the poor, it was an organized industry ensuring regular payment, and in some parishes the major source of income. The abuse of wet nursing, especially the taking in of several nurslings, prompted legislation which became the basis of public health laws in the second half of the 19th century. The qualifications demanded from a mercenary nurse codified by Soran in the 2nd century CE remained unchanged for 1,700 years. When artificial feeding lost its threat thanks to sewage disposal, improved plumbing, the introduction of rubber teats, cooling facilities and commercial formula, wet nursing declined towards the end of the 19th century. Copyright © 2012 S. Karger AG, Basel.


Blankenstein T.,Max Delbruck Center for Molecular Medicine | Blankenstein T.,Charite - Medical University of Berlin | Coulie P.G.,Catholic University of Louvain | Gilboa E.,University of Miami | Jaffee E.M.,Johns Hopkins University
Nature Reviews Cancer | Year: 2012

Many standard and targeted therapies, as well as radiotherapy, have been shown to induce an anti-tumour immune response, and immunotherapies rely on modulating the host immune system to induce an anti-tumour immune response. However, the immune response to such therapies is often reliant on the immunogenicity of a tumour. Tumour immunogenicity varies greatly between cancers of the same type in different individuals and between different types of cancer. So, what do we know about tumour immunogenicity and how might we therapeutically improve tumour immunogenicity? We asked four leading cancer immunologists around the world for their opinions on this important issue. © 2012 Macmillan Publishers Limited. All rights reserved.


Ufer C.,Charite - Medical University of Berlin
Current Protein and Peptide Science | Year: 2012

The mechanisms that drive the expression of a gene into its final protein product can be sub-divided into three levels: transcriptional, post-transcriptional and post-translational events. To facilitate the development and maintenance of a multi-cellular organism precise regulatory circuits are needed to ensure the survival of the organism and its ability to respond to changes in its environment. The key element of post-transcriptional regulation is RNA. Within the cell RNA exists in the form of ribonucleoproteins (RNPs), which are characterised by the underlying RNA and the proteins that are associated to it. The eukaryotic cell contains a vast plethora of RNA-binding proteins (RBPs) that control the complex fate of cellular RNAs. One of such RBPs is Guanine-rich sequence binding factor 1 (Grsf1). Grsf1 belongs to a group of heterogeneous nuclear RNPs that are characterised by the presence of an RNA binding domain designated RNA recognition motif (RRM). Grsf1 is present in most eukaryotic cells and is located in the nucleus as well as in the cytoplasm. Thus, its activity has been related to nuclear processes (RNA splicing) as well as cytoplasmic events (translation initiation). However, its full functional significance is not yet understood. Grsf1 has been implicated in the influenza viral life cycle, embryonic brain development and the regulation of apoptosis. Moreover, Grsf1 is a functional component of several cellular signalling pathways as well as of the regulation of the cellular redox homeostasis. This review summarises the present knowledge of Grsf1 biology to bring the scattered reports of Grsf1 function into a proper context. © 2012 Bentham Science Publishers.


Blume-Peytavi U.,Charite - Medical University of Berlin
Journal of the European Academy of Dermatology and Venereology : JEADV | Year: 2012

Children with chronic atopic dermatitis (AD)-related itch require a comprehensive treatment approach that addresses the underlying cause of pruritus, as well as symptoms and complications that extend beyond the physical domain. In small children and infants, the short-term complications of quality of life disturbance and sleep dysfunction are closely associated with the course of adolescent development. In addition, the physical damage that results from uncontrolled pruritus and scratching can lead to disease chronification. Therefore, the rapid relief of acute pruritic flares, followed by the long-term maintenance of symptom-free skin, should be prioritized in AD treatment, in an effort to avoid the emotional, social and physical chronic manifestations described above. Alleviation of AD symptoms with fourth-generation topical anti-inflammatory agents like methylprednisolone aceponate is an appropriate choice of therapy for children and infants, due to its optimized therapeutic index and versatility in formulation. Especially in AD, supplemental disease management education should be considered, to address the psycho-social needs of children (and their families) suffering from pruritus. © 2012 The Author. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.


Stengel A.,Charite - Medical University of Berlin | Tache Y.,University of California at Los Angeles
Journal of Neurogastroenterology and Motility | Year: 2012

Ingestion of food affects secretion of hormones from enteroendocrine cells located in the gastrointestinal mucosa. These hormones are involved in the regulation of various gastrointestinal functions including the control of food intake. One cell in the stomach, the X/A-like has received much attention over the past years due to the production of ghrelin. Until now, ghrelin is the only known orexigenic hormone that is peripherally produced and centrally acting to stimulate food intake. Subsequently, additional peptide products of this cell have been described including desacyl ghrelin, obestatin and nesfatin-1. Desacyl ghrelin seems to be involved in the regulation of food intake as well and could play a counter-balancing role of ghrelin's orexigenic effect. In contrast, the initially proposed anorexigenic action of obestatin did not hold true and therefore the involvement of this peptide in the regulation of feeding is questionable. Lastly, the identification of nesfatin-1 in the same cell in different vesicles than ghrelin extended the function of this cell type to the inhibition of feeding. Therefore, this X/A-like cell could play a unique role by encompassing yin and yang properties to mediate not only hunger but also satiety. © 2012 The Korean Society of Neurogastroenterology and Motility.


Utku N.,Charite - Medical University of Berlin
Future Oncology | Year: 2012

Oncology therapeutics are less likely to reach the market than other therapeutics, at a higher cost, and only approximately one in ten cancer drugs in clinical development actually reach the market. To improve, there need to be new approaches to oncology research and development, based on understanding cancer biology and improving preclinical models and clinical trials, such as more use of biomarkers and evaluation of other targets including cancer stem cells and use of combination therapies. Biomarkers can be used to make early go/no-go decisions in drug development and can speed up drug development by selecting patients who will benefit and excluding patients likely to experience severe side effects, but they need validation before use. New approaches to preclinical and clinical trials can also speed up and improve the development of cancer therapeutics. © 2012 Future Medicine Ltd.


Schomburg L.,Charite - Medical University of Berlin
Nature reviews. Endocrinology | Year: 2012

The trace element selenium is an essential micronutrient that is required for the biosynthesis of selenocysteine-containing selenoproteins. Most of the known selenoproteins are expressed in the thyroid gland, including some with still unknown functions. Among the well-characterized selenoproteins are the iodothyronine deiodinases, glutathione peroxidases and thioredoxin reductases, enzymes involved in thyroid hormone metabolism, regulation of redox state and protection from oxidative damage. Selenium content in selenium-sensitive tissues such as the liver, kidney or muscle and expression of nonessential selenoproteins, such as the glutathione peroxidases GPx1 and GPx3, is controlled by nutritional supply. The thyroid gland is, however, largely independent from dietary selenium intake and thyroid selenoproteins are preferentially expressed. As a consequence, no explicit effects on thyroid hormone profiles are observed in healthy individuals undergoing selenium supplementation. However, low selenium status correlates with risk of goiter and multiple nodules in European women. Some clinical studies have demonstrated that selenium-deficient patients with autoimmune thyroid disease benefit from selenium supplementation, although the data are conflicting and many parameters must still be defined. The baseline selenium status of an individual could constitute the most important parameter modifying the outcome of selenium supplementation, which might primarily disrupt self-amplifying cycles of the endocrine-immune system interface rectifying the interaction of lymphocytes with thyroid autoantigens. Selenium deficiency is likely to constitute a risk factor for a feedforward derangement of the immune system-thyroid interaction, while selenium supplementation appears to dampen the self-amplifying nature of this derailed interaction.


Meyer-Lueckel H.,University of Kiel | Tschoppe P.,Charite - Medical University of Berlin
Journal of Dentistry | Year: 2010

Objective: Besides the use of saliva substitutes, patients suffering from hyposalivation are instructed to apply fluoride products to prevent caries. Some saliva substitutes have been shown to demineralise enamel; an effect that might be counteracted by the application of fluoride gels or mouthrinses. Combined use of these products with remineralising or neutral saliva substitutes might result in more pronounced remineralisation. Methods: Demineralised bovine enamel specimens were either stored in mineral water [W, control; saturation with respect to octacalcium phosphate (SOCP): 0.7], an experimental demineralising carboxymethylcellulose (CMC)-based solution (C, SOCP: 0.3), or in a modified (SOCP) saliva substitute [Saliva natura (SN), SOCP: 1.6] for five weeks (37 °C). After two weeks half of the exposed surfaces were nail varnished. The following treatments were applied twice daily for 10 min each time (n = 14-18/group): 1: no treatment, 2: Meridol mouthrinse, 3: Elmex sensitive mouthrinse, 4: ProSchmelz fluoride gel, and 5: Elmex gelée. Mineral parameters before and after storage were evaluated from microradiographs. Results: Specimens stored in C showed significantly higher mineral loss compared to W and SN (p < 0.05; ANOVA). For C additional use of fluorides resulted in less demineralisation (p < 0.05) compared to C alone. SN in combination with ProSchmelz led to significantly higher remineralisation compared to all other groups (p < 0.05). Conclusions: Use of fluorides reduces the detrimental effects of the demineralising solution. Treatment with ProSchmelz in combination with storage in a saliva substitute supersaturated with respect to OCP yielded to most pronounced remineralisation under the conditions chosen. © 2010 Elsevier Ltd. All rights reserved.


Wunder A.,Charite - Medical University of Berlin
Epilepsia | Year: 2012

The blood-brain barrier (BBB) is a highly complex structure, which separates the extracellular fluid of the central nervous system (CNS) from the blood of CNS vessels. A wide range of neurologic conditions, including stroke, epilepsy, Alzheimer's disease, and brain tumors, are associated with perturbations of the BBB that contribute to their pathology. The common consequence of a BBB dysfunction is increased permeability, leading to extravasation of plasma constituents and vasogenic brain edema. The BBB impairment can persist for long periods, being involved in secondary inflammation and neuronal dysfunction, thus contributing to disease pathogenesis. Therefore, reliable imaging of the BBB impairment is of major importance in both clinical management of brain diseases and in experimental research. From landmark studies by Ehrlich and Goldman, the use of dyes (probes) has played a critical role in understanding BBB functions. In recent years methodologic advances in morphologic and functional brain imaging have provided insight into cellular and molecular interactions underlying BBB dysfunction in animal disease models. These imaging techniques, which range from in situ staining to noninvasive in vivo imaging, have different spatial resolution, sensitivity, and capacity for quantitative and kinetic measures of the BBB impairment. Despite significant advances, the translation of these techniques into clinical applications remains slow. This review outlines key recent advances in imaging techniques that have contributed to the understanding of BBB dysfunction in disease and discusses major obstacles and opportunities to advance these techniques into the clinical realm. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.


Plockinger U.,Charite - Medical University of Berlin
International Journal of Endocrinology | Year: 2012

This paper outlines the present status of medical therapy of acromegaly. Indications for permanent postoperative treatment, postirradiation treamtent to bridge the interval until remission as well as primary medical therapy are elaborated. Therapeutic efficacy of the different available drugssomatostatin receptor ligands (SRLs), dopamine agonists, and the GH antagonist Pegvisomantis discussed, as are the indications for and efficacy of their respective combinations. Information on their mechanism of action, and some pharmakokinetic data are included. Special emphasis is given to the difficulties to define remission criteria of acromegaly due to technical assay problems. An algorithm for medical therapy in acromegaly is provided. Copyright © 2012 U. Plckinger.


Schoknecht K.,Charite - Medical University of Berlin
Epilepsia | Year: 2012

The blood-brain barrier, a unique feature of the cerebral vasculature, is gaining attention as a feature in common neurologic disorders including stroke, traumatic brain injury, epilepsy, and schizophrenia. Although acute blood-brain barrier dysfunction can induce cerebral edema, seizures, or neuropsychiatric symptoms, epileptogenesis and cognitive decline are among the chronic effects. The mechanisms underlying blood-brain barrier dysfunction are diverse and may range from physical endothelial damage in traumatic brain injury to degradation of extracellular matrix proteins via matrix metalloproteinases as part of an inflammatory response. Clinically, blood-brain barrier dysfunction is often detected using contrast-enhanced imaging. However, these techniques do not give any insights into the underlying mechanism. Elucidating the specific pathways of blood-brain barrier dysfunction at different time points and in different brain diseases using novel imaging techniques promises a more accurate blood-brain barrier terminology as well as new treatment options and personalized treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.


Astrocytes are increasingly recognized as equal partners to neurons, also contributing to neurologic disorders such as epilepsy. Activated astrocytes are a common hallmark in patients with mesial temporal lobe epilepsy and Ammon's horn sclerosis. Blood-brain barrier (BBB) opening during status epilepticus has short-term proepileptic effects, as the ionic composition of serum interferes with neuronal excitability. In the long run, astrocytic uptake of albumin induces transforming growth factor β (TGFβ)-mediated signaling cascades, leading to changes in astrocytic properties. Down-regulation of astrocytic inward rectifier K(+) channels and altered surface expression of the water channel, aquaporin 4 results in disturbances in spatial K(+) buffering, thereby rendering the tissue more seizure prone. The expression of astrocytic gap junctional proteins connexin 43 (Cx43) and connexin 30 (Cx30) is altered in epilepsy, and changes in gap junctional communication were found in sclerotic hippocampal tissue in animal models of epilepsy. Although gap junctional communication might exert both proepileptic and antiepileptic effects, double knock out of Cx43 and Cx30 resulted in occurrence of spontaneous epileptiform events. Seizures are associated with massive increases in cerebral blood flow in order to cover the increased energy demand. Hemodynamic responses at the microcirculation level are mediated by astrocyte-pericyte interactions, sharing common mechanisms with spatial K(+) buffering. Although many of the astrocytic mechanisms involving spatial K(+) buffering, nitric oxide, adenosine, and metabotropic glutamate receptor (mGluR)-mediated signalling are altered in epilepsy, little is known how these alterations affect neurovascular coupling. In conclusion, astrocytic activation preceding alterations in neuronal function might critically contribute to epileptogenesis. Therefore, astrocytes represent a promising new target for the development of antiepileptic drugs. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.


Schumann R.R.,Charite - Medical University of Berlin
Biochemical Society Transactions | Year: 2011

LBP [LPS (lipopolysaccharide)-binding protein] was discovered approximately 25 years ago. Since then, substantial progress has been made towards our understanding of its function in health and disease. Furthermore, the discovery of a large protein family sharing functional and structural attributes has helped in our knowledge. Still, key questions are unresolved, and here an overview on the old and new findings on LBP is given. LBP is an acute-phase protein of the liver, but is also synthesized in other cells of the organism. While LBP is named after the ability to bind to LPS of Gram-negative bacteria, it also can recognize other bacterial compounds, such as lipopeptides. It has been shown that LBP is needed to combat infections; however, the main mechanism of action is still not clear. New findings on natural genetic variations of LBP leading to functional consequences may help in further elucidating the mechanism of LBP and its role in innate immunity and disease. ©The Authors Journal compilation ©2011 Biochemical Society.


Hellweg R.,Charite - Medical University of Berlin | Janetzky W.,Lundbeck | Hartmann S.,Merz Pharmaceuticals GmbH
International Journal of Geriatric Psychiatry | Year: 2012

Objective Responder analyses are of relevance to evaluate the benefits of a medical treatment. The aim of the current paper is to analyse the response of patients with moderate to severe Alzheimer's disease (AD) to memantine, and clinical relevant response is defined as a delay of clinical worsening. Methods Post hoc analyses were performed over the results of nine individual clinical trials including 2506 study patients. Overall, estimates of the odds ratio (OR) and corresponding confidence intervals were based upon a random-effect model for three individual domains (cognition, activities of daily living and clinical global impression). In addition, a combined responder criterion (triple response) includes all three individual domains. Results Responder analyses have shown that AD patients treated with memantine benefited from a significant delay of clinical worsening compared with placebo-treated patients, and fewer patients faced clinical worsening in the relevant domains cognition (24.6% vs 36.2%, p<0.001), activities of daily living (56.2% vs 61.6%, p<0.05) and global impression of change (40.9% vs 49.8, p<0.001). In addition, response to treatment on the combined domains (triple response) was significantly in favour of memantine compared with placebo, with fewer patients showing clinical worsening (11.0% vs 20.4%, p<0.001). Conclusions Treatment with memantine delays clinical worsening in patients with moderate to severe AD when compared with placebo. This effect was seen in single domains (cognition, functional abilities and clinical global impression) as well as in the combination of these domains. The consistent results prove the beneficial effects of memantine in moderate to severe AD patients. Copyright © 2011 John Wiley & Sons, Ltd.


Schimke I.,Charite - Medical University of Berlin | Jaffe A.,Mayo Medical School
Clinica Chimica Acta | Year: 2011

Background: PAPP-A is promising in improving risk stratification and invasive treatment decisions in stable cardiovascular patients. We evaluated the prognostic value of pregnancy-associated plasma protein A (PAPP-A) measured by a novel assay in stable cardiovascular patients. Methods: We investigated 228 stable cardiovascular outpatients. Blood was drawn for PAPP-A measurement after echocardiography and ergometry prior to heart catheterization. Angiographically we determined severity as well as qualitative characteristics suspect for vulnerability of coronary lesions. After 1108 ± 297. days, follow-up information was obtained by questionnaire mailings and interviews by phone. Results: 104 patients had coronary stenosis ≥ 70%, 75 had B-type lesions ≥ 50%, 46 showed complex lesions, and 68 were suspected to have vulnerable lesions. Median PAPP-A was 1.76 (interquartile range 1.21, 2.63) μIU/ml in the entire cohort. PAPP-A concentrations did not differ in dependence on coronary artery findings. A cutpoint of 2.7. μIU/ml was derived from receiver-operator characteristics for outcome measures. For this cutoff, Cox proportional hazard models with 19 further clinical variables showed that PAPP-A was predictive for all-cause death (HR 4.73, 95% CI 1.46-15.31, p = 0.01), all-cause death or nonfatal infarction (HR 4.01, 95% CI 1.58-10.13, p = 0.003) and all-cause death, nonfatal myocardial infarction or hospitalization (HR 1.96, 95% CI 1.03-3.70, p = 0.04). The predictive value of PAPP-A did not change substantially after correction for values of cardiac troponin, using a highly sensitive cardiac troponin I research assay. Conclusions: PAPP-A, measured by a new, monoclonal antibody-based assay is a promising prognostic marker in patients with stable cardiovascular disease and an indication for heart catheterization. © 2011 Elsevier B.V.


Quinkler M.,Charite - Medical University of Berlin | Hahner S.,University of Wurzburg
Clinical Endocrinology | Year: 2012

Primary adrenal insufficiency is treated with glucocorticoid and mineralocorticoid replacement therapy. Recent data revealed that health-related quality of life in adrenal insufficiency is impaired in many patients and that patients with adrenal insufficiency are also threatened by an increased mortality and morbidity. This may be caused by inadequate glucocortiocid therapy and adrenal crisis. Therefore, the optimization of hormone replacement therapy remains one of the most challenging tasks in endocrinology because it is largely based on clinical grounds because of the lack of objective assessment tools. This article provides answers to the important daily clinical questions, such as correct dose finding, dose adaptation in special situations, e g, pregnancy, improvement of quality of life and measures for protection from adrenal crisis. Other important aspects discussed are side effects of glucocortiocid replacement therapy and interactions with other drugs. © 2011 Blackwell Publishing Ltd.


Ruhnke M.,Charite - Medical University of Berlin
Clinical Microbiology and Infection | Year: 2014

Bloodstream and other invasive infections due to Candida species (invasive fungal diseases = IFD) are a major cause of morbidity and mortality in hospitalized adults and children in many countries worldwide. The high infection-related morbidity and mortality associated with invasive Candida infection/candidaemia (IC/C), combined with suboptimal diagnostic tools, have driven the overuse of antifungal drugs. Antifungal stewardship (AFS) may be regarded as subentity of the more general term Anti-infective or Antimicrobial Stewardship Program (AIS/AMS). The high costs and high contribution of antifungal agents to the management of IFDs along with their recognized toxicities have been addressed as the principal justification for antifungal stewardship. AFS programmes should be organized by an interdisciplinary team of clinicians, pharmacists, microbiologists and infection control experts with the lead of an infectious disease specialist preferably in each large hospital/institution dealing with high-risk patients for invasive fungal infections. These programmes should consider various aspects of IC/C including (i) the local fungal epidemiology, (ii) information on antifungal resistance rates, (iii) establishing and application of therapeutic guidelines, (iv) implementation of treatment strategies for empirical, pre-emptive therapy including PK/PD data for antifungal drugs, deescalation and 'switch and step-down strategies' (from intravenous to oral medication) in defined patient populations, (v) catheter management together with the application of routine diagnostic procedures such as ophthalmological and cardiac evaluations and (vi) the best available diagnostic tests for diagnosing IC and candidaemia. © 2014 The Authors. Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.


Leber A.,Charite - Medical University of Berlin
Methods in molecular biology (Clifton, N.J.) | Year: 2011

Presence of foreign tissue in a host's body would immediately lead to a strong immune response directed to destroy the alloantigens present in fetus and placenta. However, during pregnancy, the semiallogeneic fetus is allowed to grow within the maternal uterus due to multiple mechanisms of immune tolerance, which are discussed in this chapter.


Helmchen H.,Charite - Medical University of Berlin
European Archives of Psychiatry and Clinical Neuroscience | Year: 2012

This article describes ethical, legal and professional components of the two core requirements of clinical research: informed consent and risk-benefit relationships. It deals particularly with the ethically relevant reasons, criteria, procedures and validity of (1) the informed consent process, (2) the relationship between benefits and risks, and as a requirement of its assessment: (3) standards and (quasi quantitative) criteria of benefits and risks and/or burdens of a research intervention. These requirements will be discussed with specific reference to research interventions in mentally ill patients, and particularly in those who are incompetent to consent. (4) The analysis concludes by demanding a strong adherence to the ethical rules of clinical research in order to protect participants and preserve the trust of both the patients and the public and (5) yields in a set of recommendations. © Springer-Verlag 2011.


Duranton F.,RD Nephrologie | Cohen G.,Medical University of Vienna | De Smet R.,Ghent University | Rodriguez M.,University of Cordoba, Spain | And 3 more authors.
Journal of the American Society of Nephrology | Year: 2012

An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articlesmost frequently reported concentrations of β2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD. Copyright © 2012 by the American Society of Nephrology.


Trepczynski A.,Charite - Medical University of Berlin
Journal of orthopaedic research : official publication of the Orthopaedic Research Society | Year: 2012

The patellofemoral (PF) joint plays an essential role in knee function, but little is known about the in vivo loading conditions at the joint. We hypothesized that the forces at the PF joint exceed the tibiofemoral (TF) forces during activities with high knee flexion. Motion analysis was performed in two patients with telemetric knee implants during walking, stair climbing, sit-to-stand, and squat. TF and PF forces were calculated using a musculoskeletal model, which was validated against the simultaneously measured in vivo TF forces, with mean errors of 10% and 21% for the two subjects. The in vivo peak TF forces of 2.9-3.4 bodyweight (BW) varied little across activities, while the peak PF forces showed significant variability, ranging from less than 1 BW during walking to more than 3 BW during high flexion activities, exceeding the TF forces. Together with previous in vivo measurements at the hip and knee, the PF forces determined here provide evidence that peak forces across these joints reach values of around 3 BW during high flexion activities, also suggesting that the in vivo loading conditions at the knee can only be fully understood if the forces at the TF and the PF joints are considered together. Copyright © 2011 Orthopaedic Research Society.


Kuhn W.,Charite - Medical University of Berlin
Pathologe | Year: 2011

Cervical intraepithelial neoplasia and early cervical cancer are characterized by colposcopic minor and major changes and vessel abnormalities. In minor changes check-ups in most cases are sufficient. To avoid R1-resection and conization associated premature birth, conization should be performed under colposcopic visualization. In the USA and UK evidence based colposcopic guidelines were issued based on cytologic and colposcopic classifications. The German Society of Colposcopy (AG-CPC) published recommendations for the daily practice for all findings. For screening purposes there is no evidence to recommend colposcopy. In these cases, cytology is at the forefront, whereas colposcopy is only indicated in cases of conspicuous or unclear cytological results. © 2011 Springer-Verlag.


Muller-Redetzky H.C.,Charite - Medical University of Berlin
PloS one | Year: 2012

Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILI-associated lung permeability in vivo. Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1-3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxic vasoconstriction due to IMD treatment. IMD had minor impact on pulmonary leukocyte recruitment and did not reduce cytokine levels in VILI. IMD may possibly provide a new approach to attenuate VILI.


Secomb T.W.,University of Arizona | Pries A.R.,Charite - Medical University of Berlin
Comptes Rendus Physique | Year: 2013

The apparent viscosity of blood flowing through narrow glass tubes decreases strongly with decreasing tube diameter over the range from about 300 μm to about 10 μm. This phenomenon, known as the Fåhraeus-Lindqvist effect, occurs because blood is a concentrated suspension of deformable red blood cells with a typical dimension of about 8 μm. Most of the resistance to blood flow through the circulatory system resides in microvessels with diameters in this range. Apparent viscosity of blood in microvessels in vivo has been found to be significantly higher than in glass tubes with corresponding diameters. Here we review experimental observations of blood's apparent viscosity in vitro and in vivo, and progress towards a quantitative theoretical understanding of the mechanisms involved. © 2013 Académie des sciences.


Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system in young adults. Despite the fact that numerous lines of evidence link both the risk of disease development and the disease course to the serum level of 25-hydroxyvitamin D it still remains elusive whether multiple sclerosis patients benefit from boosting the serum level of 25-hydroxyvitamin D, mainly because interventional clinical trials that directly address the therapeutic effects of vitamin D in multiple sclerosis are sparse. We here present the protocol of an interventional clinical phase II study to test the hypothesis, that high-dose vitamin D supplementation of multiple sclerosis patients is safe and superior to low-dose supplementation with respect to beneficial therapeutic effects. The EVIDIMS trial is a German multi-center, stratified, randomized, controlled and double-blind clinical phase II pilot study. Eighty patients with the diagnosis of definite multiple sclerosis or clinically isolated syndrome who are on a stable immunomodulatory treatment with interferon-β1b will be randomized to additionally receive either high-dose (average daily dose 10.200 IU) or low-dose (average daily dose 200 IU) cholecalciferol for a total period of 18 months. The primary outcome measure is the number of new lesions detected on T2-weighted cranial MRI at 3 tesla. Secondary endpoints include additional magnetic resonance imaging and optical coherence tomography parameters for neuroinflammation and -degeneration, clinical parameters for disease activity, as well as cognition, fatigue, depression, and quality of life. Safety and tolerability of high-dose vitamin D supplementation are further outcome parameters. In light of the discrepancy between existing epidemiological and preclinical data on the one hand and available clinical data on the other the EVIDIMS trial will substantially contribute to the evaluation of the efficacy of high-dose vitamin D supplementation in MS patients. The study design presented here fulfills the criteria of a high-quality clinical phase II trial in MS. ClinicalTrials.gov Identifier: NCT01440062.


Lorenz M.,Charite - Medical University of Berlin
American Journal of Clinical Nutrition | Year: 2013

Green and black teas contain different biologically active polyphenolic compounds that might offer protection against a variety of human diseases. Although promising experimental and clinical data have shown protective effects, limited information is available on how these beneficial effects of tea polyphenols are mediated at the cellular level. Evidence is accumulating that catechins in green tea as well as theaflavins and thearubigins from black tea are the substances responsible for the physiologic effects of tea in vitro. The green tea catechin epigallocatechin-3-gallate (EGCG) is generally considered to be the biologically most active compound in vitro. The changes in the activities of various protein kinases, growth factors, and transcription factors represent a common mechanism involved in cellular effects of tea polyphenols. In addition to modification of intracellular signaling by activation of cellular receptors, it was shown that, at least for EGCG, tea polyphenols can enter the cells and directly interact with their molecular targets within cells. There, they frequently result in opposite effects in primary compared with tumor cells. Although tea polyphenols were long regarded as antioxidants, research in recent years has uncovered their prooxidant properties. The use of high nonphysiologic concentrations in many cell culture studies raises questions about the biological relevance of the observed effects for the in vivo situation. Efforts to attribute functional effects in vivo to specific molecular targets at the cellular level are still ongoing. Am J Clin Nutr 2013;98 (suppl):1642S-50S. © 2013 American Society for Nutrition.


Obladen M.,Charite - Medical University of Berlin
Journal of Child Neurology | Year: 2011

Deformations have been attributed to supernatural causes since antiquity. Cerebral palsy was associated with God's wrath, witchcraft, the evil eye, or maternal imagination. Greek scholars recommended prevention by tight swaddling, a custom that persisted into modern times. In the Middle Ages, the midwife's negligence was held responsible as was difficult teething. Morgagni described in 1769 that the neonatal brain can liquefy, and Bednar described leukomalacia in 1850 as a distinct disorder of the newborn. In 1861, Little associated cerebral palsies with difficult or protracted labor and neonatal asphyxia, but he was challenged by Freud, who in 1897 declared that most cases are prenatal in origin. In 1868, Virchow demonstrated inflammatory changes, a view recently confirmed by Leviton and Nelson. Although a causal relationship of cerebral palsy to the birth never has been established, the habit to put the blame for cerebral palsy on someone remained a frequent attitude. © 2011 The Author(s).


Mueller W.-D.,Charite - Medical University of Berlin | Lucia Nascimento M.,TU Berlin | Lorenzo De Mele M.F.,and University la Plata
Acta Biomaterialia | Year: 2010

The aim of this work was to collect and compare data from different published reports which focused on the description of the influence of different electrochemical setups for the assessment of magnesium corrosion. Based on this, a comparison with our own results, obtained for LAE 442 and AZ 31, was made and discussed. As the collection of data has shown, the reported inconsistencies between in vivo and electrochemical data depend greatly on the electrochemical medium used, on the alloy composition and on surface preparation. Nevertheless, these differences also exist when comparing different in vitro results using different methodologies and even different Mg alloys, and need therefore to be discussed more thoroughly in the future. The simulation of transport conditions of the in vivo interface should become a focus of research interest in order to gain a better understanding of the influence of connecting processes on the degradation of the biomaterials. © 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


Pfitzner T.,Charite - Medical University of Berlin
Orthopedics | Year: 2012

Navigated total knee arthroplasty (TKA) results in better restoration of neutral mechanical axis than does the conventional technique. Nevertheless, coronal malalignment has not been eliminated. It is yet unknown whether errors in implant positioning occur more on the femoral side, more on the tibial side, or equally on both sides. The hypothesis of this study was that a predominance of coronal component malalignment exists on the tibial side in navigated tibia-first TKA.Fifty-seven consecutive navigated (OrthoPilot; B. Braun Aesculap, Tuttlingen, Germany) TKAs were included in this retrospective study. Pre- and postoperative digital whole-leg standing radiographs were analyzed. Coronal alignment was measured for the whole leg pre- and postoperatively. Lateral distal femur angle and medial proximal tibia angle were analyzed on the preoperative radiographs. On the postoperative radiographs, coronal alignment of the femoral and tibial components were measured separately in reference to the tibial and femoral mechanical axis. The coronal alignment improved from 8.2° ± 3.7° preoperatively to 1.1° ± 1.2° postoperatively, with 5 (8%) outliers outside the 3° window. The femoral component was malaligned (0.6° ± 0.6°), whereas the tibial component showed a significantly higher deviation from the mechanical axis of 1.0° ± 1.1° (P=.009). The femoral component was positioned more precisely than the tibial component. The latter influences gap management in the tibia-first technique and may thereby have a relevant effect on joint stability. Accuracy of the surgical technique and differences in the mathematical algorithm for the determination of landmarks are possible reasons for the difference in precision between the femoral and tibial component positioning. Copyright 2012, SLACK Incorporated.


Doehner W.,Charite - Medical University of Berlin | Frenneaux M.,University of Aberdeen | Anker S.D.,University of Gottingen
Journal of the American College of Cardiology | Year: 2014

Although bioenergetic starvation is not a new concept in heart failure (HF), recent research has led to a growing appreciation of the complexity of metabolic aspects of HF pathophysiology. All steps of energy extraction, transfer, and utilization are affected, and structural metabolism is impaired, leading to compromised functional integrity of tissues. Not only the myocardium, but also peripheral tissues and organs are affected by metabolic failure, resulting in a global imbalance between catabolic and anabolic signals, leading to tissue wasting and, ultimately, to cachexia. Metabolic feedback signals from muscle and fat actively contribute to further myocardial strain, promoting disease progression. The prolonged survival of patients with stable, compensated HF will increasingly bring chronic metabolic complications of HF to the fore and gradually shift its clinical presentation. This paper reviews recent evidence on myocardial and systemic metabolic impairment in HF and summarizes current and emerging therapeutic concepts with specific metabolic targets. © 2014 American College of Cardiology Foundation.


Wallukat G.,Max Delbruck Centrum fur Molekulare Medizin | Schimke I.,Charite - Medical University of Berlin
Seminars in Immunopathology | Year: 2014

Agonistic autoantibodies (AABs) against G-protein-coupled receptor (GPCR) are present mainly in diseases of the cardiovascular system or in diseases associated with cardiovascular disturbances. The increasing knowledge about the role of autoantibodies against G-protein-coupled receptor (GPCR-AABs) as pathogenic drivers, the resulting development of strategies aimed at their removal or neutralization, and the evidenced patient benefit associated with such therapies have created the need for a summary of GPCR-AAB-associated diseases. Here, we summarize the present knowledge about GPCR-AABs in cardiovascular diseases. The identity of the GPCR-AABs and their prevalence in each of several specific cardiovascular diseases are documented. The structure of GPCR is also briefly discussed. Using this information, differences between classic agonists and GPCR-AABs in their GPCR binding and activation are presented and the resulting pathogenic consequences are discussed. Furthermore, treatment strategies that are currently under study, most of which are aimed at the removal and in vivo neutralization of GPCR-AABs, are indicated and their patient benefits discussed. In this context, immunoadsorption using peptides/proteins or aptamers as binders are introduced. The use of peptides or aptamers for in vivo neutralization of GPCR-AABs is also described. Particular attention is given to the GPCR-AABs directed against the adrenergic beta1-, beta2-, and α1-receptor as well as the muscarinic receptor M2, angiotensin II-angiotensin receptor type I, endothelin1 receptor type A, angiotensin (1-7) Mas-receptor, and 5-hydroxytryptamine receptor 4. Among the diseases associated with GPCR-AABs, special focus is given to idiopathic dilated cardiomyopathy, Chagas' cardiomyopathy, malignant and pulmonary hypertension, and kidney diseases. Relationships of GPCR-AABs are indicated to glaucoma, peripartum cardiomyopathy, myocarditis, pericarditis, preeclampsia, Alzheimer's disease, Sjörgren's syndrome, and metabolic syndrome after cancer chemotherapy. © 2014 Springer-Verlag.


Duncan N.W.,Ottawa Health Research Institute | Duncan N.W.,Hangzhou Normal University | Wiebking C.,Ottawa Health Research Institute | Wiebking C.,Charite - Medical University of Berlin | Northoff G.,Ottawa Health Research Institute
Neuroscience and Biobehavioral Reviews | Year: 2014

The integration of multiple imaging modalities is becoming an increasingly well used research strategy for studying the human brain. The neurotransmitters glutamate and GABA particularly lend themselves towards such studies. This is because these transmitters are ubiquitous throughout the cortex, where they are the key constituents of the inhibition/excitation balance, and because they can be easily measured in vivo through magnetic resonance spectroscopy, as well as with select positron emission tomography approaches. How these transmitters underly functional responses measured with techniques such as fMRI and EEG remains unclear though, and was the target of this review. Consistently shown in the literature was a negative correlation between GABA concentrations and stimulus-induced activity within the measured region. Also consistently found was a positive correlation between glutamate concentrations and inter-regional activity relationships, both during tasks and rest. These findings are outlined along with results from populations with mental disorders to give an overview of what brain imaging has suggested to date about the biochemical underpinnings of functional activity in health and disease. We conclude that the combination of functional and biochemical imaging in humans is an increasingly informative approach that does however require a number of key methodological and interpretive issues be addressed before can meet its potential. © 2014 Elsevier Ltd.


Harteneck C.,University of Tubingen | Gollasch M.,Charite - Medical University of Berlin
Current Pharmaceutical Biotechnology | Year: 2011

Members of the classic type of transient receptor potential channels (TRPC) represent important molecules involved in hormonal signal transduction. TRPC3/6/7 channels are of particular interest as they are components of phospholipase C driven signalling pathways. Upon receptor-activation, G-protein-mediated stimulation of phospholipase C results in breakdown of phosphatidylinositides leading to increased intracellular diacylglycerol and inositol-trisphosphate levels. Diacylglycerol activates protein kinase C, but more interestingly diacylglycerol directly activates TRPC2/3/6/7 channels. Molecular cloning, expression and characterization of TRP channels enabled reassignment of traditional inhibitors of receptor-dependent calcium entry such as SKF-96365 and 2-APB as blockers of TRPC3/6/7 and several members of non-classic TRP channels. Furthermore, several enzyme inhibitors have also been identified as TRP channel blockers, such as ACA, a phospholipase A2 inhibitor, and W-7, a calmodulin antagonist. Finally, the naturally occurring secondary plant compound hyperforin has been identified as TRPC6-selective drug, providing an exciting proof of concept that it is possible to generate TRPC-selective channel modulators. The description of Pyr3 as the first TRPC3-selective inhibitor shows that not only nature but also man is able to generate TRP-selective modulators. The review sheds lights on the current knowledge and historical development of pharmacological modulators of TRPC3/6/7. Our analysis indicates that Pyr3 and hyperforin provide promising core structures for the development of new, selective and more potent modulators of TRPC3/6/7 activity. © 2011 Bentham Science Publishers Ltd.


Klar M.,Charite - Medical University of Berlin
Critical Reviews in Oncogenesis | Year: 2011

The fundamental biological relevance of the transcription factor Yin Yang 1 (YY1) has been studied and described intensively in hundreds of publications. To date, however, only limited data of its structural and functional homologue YY2 are available. Especially, the impact of Yin Yang 2 (YY2) in the regulatory network of YY1 is almost unexplored. This article summarizes all critical aspects that are (or will be) relevant for a better understanding of YY1- and/or YY2-mediated cellular control mechanisms. © 2011 by Begell House, Inc.


Dorner T.,Charite - Medical University of Berlin | Shock A.,UCB Pharma | Smith K.G.C.,University of Cambridge
International Reviews of Immunology | Year: 2012

CD22 is a 140-kDa member of the Siglec family of cell surface proteins that is expressed by most mature B-cell lineages. As a co-receptor of the B-cell receptor (BCR), it is known to contribute to the sensitive control of the B-cell response to antigen. Cross-linking of CD22 and the BCR by antigen triggers the phosphorylation of CD22, which leads to activation of signaling molecules such as phosphatases. Signal transduction pathways involving CD22 have been explored in a number of mouse models, some of which have provided evidence that in the absence of functional CD22, B cells have a "hyperactivated" phenotype, and suggest that loss of CD22 function could contribute to the pathogenesis of autoimmune diseases. Modulating CD22 activity has therefore been suggested as a possible therapeutic approach to such diseases. For example, the novel CD22-targeting monoclonal antibody epratuzumab is currently under investigation as a treatment for the connective tissue disorder systemic lupus erythematosus (SLE). © 2012 Informa Healthcare USA, Inc.


Senkowski D.,Charite - Medical University of Berlin | Hofle M.,University of Hamburg | Engel A.K.,University of Hamburg
Trends in Cognitive Sciences | Year: 2014

Noxious stimuli in our environment are often accompanied by input from other sensory modalities that can affect the processing of these stimuli and the perception of pain. Stimuli from these other modalities may distract us from pain and reduce its perceived strength. Alternatively, they can enhance the saliency of the painful input, leading to an increased pain experience. We discuss factors that influence the crossmodal shaping of pain and highlight the important role of innocuous stimuli in peripersonal space. We propose that frequency-specific modulations in local oscillatory power and in long-range functional connectivity may serve as neural mechanisms underlying the crossmodal shaping of pain. Finally, we provide an outlook on future directions and clinical implications of this promising research field. © 2014 Elsevier Ltd.


Geisel O.,Charite - Medical University of Berlin
European Addiction Research | Year: 2012

Background: Brain-derived neurotrophic factor (BDNF) plays important roles in neurotransmitter release and synaptic plasticity and has been hypothesized to be involved in the development and maintenance of addictive disorders. The objective of this study was to investigate alterations of BDNF expression in a non-substance-related addiction, i.e. pathological gambling (PG). Methods: Serum levels of BDNF were assessed in male patients with PG (n = 14) and healthy control subjects (n = 13) carefully matched for sex, age, body mass index, smoking status and urbanicity. Symptoms and severity of PG were measured by the adapted form of the Yale-Brown Obsessive-Compulsive Scale. Results: BDNF serum levels were significantly increased in patients with PG in comparison to healthy control subjects (p = 0.016). There were no significant correlations between BDNF serum levels and severity of PG or clinical and demographic variables. Conclusions: Our results show alterations of BDNF serum levels in patients suffering from a behavioural addiction and suggest that non-substance-related addictions like PG might be associated with neuroendocrinological changes similar to the changes observed in substance-related addictions. Copyright © 2012 S. Karger AG, Basel.


Foulquier S.,Maastricht University | Steckelings U.M.,Charite - Medical University of Berlin | Unger T.,Maastricht University
Current Hypertension Reports | Year: 2012

It is now widely accepted that the angiotensin AT2 receptor (AT2R) plays an important protective role during pathophysiologic conditions, acting as a repair system. The development of the first selective nonpeptide AT2R agonist C21 accelerated our understanding of AT2R-mediated protective signaling and actions. This article reviews the impact of C21 on blood pressure in normotensive and hypertensive animal models. Although C21 does not act as a classical antihypertensive drug, it could be useful in preventing hypertension-induced vascular and other end organ damages via anti-apoptotic, anti-fibrotic and anti-inflammatory actions. In particular, a strong body of evidence started to emerge around its anti-inflammatory feature. This property should be further investigated for potential clinical indications in cardiovascular diseases and beyond. © Springer Science+Business Media, LLC 2012.


Winkelmann A.,Charite - Medical University of Berlin
Clinical Anatomy | Year: 2012

In this study, the author analyzed the relevance of anatomical eponyms for medical education by researching 453 anatomical eponyms and their corresponding English or Latin terms in the Medline database. The number of hits in the database ranged from 0 to 34,490 per eponym (median 11). Almost a quarter (110) of the eponyms did not appear at all. Only 11% of those articles that use anatomical eponyms in their title or abstract added a descriptive English or Latin term. In conclusion, familiarity with many of these eponyms is superfluous for medical students, as they are not in common use by the medical community. However, a number of eponyms must be actively retained by students to understand clinicians and efficiently research medical literature. © 2011 Wiley Periodicals, Inc.


Bacher P.,Miltenyi Biotec GmbH | Scheffold A.,Charite - Medical University of Berlin
Cytometry Part A | Year: 2013

The cytometric enumeration and characterization of antigen-specific lymphocytes, as introduced about 15 years ago, has contributed significantly to our understanding of adaptive immune responses in health and disease. Despite the development of several technologies, allowing to directly or indirectly analyze many aspects of lymphocyte specificity and function, several unresolved issues remain, due to the low frequency of certain antigen-specific lymphocyte subsets and the complexity of T cell antigen recognition. This is especially true for CD4+ conventional as well as regulatory T cells, which bring major contributions to immune protection and pathology. Here we review the current technologies for the analysis of antigen specific T cells within the physiologic T cell repertoire and with a special focus on recent technologies addressing the analysis of rare antigen-specific T cell populations including naive and regulatory T cells. © 2013 International Society for Advancement of Cytometry.


Hoffmann J.,Charite - Medical University of Berlin | Recober A.,University of Iowa
Current Pain and Headache Reports | Year: 2013

The influence of environmental factors on the clinical manifestation of migraine has been a matter of extensive debate over the past decades. Migraineurs commonly report foods, alcohol, meteorologic or atmospheric changes, exposure to light, sounds, or odors, as factors that trigger or aggravate their migraine attacks. In the same way, physicians frequently follow this belief in their recommendations in how migraineurs may reduce their attack frequency, especially with regard to the consumption of certain food components. Interestingly, despite being such a common belief, most of the clinical studies have shown conflicting results. The aim of the review is to critically analyze clinical and pathophysiological facts that support or refute a correlation between certain environmental stimuli and the occurrence of migraine attacks. Given the substantial discrepancy between patients' reports and objective clinical data, the methodological difficulties of investigating the link between environmental factors and migraine are highlighted. © 2013 Springer Science+Business Media New York.


Hoppe B.,Labor Berlin Charite Vivantes GmbH | Hoppe B.,Charite - Medical University of Berlin
Thrombosis and Haemostasis | Year: 2014

Fibrinogen and factor XIII are two essential proteins that are involved directly in fibrin gel formation as the final step of a sequence of reactions triggered by a procoagulant stimulus. Haemostasis is the most obvious function of the resulting fibrin clot. Different variables affect the conversion of fibrinogen to fibrin as well as the mode of fibrin polymerisation and fibrin crosslinking, hereby, critically influencing the architecture of the resulting fibrin network and consequently determining its mechanical strength and resistance against fibrinolysis. Due to fibrinogen’s structure with a multitude of domains and binding motifs the fibrin gel allows for complex interactions with other coagulation factors, with profibrinolytic as well as antifibrinolyic proteins, with complement factors and with various cellular receptors. These interactions enable the fibrin network to control its own further state (i. e. expansion or degradation), to influence innate immunity, and to function as a scaffold for cell migration processes. During the whole process of fibrin gel formation biologically active peptides and protein fragments are released that additionally influence cellular processes via chemotaxis or by modulating cell-cell interactions. Thus, it is not surprising that fibrinogen and factor XIII in addition to their haemostatic function influence innate immunity as well as cell-mediated reactions like wound healing, response to tissue injury or inflammatory processes. The present review summarises current knowledge of fibrinogen’s and factor XIII’s function in coagulation and fibrinolysis giving special emphasis on their relation to inflammation control. © Schattauer 2014.


Radtke A.,Charite - Medical University of Berlin | Neuhauser H.,Robert Koch Institute
Cephalalgia | Year: 2012

Objective: The study's objective was to assess self-awareness and medical recognition of migraine and their determinants in Germany.Methods: We conducted a nationally representative study of the general population of Germany (N-=-7341, aged ≥18 years) by means of computer-assisted telephone interviews. Migraine was diagnosed based on the International Classification of Headache Disorders, second edition (ICDH-II).Results: Twelve-month prevalence of ICHD-II-migraine was 10.6% (women 15.6%, men 5.3%). Seventy percent of ICDH-II-migraineurs recognised their headaches as migraine (moderate agreement between ICDH-II and self-diagnosis, κ-=-0.46). Only 42% of migraineurs consulted a physician in the previous 12 months. Of those, 63% reported a medical diagnosis of migraine (moderate agreement, κ-=-0.40). Women were more likely to be self-aware (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.27-2.60), but the difference was no longer significant when adjusting for migraine features. Physician recognition was more likely in patients with higher educational level (high vs. low education OR 3.90, 95% CI 1.43-10.61 after adjusting for migrainous features). Best predictors for self-awareness and medical recognition of migraine were typical migraine accompaniments and greater headache intensity.Conclusion: Self-awareness and physician recognition of migraine are low in Germany. Presence of typical migraine features and greater headache intensity facilitate medical recognition and awareness of migraine, especially in females. © International Headache Society 2012.


Plagemann A.,Charite - Medical University of Berlin
Early Human Development | Year: 2011

Alterations of the intrauterine and neonatal environment may predispose for disorders and diseases throughout later life (perinatal programming). Especially, hormones and nutrients are dose-dependent organizers of the developing organism. Studies in offspring of diabetic mothers (ODM) have paradigmatically contributed to the perception of this developmental principle and our understanding of causal mechanisms. Fetal and neonatal hyperinsulinism in consequence of materno-fetal hyperglycaemia is the pathognomic feature in ODM. Epidemiological, clinical, as well as experimental data indicate that both insulin and glucose, when occurring in elevated concentrations during perinatal life, may epigenetically program a predisposition for obesity and diabetes later on. Similar may occur due to pre- and neonatal overfeeding. From a clinical point of view, avoidance of materno-fetal overnutrition, universal diabetes screening in all pregnant women and adequate therapy of all forms of diabetes during pregnancy, as well as avoidance of neonatal overfeeding are therefore recommended. These measures might serve as causal approaches of a genuine prevention to the benefit of long-term offspring health. © 2011 Elsevier Ireland Ltd.


Baeten D.,University of Amsterdam | Sieper J.,Charite - Medical University of Berlin | Braun J.,Rheumazentrum Ruhrgebiet | Baraliakos X.,Rheumazentrum Ruhrgebiet | And 8 more authors.
New England Journal of Medicine | Year: 2015

Background: Secukinumab is an anti-interleukin-17A monoclonal antibody that has been shown to control the symptoms of ankylosing spondylitis in a phase 2 trial. We conducted two phase 3 trials of secukinumab in patients with active ankylosing spondylitis. Methods: In two double-blind trials, we randomly assigned patients to receive secukinumab or placebo. In MEASURE 1, a total of 371 patients received intravenous secukinumab (10 mg per kilogram of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. In MEASURE 2, a total of 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4. At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg. The primary end point was the proportion of patients with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16. Results: In MEASURE 1, the ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for both comparisons with placebo); in MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the 150-mg dose and P = 0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period of MEASURE 1. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn's disease were 0.7, 0.9, and 0.7 cases per 100 patientyears, respectively, in secukinumab-treated patients. Conclusions: Secukinumab at a subcutaneous dose of 150 mg, with either subcutaneous or intravenous loading, provided significant reductions in the signs and symptoms of ankylosing spondylitis at week 16. Secukinumab at a subcutaneous dose of 75 mg resulted in significant improvement only with a higher intravenous loading dose. Copyright © 2015 Massachusetts Medical Society. All rights reserved.


Illenberger E.,Free University of Berlin | Meinke M.C.,Charite - Medical University of Berlin
International Journal of Mass Spectrometry | Year: 2014

Dissociative electron attachment (DEA) to acetone (CH3COCH 3), perfluoroacetone (CF3COCF3) and acetylene (HCCH) is studied in the gas phase under collision-free conditions. The results are compared with those recently obtained from a study on electron attachment to homogeneous clusters of acetone and perfluoroacetone (Martin et al., 2009). Gas phase acetone and perfluoroacetone show a series of DEA resonances extending over a wide energy range and leading to various fragment ions. Perfluoroacetone additionally shows a strong signal due to the formation of the parent anion close to zero energy. In strong contrast to that, the cluster analogues exhibit only a low energy resonance while fragmentation is strongly suppressed. Such behaviour mirrors the intrinsic decomposition mechanisms which proceeds rather via predissociation involving a loose transition state than by direct dissociation along repulsive potential energy surfaces. This picture is confirmed by a time-of-flight (TOF) analysis of the fragment ions from the isolated compounds revealing that all fragment ions are formed with only low translational energy. DEA to acetylene leads to C2H- and C2- arising from different resonance regions, with C 2H- as the prominent signal at 3 eV resulting from predissociation of the π* resonance. © 2014 Elsevier B.V.


Munch M.,Charite - Medical University of Berlin
Therapeutische Umschau | Year: 2014

This article gives an overview of factors underlying age-related changes in sleep wake behavior in healthy older humans. The self-regulation of the sleepwake cycle [sleep-wake homeostasis] and the circadian clock, represent primary factors responsible for changes in sleep with age. As a matter of fact older healthy adults have a more superficial and less consolidated sleep and go to bed earlier compared to younger ages. Furthermore, sleep in healthy older people is more vulnerable to disturbances such as circadian desynchronisation and the lack of zeitgebers [insufficient light during the day]. © 2014 Verlag Hans Huber, Hogrefe AG, Bern.


The connection between the development of anesthesiology and pain therapy in the twentieth century is close. The optimistic idea to overcome pain by using general anesthesia derives from the nineteenth century. Treatment of nonsurgical pain remained in the background for a long time and innovations in pain medicine did not improve the insufficient care for patients with postoperative pain. Therapy of chronic pain was mainly surgical and the extreme of this surgical approach was psychosurgery. In the years following World War II leucotomy and lobotomy were established as methods to separate the psychological processing of pain from the experience of pain. Meanwhile, the French "pain surgeon" René Leriche elaborated a theory of pain where chronic pain was no longer seen as a symptom but as a "douleur- maladie", a pain disease. His theory was considered on various occasions but did not gain acceptance before the 1950s. Research in anesthesiology, such as that conducted by the American scientist Henry Beecher separated psyche and physiology with respect to pathological pain. This was contrasted by the approach of clinical anesthesia to pain therapy, which was based on regional anesthesia. The first "pain clinics" were "nerve block clinics". John Bonica, a regional anesthesiologist, extended the framework of pain therapy by introducing multidisciplinary teamwork into the therapy of chronic pain. From today's viewpoint his 1953 monograph The Management of Chronic Pain is a milestone in the development of modern pain therapy. However, Bonica's work did not attain major importance until 1960 when he was appointed to a newly established chair. Gradually, chronic pain was recognized as an independent illness and differentiated as such from acute pain. In 1965 the gate control theory by Melzack and Wall offered a possible explanation for the mechanisms of chronic pain. By the end of the 1970s the spectrum was extended to the biopsychosocial approach which was foremost developed by the American psychiatrist George Engel, defined chronic pain as an illness rather than a disease. Concurrently, the radical behaviorism of the late 1960s affected both the therapy of chronic and of acute pain. Based on this theory, patient-controlled analgesia (PCA) was introduced in the 1970s and 1980s. Acute pain services (APS) in hospitals, were developed beginning in the 1980s using the continuous release of opioids. Regional anesthesia played a greater role than general anesthesia in developing pain therapy in the twentieth century and paved the way for pain therapy. The restriction to nerve blocks in pain centers was overcome by the expansion of theoretical foundations beyond the framework of anesthesiology. Impulses from psychology and psychosomatic medicine were crucial. The evolution of cancer pain therapy was distinct from non-cancer pain therapy. © 2011 Springer-Verlag.


Martino-Andrade A.J.,Federal University of Parana | Chahoud I.,Charite - Medical University of Berlin
Molecular Nutrition and Food Research | Year: 2010

Phthalate esters are ubiquitous environmental contaminants that in general display low-toxicity. Overall, the reproductive effects of these compounds are well characterized in adult's animals, with gonadal injury observed after high dose exposure. However, results of recent transgeneration studies indicate that the reproductive system of developing animals is particularly vulnerable to certain phthalates. The phenotypic alterations observed in male offspring rats exposed during the perinatal period have remarkable similarities with common human reproductive disorders, including cryptorchidism, hypospadias and low-sperm counts. Recent results also indicate that high phthalate doses can adversely affect adult and devel- oping female rats. However, the main question involving phthalates is whether the current level of human exposure is sufficient to adversely affect male and/or female reproductive health. Here, we review the reproductive toxicity data of phthalates in adult and developing animals as well as possible modes of action. In addition, we briefly discuss the relevance of animal studies to humans in light of recent epidemiological data and experimental research with low (human relevant) doses. Finally, we point out some critical issues that should be addressed in order to clarify the implications of phthalates for human reproduction. © 2009 WILEY-VCH Verlag GmbH & Co.


Targeting CD74 as the invariant chain of major histocompatibility complexes (MHC) became possible by the availability of a specific humanized monoclonal antibody, milatuzumab, which is under investigation in patients with hematological neoplasms. CD74 has been reported to regulate chemo-attractant migration of macrophages and dendritic cells, while the role of CD74 on peripheral naïve and memory B cells also expressing CD74 remains unknown. Therefore, the current study addressed the influence of milatuzumab on B-cell proliferation, chemo-attractant migration, and adhesion molecule expression. Surface expression of CD74 on CD27- naïve and CD27+ memory B cells as well as other peripheral blood mononuclear cells (PBMCs) obtained from normals, including the co-expression of CD44, CXCR4, and the adhesion molecules CD62L, β7-integrin, β1-integrin and CD9 were studied after binding of milatuzumab using multicolor flow cytometry. The influence of the antibody on B-cell proliferation and migration was analyzed in vitro in detail. In addition to monocytes, milatuzumab also specifically bound to human peripheral B cells, with a higher intensity on CD27+ memory versus CD27- naïve B cells. The antibody reduced B-cell proliferation significantly but moderately, induced enhanced spontaneous and CXCL12-dependent migration together with changes in the expression of adhesion molecules, CD44, β7-integrin and CD62L, mainly of CD27- naïve B cells. This was independent of macrophage migration-inhibitory factor as a ligand of CD74/CD44 complexes. Milatuzumab leads to modestly reduced proliferation, alterations in migration, and adhesion molecule expression preferentially of CD27- naïve B cells. It thus may be a candidate antibody for the autoimmune disease therapy by modifying B cell functions.


Gebhardt C.,Charite - Medical University of Berlin | Cull-Candy S.G.,University College London
Journal of Physiology | Year: 2010

Recent evidence suggests that lithium, which is used in the treatment of bipolar disorders, may act by influencing AMPAR properties at central glutamatergic synapses. While it is clear that lithium potentiates recombinant AMPAR responses in a subunit specific way, the origin of this potentiation is not known. We examined the effects of lithium on native AMPAR channels in CA1 pyramidal cells in hippocampal slices where AMPARs are expected to be associated with auxiliary subunits. We found that lithium produced a selective increase in single-channel open probability (Popen), with little effect on single-channel conductance or burst length. From the present and previous finding it is likely that lithium causes a reduction in the time to recovery from desensitization, resulting in the observed increase in Popen. This would be consistent with the view that lithium acts like certain other allosteric AMPAR modulators to reduce the time spent in the desensitized state, but differs from those that act by slowing dissociation of glutamate. Lithium has been used for more than 50 years to treat bipolar disorder worldwide. Remarkably, although lithium is effective, its site and mode of action are unknown. Information about this could provide insight that would benefit future treatments of mood disorders. We examined the effects of lithium, at clinically relevant concentrations, on AMPA type glutamate receptors in nerve cells. When activated by neurotransmitter (glutamate) these receptors mediate the majority of fast information transfers in the brain. Our experiments show that lithium potentiates certain subtypes of AMPA receptors. However, it does so in a way that appears to differ from certain other well studied AMPAR potentiators, which are thought to act by slowing down dissociation of the neurotransmitter from the receptor. © 2010 The Authors. Journal compilation © 2010 The Physiological Society.


Bischoff P.,Ruhr University Bochum | Rundshagen I.,Charite - Medical University of Berlin
Deutsches Arzteblatt | Year: 2011

Background: Awareness while under general anesthesia, and the later recall of what happened during surgery, can be experienced by patients as horrific events that leave lasting mental trauma behind. Patients may have both auditory and tactile perception, potentially accompanied by feelings of helplessness, inability to move, pain, and panic ranging to an acute fear of death. For some patients, the experience of awareness under anesthesia has no sequelae; for others, however, it can lead to the development of post-traumatic stress disorder, consisting of complex psychopathological phenomena such as anxiety, insomnia, nightmares, irritability, and depression possibly leading to suicidality. Methods: The literature on the subject was selectively reviewed. Results: In the absence of risk factors awareness phenomena occur in one to two per 1000 operations under general anesthesia (0.1 % to 0.2 %) and are thus classed as an occasionally occurring critical event. In children, the risk of such phenomena occurring is 8 to 10 times higher. These phenomena are due to an inadequate depth of anesthesia with incomplete unconsciousness. They can be promoted by a number of risk factors that are either patient-related (ASA class III or above, medication abuse), surgery-related (Caesarean section, emergency procedures, surgery at night), or anesthesia-related (anesthesia without benzodiazepines, use of muscle relaxants). Conclusion: Strategies for avoiding awareness phenomena under anesthesia include the training of staff to know about the problem and, specifically, the use of benzodiazepines, the avoidance of muscle relaxants if possible, and shielding the patient from excessive noise. EEG monitoring is effective but provides no guarantee against awareness. If awareness under anesthesia occurs despite these measures, the patient must be given expert, interdisciplinary treatment as soon after the event as possible in order to minimize its potential sequelae.


Kuhn S.,Charite - Medical University of Berlin
Translational psychiatry | Year: 2012

Alterations of hippocampal anatomy have been reported consistently in schizophrenia. Within the present study, we used FreeSurfer to determine hippocampal subfield volumes in 21 schizophrenic patients. A negative correlation between PANSS-positive symptom score and bilateral hippocampal subfield CA2/3 as well as CA1 volume was found on high-resolution magnetic resonance images. Our observation opens the gate for advanced investigation of the commonly reported hippocampal abnormalities in schizophrenia in terms of specific subfields.


Verlohren S.,Charite - Medical University of Berlin | Stepan H.,University of Leipzig | Dechend R.,Experimental and Clinical Research Center
Clinical Science | Year: 2012

The pathogenesis of pre-eclampsia is still not completely known; however, in the recent decade, there have been tremendous research efforts leading to impressive results highlighting the role of a disturbed angiogenic balance as one of the key features of the disease. Numerous studies have shown the key role of the placenta in the pathogenesis of pre-eclampsia. A shift in the sFlt-1 (soluble Fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio is associated with the disease. Although pre-eclampsia seems to be a clearly defined disease, clinical presentation, and particularly the dynamics of the clinical course, can vary enormously. The only available tools to diagnose pre-eclampsia are blood pressure measurement and urine protein sampling. However, these tools have a low sensitivity and specificity regarding the prediction of the course of the disease or maternal and perinatal outcomes. The only cure for the disease is delivery, although a timely diagnosis helps in decreasing maternal and fetal morbidity and mortality. The sFlt1/PlGF ratio is able to give additional valuable information on the status and progression of the disease and is apt to be implemented in the diagnostic algorithm of pre-eclampsia. In the present review, we aim to provide an overview of the vast literature on angiogenesis and anti-angiogenesis factors in pre-eclampsia that have been published over the last decade. We introduce work from basic research groups who have focused on the pathophysiological basis of the disease. Furthermore, we review studies with a clinical focus in which the sFlt-1/PlGF ratio has been analysed along with other candidates for routine clinical assessment of pre-eclampsia. © The Authors Journal compilation. © 2012 Biochemical Society.


Kolzsch M.,Charite - Medical University of Berlin
European journal of pain (London, England) | Year: 2012

Current knowledge about the quality and appropriateness of pharmacological pain treatment in nursing home residents (NHR), particularly in NHR with moderate to severe cognitive impairment, is poor. This observational cross-sectional study assessed pain treatment in a random sample of NHR with or without cognitive impairment from nursing homes in Germany. Prescribed drugs, pain intensity and frequency, diagnoses, and surgical procedures and injuries during the last 4 weeks were documented. Quality and appropriateness of pain medication were assessed by analysis of pain medications and the Pain Medication Appropriateness Scale (PMAS) score (S(PMAS) ), with a cut-off value of >67% indicating appropriate pain treatment. A total of 321 residents (62% women) were studied, including 152 (47%) with severe cognitive impairment. The most frequently prescribed analgesics were dipyrone, fentanyl, tramadol and ibuprofen. The mean S(PMAS) was 48.5 ± 1.5 (range, -33 to +100). Residents with prescribed scheduled analgesics had a significantly better S(PMAS) than patients without such treatment (S(PMAS) 58 ± 1.5 vs. 37 ± 2.5, p < 0.01). NHR without current pain had significantly better S(PMAS) than residents suffering from pain (S(PMAS) 47 ± 1.9 vs. 59 ± 4.2, p = 0.01). With an S(PMAS) of 69 ± 1.5, residents (n = 106) with scheduled pain medication plus PRN analgesics achieved the highest scores in the population. Overall, similar results were found in NHR with and in NHR without cognitive impairment. Our study points to a significant deficit in pain treatment in German NHR, including NHR with or without cognitive impairment. © 2011 European Federation of International Association for the Study of Pain Chapters.


Sieper J.,Charite - Medical University of Berlin
Current Rheumatology Reports | Year: 2013

Major progress has been made in recent years in the management of axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA). Most predictors of response have been defined for TNF-blocker therapy, and new treatment strategies are being discussed about how to best reach remission and how to maintain remission. Other biologics besides TNF-blockers have been tested in AS but have so far failed. The IL-17/IL-23 cytokines currently seem to be the most interesting targets. Short-term TNF-blocker therapy does not inhibit radiographic progression but long-term might do so. NSAIDs have been proven to inhibit such progression, even after 2 years of treatment. The effect of a combined therapy of NSAIDs with TNF-blockers on the inhibition of new bone formation in AS patients is currently unknown. © Springer Science+Business Media New York 2013.


Gelis L.,Ruhr University Bochum | Wolf S.,CAS Shanghai Institutes for Biological Sciences | Hatt H.,Ruhr University Bochum | Neuhaus E.M.,Charite - Medical University of Berlin | Gerwert K.,Ruhr University Bochum
Angewandte Chemie - International Edition | Year: 2012

Reprogramming a smell receptor: The ligand-binding niche within a three-dimensional model of a human olfactory receptor has been predicted by dynamic homology modeling and confirmed experimentally by functional studies of site-directed receptor mutants. Even a proposed reprogramming of the receptor's binding and activation properties was experimentally confirmed. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Kreuchwig A.,Leibniz Institute for Molecular Pharmacology | Kleinau G.,Charite - Medical University of Berlin | Krause G.,Leibniz Institute for Molecular Pharmacology
Molecular Endocrinology | Year: 2013

The first version of a glycoprotein hormone receptor (GPHR) information resource was designed to link functional with structural GPHR information, in order to support sequence-structurefunction analysis of the LH, FSH, and TSH receptors (http://ssfa-gphr.de). However, structural information on a binding- and signaling-sensitive extracellular fragment (100 residues), the hinge region, had been lacking. A new FSHR crystal structure of the hormone-bound extracellular domain has recently been solved. The structure comprises the leucine-rich repeat domain and most parts of the hinge region. We have not only integrated the new FSHR/FSH structure and the derived homology models of TSHR/TSH, LHCGR/CG, and LHCGR/LH into our web-based information resource, but have additionally provided novel tools to analyze the advanced structural features, with the common characteristics and distinctions between GPHRs, in a more precise manner. The hinge region with its second hormone-binding site allows us to assign functional data to the new structural features between hormone and receptor, such as binding details of a sulfated tyrosine (conserved throughout the GPHRs) extending into a pocket of the hormone. We have also implemented a protein interface analysis tool that enables the identification and visualization of extracellular contact points between interaction partners. This provides a starting point for comparing the binding patterns of GPHRs. Together with the mutagenesis data stored in the database, this will help to decipher the essential residues for ligand recognition and the molecular mechanisms of signal transduction, extending from the extracellular hormone-binding site toward the intracellular G protein-binding sites. © 2013 by The Endocrine Society.


Mueller W.-D.,Charite - Medical University of Berlin
BioNanoMaterials | Year: 2015

During the recent years different reviews have been published focusing on several aspects: the challenge of application of Mg-alloys as biomaterials, manufacturing procedure and its influence on the corrosion stability, application of different techniques to produce protection layers, coatings onto the surface of Mg-bulk devices, the influence of various elements applied as alloying part for Mg in order to change the mechanical as well as the electrochemical properties. The aim of this paper is to review and to comment electrochemical techniques applied to assess the corrosion/degradation behaviour of Mg and Mg-alloys for biomedical application. © 2015 by De Gruyter.


Kuhn S.,Max Planck Institute for Human Development | Gallinat J.,Charite - Medical University of Berlin | Gallinat J.,University of Hamburg
JAMA Psychiatry | Year: 2014

IMPORTANCE Since pornography appeared on the Internet, the accessibility, affordability, and anonymity of consuming visual sexual stimuli have increased and attracted millions of users. Based on the assumption that pornography consumption bears resemblance with reward-seeking behavior, novelty-seeking behavior, and addictive behavior, we hypothesized alterations of the frontostriatal network in frequent users. OBJECTIVE To determine whether frequent pornography consumption is associated with the frontostriatal network. DESIGN, SETTING, AND PARTICIPANTS In a study conducted at the Max Planck Institute for Human Development in Berlin, Germany, 64 healthy male adults covering a wide range of pornography consumption reported hours of pornography consumption per week. Pornography consumption was associated with neural structure, task-related activation, and functional resting-state connectivity. MAIN OUTCOMES AND MEASURES Gray matter volume of the brainwas measured by voxel-based morphometry and resting state functional connectivity was measured on 3-T magnetic resonance imaging scans. RESULTS We found a significant negative association between reported pornography hours per week and gray matter volume in the right caudate (P < .001, corrected for multiple comparisons) as well as with functional activity during a sexual cue-reactivity paradigm in the left putamen (P < .001). Functional connectivity of the right caudate to the left dorsolateral prefrontal cortex was negatively associated with hours of pornography consumption. CONCLUSIONS AND RELEVANCE The negative association of self-reported pornography consumption with the right striatum (caudate) volume, left striatum (putamen) activation during cue reactivity, and lower functional connectivity of the right caudate to the left dorsolateral prefrontal cortex could reflect change in neural plasticity as a consequence of an intense stimulation of the reward system, together with a lower top-down modulation of prefrontal cortical areas. Alternatively, it could be a precondition that makes pornography consumption more rewarding. © 2014 American Medical Association. All rights reserved.


Flottmann R.,Charite - Medical University of Berlin
European Journal of Human Genetics | Year: 2016

Parathyroid hormone-like hormone (PTHLH, MIM 168470) plays an important role in endochondral bone development and prevents chondrocytes from differentiating. Disease-causing variants and haploinsufficiency of PTHLH are known to cause brachydactyly type E and short stature. So far, three large duplications encompassing several genes including PTHLH associating with enchondromatas and acro-osteolysis have been described in the literature. Here, we report on a three-generation pedigree with short humerus, curved radius, and a specific type of severe brachydactyly with features of types E and A1 but without the enchondromatas and the acro-osteolysis. Microarray-based comparative genomic hybridization (array-CGH) revealed a 70-kb duplication on chromosome 12p11.22 encompassing only PTHLH. Our data extend the phenotypic spectrum associated with copy number variations of PTHLH, and this family is to our knowledge the first description harboring a microduplication encompassing only PTHLH.European Journal of Human Genetics advance online publication, 6 January 2016; doi:10.1038/ejhg.2015.266. © 2016 Macmillan Publishers Limited


Doehner W.,Charite - Medical University of Berlin
Heart Failure Reviews | Year: 2014

Overweight has been shown in multiple studies to carry a survival benefit in heart failure (HF) patients. This finding is, of course, counterintuitive to the well-established role of obesity as a modifiable risk factor for incident cardiovascular disease. The debate on the relevance of this obesity paradox is on-going, and clinical, methodological and teleological aspects are discussed. Particularly, younger age and a seemingly favourable clinical status of obese patients are repeatedly discussed together with the lack of prospective data to question the validity of the observed survival advantage in obese HF patients. Recent risk score calculators, however, have included body weight as an inverse risk factor, i.e. higher body mass index is predicting better outcome. Emerging prospective interventional trials support the concept that in patients with established disease, intentional weight reduction may not necessarily translate into improved outcome. The clinically most relevant consequence from the emerging data is, of course, the practical recommendation on body weight management that we may give our (overweight) patients. While the terminology as a paradox is critically discussed, a more differentiated concept for weight management should be emphasized that distinguishes between healthy subjects and those with an established cardiovascular disease such as heart failure. © Springer Science+Business Media 2014.


Sieper J.,Charite - Medical University of Berlin | Porter-Brown B.,Roche Holding AG | Thompson L.,Roche Holding AG | Harari O.,Roche Holding AG | Dougados M.,University of Paris Descartes
Annals of the Rheumatic Diseases | Year: 2014

Objectives BUILDER-1 and BUILDER-2 aimed to assess the efficacy and safety of tocilizumab (TCZ) in patients with ankylosing spondylitis (AS). Methods BUILDER-1 was a two part, phase II-III parallel-group trial in patients with AS naive to antitumour necrosis factor (aTNF) treatment. Patients in part 1 received TCZ 8 mg/kg or placebo for 12 weeks. In part 2 (beginning after part 1 enrolment ended), newly enrolled patients received TCZ 4 or 8 mg/kg or placebo for 24 weeks. The same treatment arms were used in BUILDER-2, a phase III study in aTNF-inadequate responders. The primary endpoint for both studies was the proportion of patients achieving 20% improvement in the Assessments in Axial SpondyloArthritis international Society (ASAS). Secondary and exploratory endpoints included ASAS40 response rates, Bath Ankylosing Spondylitis Disease Activity Index improvement, changes in joint counts, enthesitis score and C reactive protein (CRP). Results 102 patients were randomised in BUILDER-1 part 1; 99 (48 TCZ, 51 placebo) completed 12 weeks. Week 12 ASAS20 response rates were 37.3% and 27.5% in the TCZ and placebo arms, respectively (p=0.2823). Secondary and exploratory endpoints did not differ between treatment arms. CRP levels declined with TCZ treatment, suggesting adequate IL-6 receptor blockade. As a result, BUILDER-1 part 2 and BUILDER-2 were terminated. TCZ safety results were consistent with previous observations in rheumatoid arthritis, except for a cluster of anaphylactic and hypersensitivity events at Bulgarian study sites. No apparent explanation for this clustering could be found. Conclusions BUILDER-1 failed to demonstrate TCZ efficacy in treating aTNF-naive patients with AS.


Young J.B.,Cleveland Clinic | Neumayer H.-H.,Charite - Medical University of Berlin | Gordon R.D.,CTI Clinical Trial and Consulting Services
Kidney International | Year: 2010

Modern immunosuppression has expanded access to kidney transplantation by limiting the risk of rejection. However, cardiovascular disease (CVD) remains the principal cause of death with a functioning graft, threatening the long-term survival of transplant recipients. The article reviews the leading risk factors for cardiovascular morbidity both before and after kidney transplantation. Evidence linking poor renal function to CVD is discussed. The function of immunosuppression in exacerbating the risk of both nephrotoxicity and CVD is explored through means of a clinical case study. Underlying kidney disease, hypertension, hyperlipidemia, and diabetes are recognized risk factors for CVD both before and after kidney transplantation. Worsening kidney function and posttransplant immunosuppression exacerbate the risk. Although underlying medical conditions and demographic factors are not easily modifiable, immunosuppression has been recognized as a suitable target. Multiple risk factors converge to increase the risk of cardiovascular events and cardiovascular mortality after kidney transplantation. Clinicians are charged with isolating and treating modifiable risk factors to reduce the risk to long-term survival. © 2010 International Society of Nephrology.


Senkowski D.,Charite - Medical University of Berlin | Gallinat J.,University of Hamburg
Biological Psychiatry | Year: 2015

Impairments in working memory (WM) and other cognitive functions are cardinal neuropsychological symptoms in schizophrenia (ScZ). The prefrontal cortex (PFC) is important for mediating and executing these functions. Functional neuroimaging and molecular studies have consistently shown PFC abnormalities in ScZ. In addition, recent studies have suggested that impairments in oscillatory activity, especially in the gamma band (approximately 30-80 Hz), reflect disturbed cortical information processing in this patient group. Here we review evidence that dysfunctional gamma-band responses (GBR) in the PFC could be a factor contributing to WM and other cognitive deficits in ScZ. We provide an overview of noninvasive electrophysiological studies reporting frontal GBR abnormalities in ScZ patients during WM and other cognitive tasks. In agreement with the often-reported hypofrontality in functional neuroimaging studies, the majority of reviewed studies revealed reduced amplitudes or reduced phase locking of GBR over frontal areas in this patient group. Clinical implications derived from these findings and possibilities to foster future studies on GBR abnormalities in ScZ patients, are discussed. Since oscillatory activity in the gamma band has previously been linked to a variety of neurotransmitters, such as the gamma-aminobutyric acid-ergic system, the study of prefrontal GBR could also have implications for pharmacologic approaches in the treatment of WM and other cognitive deficits in ScZ. © 2015 Society of Biological Psychiatry.


Obladen M.,Charite - Medical University of Berlin
Neonatology | Year: 2016

This is the second of three papers investigating the legislative history concerning infanticide. It compares the efforts of various states to protect the newborn infant between 534 and 1532 CE. When the Roman Empire collapsed in the 5th century, the jurisdiction of infanticide was relegated to the church, which regarded carnal delicts a sin rather than a crime. The punishment - public penance of the mother for 7-15 years - was milder than that which the murder of an adult would incur. The Council of Florence decreed in 1439 that the souls of children who died without having been baptized descend to hell. This turned infanticide from a penitential sin to the most heinous of all crimes. The states passed laws that abominated infanticide even more than the murder of older humans and punished women with ever more cruel forms of execution. Towards the men, however, who usually abandoned the women they had impregnated, the laws were lenient. Churches and society continued to vilify illegitimate birth, thus enhancing rather than preventing infanticide. The Habsburg-German legislation of 1532 ordained to torture any woman who had concealed pregnancy and birth and claimed the infant was stillborn. Legislation developed similarly in other countries, albeit at a different speed. French (1556) and British (1623) legislation reversed the burden of proof and demanded the death penalty for concealing pregnancy and birth when a dead infant was found. © 2015 S. Karger AG, Basel.


Kohler S.,Charite - Medical University of Berlin | Hofmann A.,IB University of Applied Social Sciences Berlin
Alcohol and Alcoholism | Year: 2015

Aims: We investigate the effect of motivational interviewing (MI), delivered in a brief intervention during an emergency care contact, on the alcohol consumption of young people who screen positively for present or previous risky alcohol consumption. Methods: MEDLINE, CINAHL, EMBASE, PsycARTICLES, PsycINFO, PSYNDEX and Scopus were searched for randomized controlled trials with adolescents or young adults that compared MI in an emergency care setting to control conditions and measured drinking outcomes. Results: Six trials with 1433 participants, aged 13-25 years, were included in the systematic review and meta-analysis. MI was never less efficacious than a control intervention. Two trials found significantly more reduction in one or more measures of alcohol consumption in the MI intervention group. One trial indicated that MI may be used most effectively in young people with high-volume alcohol consumption. Separate random effects meta-analyses were performed based on the highest impact that MI added on reducing the drinking frequency and the drinking quantity at any point in time during the different study periods. Their results were expressed as standardized mean differences (SMDs). The frequency of drinking alcohol decreased significantly more after MI than after control interventions (SMD ≤ 10.17, P ≤ 0.03). In addition, MI reduced the drinking quantity further than control interventions in a meta-analysis of the subset of trials that were implemented in the USA (SMD = -0.12, P = 0.04). Meta-analyses of the smallest mean differences between MI and control groups detected no differences in alcohol use (SMD ≤ 0.02, P ≤ 0.38). Conclusion: MI appears at least as effective and may possibly be more effective than other brief interventions in emergency care to reduce alcohol consumption in young people. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.


Cohen M.X.,University of Amsterdam | Cohen M.X.,University of Arizona | Donner T.H.,University of Amsterdam | Donner T.H.,Charite - Medical University of Berlin
Journal of Neurophysiology | Year: 2013

Action monitoring and conflict resolution require the rapid and flexible coordination of activity in multiple brain regions. Oscillatory neural population activity may be a key physiological mechanism underlying such rapid and flexible network coordination. EEG power modulations of theta-band (4 - 8 Hz) activity over the human midfrontal cortex during response conflict have been proposed to reflect neural oscillations that support conflict detection and resolution processes. However, it has remained unclear whether this frequency-band-specific activity reflects neural oscillations or nonoscillatory responses (i.e., event-related potentials). Here, we show that removing the phase-locked component of the EEG did not reduce the strength of the conflict-related modulation of the residual (i.e., non-phase-locked) theta power over midfrontal cortex. Furthermore, within-subject regression analyses revealed that the non-phase-locked theta power was a significantly better predictor of the conflict condition than was the time-domain phase-locked EEG component. Finally, non-phase-locked theta power showed robust and condition-specific (highvs. low-conflict) cross-trial correlations with reaction time, whereas the phase-locked component did not. Taken together, our results indicate that most of the conflict-related and behaviorally relevant midfrontal EEG signal reflects a modulation of ongoing theta-band oscillations that occurs during the decision process but is not phase-locked to the stimulus or to the response. © 2013 the American Physiological Society.


Obladen M.,Charite - Medical University of Berlin
Neonatology | Year: 2015

Hemorrhages occurring in the newborn without trauma have been observed by obstetricians since the 17th century, but have been considered different diseases depending on their location. Umbilical hemorrhage associated with obstructed bile canals was described by Cheyne in 1802. Grandidier in 1871 and Townsend in 1894 grouped together various forms of neonatal bleeds and associated them with disturbed coagulation. When the clotting system became better understood in the last decade of the 19th century, effective symptomatic treatment was developed: gelatin, serum injection, and the transfusion of fresh blood. In 1935, Dam detected the function of vitamin K in the coagulation system and 4 years later, Waddell introduced vitamin K administration into therapy and prevention of neonatal hemorrhagic disease. Kernicterus occurred when high doses of synthetic water-soluble vitamin K analogues were given to preterm infants, reminding physicians that progress in neonatal therapy rests on the cornerstones of controlled trials and follow-up. © 2015 S. Karger AG, Basel.


To compare 0.15 mmol/kg gadobutrol with 0.20 mmol/kg gadopentetate dimeglumine with regard to late gadolinium enhancement (LGE) of infarcted myocardium at magnetic resonance (MR) imaging. Twenty patients with history of chronic myocardial infarction underwent 2 cardiac MR examinations at 1.5 Tesla. For the evaluation of myocardial infarction, late gadolinium enhancement (LGE) imaging was performed with an inversion recovery-prepared gradient-echo sequence 15 minutes after administration of either gadobutrol (r1 = 5.2 mmol(-1)s(-1)) or gadopentetate dimeglumine (r1 = 4.1 mmol(-1)s(-1)). The dose of the contrast agents was adjusted based on the relaxivity of both contrast agents. Hence, gadobutrol and gadopentetate dimeglumine were administered at 0.15 mmol/kg and 0.20 mmol/kg, respectively. Contrast-to-noise ratios (CNR) between infarcted myocardium and remote myocardium (CNR remote) and between infarcted myocardium and left ventricular lumen (CNR lumen) were assessed by 2 independent readers. Additionally, infarct size was assessed semiautomatically by using a threshold of 5 standard deviations above the mean signal intensity of remote myocardium. Subendocardial or transmural LGE was present in 16 of 20 (80%) patients. The optimal inversion time for LGE imaging did not differ significantly between gadobutrol and gadopentetate dimeglumine (275 ± 21 milliseconds [range, 240-320 milliseconds] and 282 ± 23 milliseconds [range, 240-330 milliseconds], respectively; P = 0.32). The CNR remote after administration of gadobutrol (40.0 ± 4.6; 95% confidence interval [CI]: 30.3; 49.7) and gadopentetate dimeglumine (40.6 ± 4.6; 95% CI: 30.9; 50.3) did not show significant differences (P = 0.90), whereas gadobutrol yielded a significantly higher CNR lumen (6.2 ± 3.6; 95% CI: -1.5; 13.9) compared with gadopentetate dimeglumine (0.8 ± 3.6; 95% CI: -6.9; 8.5). Infarct size after administration of gadobutrol (23.7 ± 4.7 mL; 95% CI: 13.6; 33.7) and gadopentetate dimeglumine (23.7 ± 4.7 mL;95% CI: 13.7; 33.8) was not statistically different (P = 0.94). There was an excellent correlation between gadobutrol- and gadopentetate dimeglumine-enhanced assessment of infarct size (Spearman r = 0.99 and r = 0.97 for reader 1 and 2, respectively). This pilot study shows that 0.15 mmol/kg gadobutrol is an effective contrast agent for LGE imaging with better delineation of infarcted myocardium from left ventricular lumen than 0.20 mmol/kg gadopentetate dimeglumine.


Aims/hypothesis: In the February 2006 issue of Diabetologia, the observational Retrolective Study: Self-monitoring of Blood Glucose and Outcome in Patients with Type 2 Diabetes (ROSSO) reported a 51% reduction in the risk of all-cause mortality in patients with type 2 diabetes who performed self-monitoring of blood glucose (SMBG). However, these impressive benefits conflict with results from observational studies and randomised controlled trials. We aimed to show that these findings are caused by a flawed design that introduced immortal time bias. Methods: We illustrate the bias in the ROSSO study and demonstrate that it is large enough to completely explain the apparently protective effect of SMBG on all-cause mortality. Results: In the ROSSO study, patients were classified as exposed to SMBG for their whole follow-up time if they performed self-monitoring for at least 1 year during the study period. Thus, the time between cohort entry and the date after 1 year self-monitoring was performed is unavoidably 'immortal' for patients with SMBG. Patients had to survive at least 1 year to be classified as exposed to this intervention and were artificially 'protected' from death. Based on published information, the total amount of misclassified immortal person-time in the SMBG group is at least 5,082 of 9,248 person-years at risk (55%). After re-classification of immortal person-time as unexposed, the unadjusted relative risk changed from 0.59 to 1.95. Conclusions/interpretation: The apparently protective effect of SMBG on all-cause mortality observed in the ROSSO study is completely explained by immortal time bias. © 2010 Springer-Verlag.


Dahlmann B.,Charite - Medical University of Berlin
Archives of Biochemistry and Biophysics | Year: 2016

The 20S proteasome is a multicatalytic proteinase catalysing the degradation of the majority of intracellular proteins. Thereby it is involved in almost all basic cellular processes, which is facilitated by its association with various regulator complexes so that it appears in different disguises like 26S proteasome, hybrid-proteasome and others. The 20S proteasome has a cylindrical structure built up by four stacked rings composed of α- and β-subunits. Since the three active site-containing β-subunits can all or in part be replaced by immuno-subunits, three main subpopulations exist, namely standard-, immuno- and intermediate-proteasomes. Due to posttranslational modifications or/and genetic variations all α- and β-subunits occur in multiple iso- or proteoforms. This leads to the fact that each of the three subpopulations is composed of a variety of 20S proteasome subtypes. This review summarizes the knowledge of proteasome subtypes in mammalian cells and tissues and their possible biological and medical relevancy. © 2016 Elsevier Inc. All rights reserved.


Schweiger M.-R.,Max Planck Institute for Molecular Genetics | Barmeyer C.,Charite - Medical University of Berlin
Briefings in Functional Genomics | Year: 2013

Recent years have brought about a marked extension of our understanding of the somatic basis of cancer. Parallel to the large-scale investigation of diverse tumor genomes the knowledge arose that cancer pathologies are most often not restricted to single genomic events. In contrast, a large number of different alterations in the genomes and epigenomes come together and promote the malignant transformation. The combination of mutations, structural variations and epigenetic alterations differs between each tumor, making individual diagnosis and treatment strategies necessary. This view is summarized in the new discipline of personalized medicine. To satisfy the ideas of this approach each tumor needs to be fully characterized and individual diagnostic and therapeutic strategies designed. Here, we will discuss the power of high-throughput sequencing technologies for genomic and epigenomic analyses.We will provide insight into the current status and how these technologies can be transferred to routine clinical usage. © The Author 2013. Published by Oxford University Press. All rights reserved.


Dubiel W.,Charite - Medical University of Berlin
Sub-Cellular Biochemistry | Year: 2010

The interplay between ubiquitin (Ub) family modifiers creates a regulatory network of Ub family proteins which is essential for cell growth and differentiation. One of the best studied crosstalks between Ub family modifiers is the stimulation of ubiquitination by Nedd8 (neural precursor cell expressed developmentally down regulated 8) modification. The neddylation-deneddylation pathway controls the selective ubiquitination of important cellular regulators targeted for proteolysis by the Ub proteasome system (UPS). In this process the cullin scaffolds of cullin-RING Ub ligases (CRLs) are neddylated, which allosterically activates the transfer of Ub to substrates of the CRLs. A major reaction of the regulatory network is the removal of Nedd8 by the COP9 signalosome (CSN), which converts CRLs into an inactive state. The CSN is a conserved protein complex that interacts with CRLs and possesses an intrinsic metalloprotease with a Jab1/Pad1/MPN+ (JAMM) motif responsible for deneddylation.In the present chapter we focus on the CSN-mediated deneddylation and its biological significance. We summarize latest developments on the mechanism of the CSN and its association with supercomplexes. In addition, data on the regulation of CSN-mediated deneddylation are described. Moreover, dysfunctions of the CSN and their implication in the pathogenesis of diseases are discussed. © 2010 Landes Bioscience and Springer Science+Business Media


Hesselmann G.,Charite - Medical University of Berlin
Neuroscientist | Year: 2013

In recent years, substantial progress has been made in the scientific study of perceptual awareness, or synonymously, the contents of consciousness. By many standards, the field of consciousness research is in a phase of unprecedented productivity and progress, with high-impact publications, popular science books, specialized journals, dedicated academic societies, scientific conferences, and, above all, competing cognitive and neurobiological theories of consciousness. In the present review, I highlight a selection of recent fMRI and related behavioral studies that examine the neuronal underpinnings of awareness in higher order and early visual cortex. After the introduction, I also provide a brief overview of the crucial problem of measurement, that is, the fact that any exploration of consciousness depends on some kind of report, which pertains to all studies summarized in this review. © The Author(s) 2013.


Kupsch A.,Charite - Medical University of Berlin
Movement disorders : official journal of the Movement Disorder Society | Year: 2011

Early postoperative management in deep brain stimulation-treated patients with dystonia differs from that of patients with essential tremor and Parkinson's disease, mainly due to the usually delayed effects of deep brain stimulation and the heterogenous clinical manifestation and etiologies of dystonia. The present chapter summarizes the available data about and concentrates on practical clinical aspects of early postoperative management in deep brain stimulation-treated patients with dystonia. Copyright © 2011 Movement Disorder Society.


Salama A.,Charite - Medical University of Berlin
Transfusion Medicine and Hemotherapy | Year: 2015

Autoimmune haemolytic anaemias (AIHAs) are well-characterized disorders. They can be differentiated from one another and from other non-immune haemolytic anaemias by clinical, laboratory and serological testing. However, several misleading clinical presentations and/or serological findings may result in misinterpretation, delay and/or misdiagnosis. Such failures are avoidable by adequate clinical and serological experience of the responsible physicians and serologists or, at least, by an optimised bidirectional communication. As long as this has not been achieved, unpleasant failures are to be expected. A true diagnosis of AIHA can neither be verified by clinical nor serological findings alone. Thus, a collective clinical and serological picture remains obligatory for fulfilling the criteria of optimal diagnosis and therapy. Ultimately, the majority of pioneer scientific and practical work in this field stems from scientists who were simultaneously involved in both the clinic and serology. © 2015 S. Karger GmbH, Freiburg.


Salama A.,Charite - Medical University of Berlin
Transfusion Medicine and Hemotherapy | Year: 2015

Until now, treatment of primary autoimmune hemolytic anemia of the warm type (wAIHA) is primarily based on immunosuppression. However, many patients do not respond adequately to treatment, and treated patients may develop severe side effects due to uncontrolled, mixed and/or long-lasting immunosuppression. Unfortunately, the newly used therapeutic monoclonal antibodies are unspecific and remain frequently ineffective. Thus, development of a specific therapy for AIHA is necessary. The ideal therapy would be the identification and elimination of the causative origin of autoimmunization and/or the correction or reprogramming of the dysregulated immune components. Blood transfusion is the most rapidly effective measure for patients who develop or may develop hypoxic anemia. Although some effort has been made to guide physicians on how to adequately treat patients with AIHA, a number of individual aspects should be considered prior to treatment. Based on my serological and clinical experience and the analysis of evidence-based studies, we remain far from any optimized therapeutic measures for all AIHA patients. Today, the old standard therapy using controlled steroid administration, with or without azathioprine or cyclophosphamide, is, when complemented with erythropoiesis-stimulating agents, still the most effective therapy in wAIHA. Rituximab or other monoclonal antibodies may be used instead of splenectomy in therapy-refractory patients. © 2015 S. Karger GmbH, Freiburg.


Gunther T.,Charite - Medical University of Berlin
Magnesium Research | Year: 2010

Insulin secretion is started by a Ca2+ influx that is competitively inhibited by extracellular Mg2+. This can explain the inverse correlation between serum Mg2+ and serum insulin concentration. After binding of insulin to its receptor, receptor tyrosine kinase is activated. The autophosphorylation of the receptor kinase and all protein kinases in the insulin signal transduction cascade are dependent on Mg2+. Besides MgATP as substrate, protein tyrosine kinases are activated by a second Mg2+. Other protein kinases and some protein phosphatases involved in insulin resistance are dependent on Mg2+ as well. In the complex action of Mg2+ on tyrosine protein kinases and serine/threonine kinases, which mediate or inhibit insulin signaling, the concentration of intracellular free Mg2+ ([Mg2+]i) may have a permissive function. The secretion of various effectors such as adipokines, interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-α (TNF-α), β-adrenergics and reactive oxygen species (ROS) involved in insulin resistance is enhanced in Mg deficiency and obesity. Adipocytes produce chemotactic signals, leading to macrophage recruitment and in addition to adipocytes, to the production of proinflammatory cytokines. The concentration of free fatty acids (FFA), particularly palmitate, is increased in obesity and by the action of β-adrenergics. The complex actions of adipokines, cytokines and palmitate in the induction of insulin resistance are reviewed. The concentration of extracellular and intracellular Mg2+ in patients and the experimental effects of insulin and catecholamines on [Mg2+]i in various tissues are described. The controversial effects of different serum Mg2+ concentrations and Mg2+ supplementation on plasma glucose and insulin concentration in studies with human subjects and the controversial results of epidemiological studies are reported.


Due to its high life-time prevalence, major depression is one of the most urging medical problems in public health care. In many depressed patients cognitive dysfunction is present not only during the depressive episode but also as a residual symptom after remission has been achieved. Residual symptoms like cognitive dysfunction impair the patients' social functional level as well as their quality of life and they increase the risk of relapse. Up to now, only few studies have specifically examined the effects of antidepressants on cognitive dysfunction in depressed patients. Vortioxetine is a multimodal antidepressant acting on serotonin (5-HT) receptors in several ways: as an antagonist on 5-HT3, 5-HT7, and 5-HT1D receptors, as a partial agonist on 5-HT1B receptors, and as an agonist on 5-HT1A receptors; furthermore, it inhibits the 5-HT transporter. In preclinical animal studies, vortioxetine showed positive effects on learning and memory. The effects of vortioxetine on cognitive dysfunction in depressed patients are discussed in the context of available studies with other antidepressants. © 2015, Wissenschaftliche Verlagsgesellschaft MBH. All rights reserved.


Krampe H.,Charite - Medical University of Berlin | Ehrenreich H.,Max Planck Institute for Experimental Medicine
Current Pharmaceutical Design | Year: 2010

Supervised intake of the alcohol deterrent (AD) disulfiram has proven to be an effective adjunct to biopsychosocial alcoholism therapy for more than 60 years. This article summarizes disulfiram literature between 1937 and 2000 and reviews 13 clinical trials of disulfiram in alcoholism treatment from the years 2000 to 2008. After giving an update of general safety issues and recent case reports concerning safety problems with disulfiram, we focus on the introduction of psychotherapeutic application of supervised disulfiram. The results of our review show: (1) Disulfiram proved to be an effective therapeutic tool in all clinical studies published from 2000 to 2008. (2) Comparisons with other pharmacological agents - naltrexone, acamprosate, topiramate and gamma-hydroxybutyrate - indicate that disulfiram was equal in two trials but superior in the majority of trials. (3) Therapy programs that make use of the psychological effects of supervised disulfiram have - independently of the dose - better results than programs that neglect psychological effects. As a consequence, we suggest that supervised low-dose disulfiram (not more than 100mg/d), will show highest success when it is carefully integrated into psychotherapeutic alcoholism therapy. The major program of psychotherapy with disulfiram comprises the steps "Initial psychoeducation about the effect of disulfiram and its therapeutic implications", "Advanced psychoeducation", and "Disulfiram as coping skill and extension of repertoire of coping skills". As psychological mechanisms of supervised disulfiram we suggest: (1) deterrence; (2) (auto)suggestion; (3) therapeutic ritual around (4) a frequently renewed active decision process; (5) continuous reinforcement of a sober lifestyle and development of new coping skills. © 2010 Bentham Science Publishers Ltd.


Bussing A.,Witten/Herdecke University | Ostermann T.,Witten/Herdecke University | Ludtke R.,Veronica | Michalsen A.,Charite - Medical University of Berlin
Journal of Pain | Year: 2012

We searched databases for controlled clinical studies, and performed a meta-analysis on the effectiveness of yoga interventions on pain and associated disability. Five randomized studies reported single-blinding and had a higher methodological quality; 7 studies were randomized but not blinded and had moderate quality; and 4 nonrandomized studies had low quality. In 6 studies, yoga was used to treat patients with back pain; in 2 studies to treat rheumatoid arthritis; in 2 studies to treat patients with headache/migraine; and 6 studies enrolled individuals for other indications. All studies reported positive effects in favor of the yoga interventions. With respect to pain, a random effect meta-analysis estimated the overall treatment effect at SMD = -.74 (CI: -.97; -.52, P <.0001), and an overall treatment effect at SMD = -.79 (CI: -1.02; -.56, P <.0001) for pain-related disability. Despite some limitations, there is evidence that yoga may be useful for several pain-associated disorders. Moreover, there are hints that even short-term interventions might be effective. Nevertheless, large-scale further studies have to identify which patients may benefit from the respective interventions. Perspective: This meta-analysis suggests that yoga is a useful supplementary approach with moderate effect sizes on pain and associated disability. © 2012 by the American Pain Society.


Daumke O.,Max Delbruck Centrum fur Molekulare Medizin | Daumke O.,Free University of Berlin | Roux A.,University of Geneva | Haucke V.,Leibniz Institute for Molecular Pharmacology | Haucke V.,Charite - Medical University of Berlin
Cell | Year: 2014

Biological membranes undergo constant remodeling by membrane fission and fusion to change their shape and to exchange material between subcellular compartments. During clathrin-mediated endocytosis, the dynamic assembly and disassembly of protein scaffolds comprising members of the bin-amphiphysin-rvs (BAR) domain protein superfamily constrain the membrane into distinct shapes as the pathway progresses toward fission by the GTPase dynamin. In this Review, we discuss how BAR domain protein assembly and disassembly are controlled in space and time and which structural and biochemical features allow the tight regulation of their shape and function to enable dynamin-mediated membrane fission. © 2014 Elsevier Inc.


Trichuris suis ova is a probiotic treatment based on the hygiene hypothesis. It has been demonstrated as safe and effective in autoimmune inflammatory bowel diseases and clinical trials indicate that helminth infections also have an immunomodulatory effect in multiple sclerosis.We hypothesize that administering 2,500 Trichuris suis ova eggs orally every two weeks for 12 months is--due to its immunomodulatory and anti-inflammatory effect--significantly more effective than oral placebo in preventing new T2 and Gd+ lesions, as quantified by cerebral MRI and clinical examination, in relapsing-remitting multiple sclerosis and clinically isolated syndrome. Fifty patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome with clinical activity, not undergoing any standard therapies, will be randomized 1:1 to Trichuris suis ova 2,500 eggs every two weeks or matching placebo. The safety, tolerability and effect on disease activity and in vivo mechanisms of action of Trichuris suis ova in MS will be assessed by neurological, laboratory and immunological exams and magnetic resonance imaging throughout the 12-month treatment period and over a follow-up period of 6 months. Various immunological analyses will be used to assess the overall patient immune response prior to and at varying time points following treatment with Trichuris suis ova. We anticipate that Trichuris suis ova will be well tolerated and more effective than the placebo in preventing new T2 and Gd+ lesions, as quantified by MRI. We also expect the Th1/Th17 proinflammatory response to shift towards the more anti-inflammatory Th2 response. This study has important clinical implications and will involve extensive research on the immunology of helminth therapy. ClinicalTrials.gov: NCT01413243.


Eckert C.,Charite - Medical University of Berlin
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

In children with intermediate risk of relapse of acute lymphoblastic leukemia (ALL), it is essential to identify patients in need of treatment intensification. We hypothesized that the prognosis of patients with unsatisfactory reduction of minimal residual disease (MRD) can be improved by allogeneic hematopoietic stem-cell transplantation (HSCT). In the Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 2002, patients with an MRD level of ≥ 10(-3) (n = 99) at the end of induction therapy were allocated to HSCT, whereas those with an MRD level less than 10(-3) (n = 109) continued to receive chemotherapy. MRD was quantified by real-time polymerase chain reaction for clone-specific T-cell receptor/immunoglobulin gene rearrangements. The probability of event-free survival for patients with MRD ≥ 10(-3) was 64% ± 5% in ALL-REZ BFM 2002 compared with 18% ± 7% in the predecessor study ALL-REZ BFM P95/96 (P < .001). This was mainly achieved by reducing the cumulative incidence of subsequent relapse (CIR) at 8 years from 59% ± 9% to 27% ± 5% (P < .001). The favorable prognosis of patients with MRD less than 10(-3) could be confirmed in those with a late combined or isolated bone marrow B-cell precursor (BCP) -ALL relapse (CIR, 20% ± 5%), whereas patients with an early combined BCP-ALL relapse had an unfavorable outcome (CIR, 63% ± 13%; P < .001). Allogeneic HSCT markedly improved the prognosis of patients with intermediate risk of relapse of ALL and unsatisfactory MRD response. As a result, outcomes in this group approximated those of patients with favorable MRD response. Patients with early combined relapse require treatment intensification even in case of favorable MRD response, demonstrating the prognostic impact of time to relapse.


Obladen M.,Charite - Medical University of Berlin
Neonatology | Year: 2011

Ductus arteriosus and foramen ovale were described by Galen without understanding their functions. His beliefs in soul localization and spiritization within the left ventricle established religious pneumatology which became a theological need in the Middle Ages. Pulmonary transit was recognized by Servetus and Colombo after the Reformation around 1550. This prompted Harvey's full understanding of the fetal circulation. Botallo did not describe the ductus arteriosus, but in 1564 redescribed the foramen ovale, making his way into the nomina anatomica by mistake. Most authors of the 19th and 20th century believed ductal patency to be passive, and postnatal closure to be an active process, explained by mechanical theories. After the discovery of prostaglandins by Bergstrom and Vane, Coceani proved that ductal patency is maintained by the relaxant action of prostaglandins. Copyright © 2010 S. Karger AG, Basel.


Witt C.M.,Charite - Medical University of Berlin
Journal of Ethnopharmacology | Year: 2013

Ethnopharmacological relevance: In the traditional context, herbs are often used as herbal whole system therapies, however, most clinical trials included highly selected patients and applied standardized treatment protocols with the aim to exclude as much bias as possible. These studies have contributed important information on the efficacy of herbal medicine extracts; however, their results are only marginally helpful to understand the value of herbal medicine and food items in a more traditional usual care context. Methods: The new development of comparative effectiveness research (CER) will be introduced and synergies with ethnopharmacology will be outlined. Results: CER provides great opportunities for guiding researchers and clinicians in improving management of disease. CER compares two or more health interventions in order to determine which of these options works best for which types of patients in settings that are similar to those in which the intervention will be used in practice. CER uses a broad spectrum of methodologies including randomized pragmatic trials that can also be applied to herbal whole system therapies. Ethnopharmacological research can provide highly relevant information for CER including data on characteristics of typical patients as well as traditional usage including methods of collection, extraction, and preparation. Recommendations for future research on traditional herbal medicine and food items are (1) a systematic cooperation between ethnopharmacology and clinical researchers and (2) a call for more CER on traditional herbal medicines and food items. Conclusion: Multiple stakeholders, including ethnopharmacologists, should cooperate to identify relevant study questions as well share their knowledge to determine the optimal placement of a clinical trial in the efficacy-effectiveness-continuum. © 2013 Elsevier Ireland Ltd.


Von Eichborn J.,Charite - Medical University of Berlin
Genome informatics. International Conference on Genome Informatics | Year: 2010

Solved structures of protein-protein complexes give fundamental insights into protein function and molecular recognition. Although the determination of protein-protein complexes is generally more difficult than solving individual proteins, the number of experimentally determined complexes increased conspicuously during the last decade. Here, the interfaces of 750 transient protein-protein interactions as well as 2,000 interactions between domains of the same protein chain (obligate interactions) were analyzed to obtain a better understanding of molecular recognition and to identify features applicable for protein binding site prediction. Calculation of knowledge-based potentials showed a preference of contacts between amino acids having complementary physicochemical properties. The analysis of amino acid conservation of the entire interface area showed a weak but significant tendency to a higher evolutionary conservation of protein binding sites compared to surface areas that are permanently exposed to solvent. Remarkably, contact frequencies between outstandingly conserved residues are much higher than expected confirming the so-called "hot spot" theory. The comparisons between obligate and transient domain contacts reveal differences and point out that structural diversification and molecular recognition of protein-protein interactions are subjected to other evolutionary aspects than obligate domain-domain interactions.


Qazi T.H.,Friedrich - Alexander - University, Erlangen - Nuremberg | Qazi T.H.,Charite - Medical University of Berlin | Rai R.,Friedrich - Alexander - University, Erlangen - Nuremberg | Boccaccini A.R.,Friedrich - Alexander - University, Erlangen - Nuremberg
Biomaterials | Year: 2014

Conducting polymers have found numerous applications as biomaterial components serving to effectively deliver electrical signals from an external source to the seeded cells. Several cell types including cardiomyocytes, neurons, and osteoblasts respond to electrical signals by improving their functional outcomes. Although a wide variety of conducting polymers are available, polyaniline (PANI) has emerged as a popular choice due to its attractive properties such as ease of synthesis, tunable conductivity, environmental stability, and biocompatibility. PANI in its pure form has exhibited biocompatibility both invitro and invivo, and has been combined with a host of biodegradable polymers to form composites having a range of mechanical, electrical, and surface properties. Moreover, recent studies in literature report on the functionalization of polyaniline oligomers with end segments that make it biodegradable and improve its biocompatibility, two properties which make these materials highly desirable for applications in tissue engineering. This review will discuss the features and properties of PANI based composites that make them effective biomaterials, and it provides a comprehensive summary of studies where the use of PANI as a biomaterial component has enhanced cellular function and behavior. We also discuss recent studies utilizing functionalized PANI oligomers, and conclude that electroactive PANI and its derivatives show great promise in eliciting favorable responses from various cell lines that respond to electrical stimuli, and are therefore effective biomaterials for the engineering of electrically responsive biological tissues and organs. © 2014 Elsevier Ltd.


Obladen M.,Charite - Medical University of Berlin
Neonatology | Year: 2016

This is the third of three papers investigating the legislative history concerning infanticide. After Antiquity and the Middle Ages, this paper focuses on legislative reforms during the last 400 years. Despite dreadful punishment, the practice remained frequent until safe abortion became available. In the 17th century, the rate of executions of women for this crime was 1 per 100,000 inhabitants. The actual incidence greatly exceeded this figure. The death penalty failed to deter, and punishing fornication promoted rather than prevented infanticide. Well into the 18th century, severely malformed infants were killed. The lung flotation test, albeit unreliable, was used to save the mother from the death penalty. When the motives for infanticide - poverty, shame, despair, and preserving honour - became understood in the late 18th century, the image of the ‘child murderess' changed, and infanticide shifted from constituting a capital crime to a privileged delict. Illegitimate pregnancy was no longer punished, and lying-in hospitals for pregnant unmarried women and foundling hospitals for their children were established. Specific infanticide laws were issued in Prussia in 1756, Britain in 1803, and France in 1811. Once psychosis and denial of pregnancy became understood, severe penalties were no longer issued. The justifications for lenient legislation included social circumstances, difficult proof, and curtailed protection of the newborn due to its illegitimacy, helplessness, and diminished awareness. Thoughts on the limited right to live of newborn infants are still hampering ethical decisions when the beginning and end of life are near each other. © 2016 S. Karger AG, Basel


Makowski M.R.,Kings College London | Botnar R.M.,Kings College London | Botnar R.M.,Charite - Medical University of Berlin
Radiology | Year: 2013

Cardiovascular diseases remain the leading cause of morbidity and mortality in the Western world and developing countries. In clinical practice, in vivo characterization of atherosclerotic lesions causing myocardial infarction, ischemic stroke, and other complications remains challenging. Imaging methods, limited to the assessment luminal stenosis, are the current reference standard for the assessment of clinically significant coronary and carotid artery disease and the guidance of treatment. These techniques do not allow distinction between stable and potentially vulnerable atherosclerotic plaque. Magnetic resonance (MR) imaging is a modality well suited for visualization and characterization of the relatively thin arterial vessel wall, because it allows imaging with high spatial resolution and excellent soft-tissue contrast. In clinical practice, atherosclerotic plaque components of the carotid artery and aorta may be differentiated and characterized by using unenhanced vessel wall MR imaging. Additional information can be gained by using clinically approved nonspecific contrast agents. With the advent of targeted MR contrast agents, which enhance specific molecules or cells, pathologic processes can be visualized at a molecular level with high spatial resolution. In this article, the pathophysiologic changes of the arterial vessel wall underlying the development of atherosclerosis will be first reviewed. Then basic principles and properties of molecular MR imaging contrast agents will be introduced. Additionally, recent advances in preclinical molecular vessel wall imaging will be reviewed. Finally, the clinical feasibility of arterial vessel wall imaging at unenhanced and contrast material-enhanced MR imaging of the aortic, carotid, and coronary vessel wall will be discussed. © RSNA, 2013.


Zuberbier T.,Charite - Medical University of Berlin
Current Allergy and Asthma Reports | Year: 2012

Chronic urticaria is defined as case of spontaneous wheals and/or angioedema persisting for a period of at least six weeks. The disease has an average duration of three to five years and is strongly associated with a decrease of quality of life and performance. Current international guidelines recommend the use of non-sedating antihistamines as the first choice in therapy and updosing these up to fourfold in cases of non-response. Alternative treatments for the afflicted who do not respond to antihistamine-treatment are also available but are not approved for use on urticaria. © Springer Science+Business Media, LLC 2012.


Holtkamp M.,Charite - Medical University of Berlin
Aktuelle Neurologie | Year: 2012

Any epileptic seizure lasting more than 5min should promptly be treated as status epilepticus (SE) by anticonvulsants. Drug of choice is intravenous lorazepam (48mg). If SE persists, second-line anticonvulsants such as levetiracetam, phenytoin and valproate are administered. In every third patient, epileptic activity further continues, this condition is termed refractory status epilepticus (RSE). Complex-partial SE does neither result in acute systemic complications nor in neuronal long-term consequences. Therefore, anticonvulsant treatment after failure of first- and second-line agents should be based on non-anaesthetising substances including if not already given second-line lacosamide, levetiracetam, phenytoin or valproate. Anaesthetics should be avoided if possible, as side-effects may be more harmful than continuing non-convulsive epileptic activity. In contrast, generalised- convulsive SE is associated with a high risk of acute systemic morbidity (e.g. cardial arrhythmias), therefore refractory courses should promptly be treated with anaesthetics (midazolam, propofol or thiopental). After bolus administration, these components are titrated against an EEG burst-suppression-pattern for at least 24h. Pathophysiologically, prolonged epileptic activity results in a decrease of post-synaptic inhibitory GABA A receptors. The later anticonvulsants are administered, the less likely they terminate epileptic activity. In contrast, excitatory NMDA receptors increase with ongoing SE. Therefore, NMDA receptor antagonists such as ketamine may be efficient in later stages of SE after GABAergic anaesthetics have failed. Recent data demonstrate that even patients with prolonged RSE can survive with favourable functional outcome. Therefore, end-of-life decisions in SE may be based on the expected prognosis of the underlying brain disorder rather than on duration of SE. © Georg Thieme Verlag KGStuttgart · New York.


Bayerlein B.,Max Planck Institute of Colloids and Interfaces | Zaslansky P.,Charite - Medical University of Berlin | Dauphin Y.,University Pierre and Marie Curie | Rack A.,European Synchrotron Radiation Facility | And 2 more authors.
Nature Materials | Year: 2014

Significant progress has been made in understanding the interaction between mineral precursors and organic components leading to material formation and structuring in biomineralizing systems. The mesostructure of biological materials, such as the outer calcitic shell of molluscs, is characterized by many parameters and the question arises as to what extent they all are, or need to be, controlled biologically. Here, we analyse the three-dimensional structure of the calcite-based prismatic layer of Pinna nobilis, the giant Mediterranean fan mussel, using high-resolution synchrotron-based microtomography. We show that the evolution of the layer is statistically self-similar and, remarkably, its morphology and mesostructure can be fully predicted using classical materials science theories for normal grain growth. These findings are a fundamental step in understanding the constraints that dictate the shape of these biogenic minerals and shed light on how biological organisms make use of thermodynamics to generate complex morphologies. © 2014 Macmillan Publishers Limited. All rights reserved.


Saad F.,University of Montreal | Miller K.,Charite - Medical University of Berlin
Urologic Oncology: Seminars and Original Investigations | Year: 2014

Background: Docetaxel-based chemotherapy remains the standard of care for metastatic castration-resistant prostate cancer (mCRPC) and it is the only globally approved first-line therapy. Although docetaxel offers improved survival for this patient population, it is also associated with toxicity and resistance in many patients, representing a need for more efficacious therapies. Preclinical advances have led to improved understanding of the molecular biology of prostate cancer, and targeted therapies that exploit the signaling pathways and molecular targets that underscore the disease are being clinically investigated in combination with docetaxel. Design: This article briefly highlights recent data from phase III trials in mCRPC that have led to agent approval. This article also reviews phase II and III trials in which docetaxel-based regimens have been investigated in mCRPC. Results: Recently approved agents, including sipuleucel-T, cabazitaxel, abiraterone acetate, and enzalutamide, have diversified the mCRPC treatment landscape. Phase III trials evaluating docetaxel in combination with targeted therapies, including potent oral tyrosine kinase inhibitor, dasatinib, in the READY trial and clusterin inhibitor, custirsen, in the SYNERGY trial, are currently ongoing. Conclusions: In combination with docetaxel, targeted agents dasatinib and custirsen will likely expand the existing treatment paradigm for mCRPC if results from phase III trials are positive. © 2014 Elsevier Inc.


Quinkler M.,Charite - Medical University of Berlin
Medizinische Klinik - Intensivmedizin und Notfallmedizin | Year: 2012

The clinical signs and symptoms of primary adrenal insufficiency are unspecific often causing a delayed diagnosis or even misdiagnosis. In the diagnostic work-up the short synacthen test is regarded as the gold standard. Hydrocortisone and fludrocortisone are the preferred therapy for Addison's disease. The management and surveillance of therapy requires experience and several aspects need to be followed to prevent side effects which might occur due to overtreatment or undertreatment. Very important aspects in therapy are the repeated teaching of the patient and relatives, the issuing of an emergency steroid card and the prescription of a glucocorticoid emergency set. Acute adrenal failure (adrenal crisis), which might be the first manifestation of adrenal insufficiency, is a life-threatening situation requiring immediate glucocorticoid administration and fluid substitution. The most common causes for an adrenal crisis are gastrointestinal infections and fever and discontinuation of glucocorticoid therapy. This article gives an up-to-date overview of diagnostic and therapeutic aspects of Addison's disease. © 2012 Springer-Verlag.


Choi Y.-H.,University of Cologne | Kurtz A.,Berlin Brandenburg Center for Regenerative Therapies | Kurtz A.,Charite - Medical University of Berlin | Stamm C.,Berlin Brandenburg Center for Regenerative Therapies
Human Gene Therapy | Year: 2011

Despite refinements of medical and surgical therapies, heart failure remains a fatal disease. Myocardial infarction is the most common cause of heart failure, and only palliative measures are available to relieve symptoms and prolong the patient's life span. Because mammalian cardiomyocytes irreversibly exit the cell cycle at about the time of birth, the heart has traditionally been considered to lack any regenerative capacity. This paradigm, however, is currently shifting, and the cellular composition of the myocardium is being targeted by various regeneration strategies. Adult progenitor and stem cell treatment of diseased human myocardium has been carried out for more than 10 years (Menasche et al., 2001; Stamm et al., 2003), and it has become clear that, in humans, the regenerative capacity of hematopoietic stem cells and endothelial progenitor cells, despite potent proangiogenic effects, is limited (Stamm et al., 2009). More recently, mesenchymal stem cells (MSCs) and related cell types are being evaluated in preclinical models of heart disease as well as in clinical trials (see Published Clinical Trials, below). MSCs have the capacity to self-renew and to differentiate into lineages that normally originate from the embryonic mesenchyme (connective tissues, blood vessels, blood-related organs) (Caplan, 1991; Prockop, 1997; Pittenger et al., 1999). The current definition of MSCs includes plastic adherence in cell culture, specific surface antigen expression (CD105 +/CD90 +/CD73 +, CD34 -/CD45 -/CD11b - or CD14 -/CD19 - or CD79α -/HLA-DR1 -), and multilineage in vitro differentiation potential (osteogenic, chondrogenic, and adipogenic) (Dominici et al., 2006). If those criteria are not met completely, the term "mesenchymal stromal cells" should be used for marrow-derived adherent cells, or other terms for MSC-like cells of different origin. For the purpose of this review, MSCs and related cells are discussed in general, and cell type-specific properties are indicated when appropriate. We first summarize the preclinical data on MSCs in models of heart disease, and then appraise the clinical experience with MSCs for cardiac cell therapy. © 2011 Mary Ann Liebert, Inc.


Rzany B.,Charite - Medical University of Berlin
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] | Year: 2013

IncobotulinumtoxinA has been approved for treatment of glabellar frown lines (GFL) in the United States, all major European markets, South Korea, and Argentina and in Russia and Mexico for the treatment of mimic wrinkles and hyperkinetic facial lines, respectively. Prospective, 2-year, open-label, multicenter, repeat-dose, Phase III trial investigating the safety and efficacy of incobotulinumtoxinA for the treatment of GFL. Subjects with moderate or severe GFL on the Facial Wrinkle Scale (FWS), enrolled from previous trials, were treated with 20 U of incobotulinumtoxinA per cycle (up to eight treatment cycles, treatment interval at least 85 days). Efficacy was measured according to the investigator-assessed percentage of responders on the FWS (subjects with a score of 0 or 1) at rest and maximum frown on Day 30 of each cycle, subject assessments, and onset and duration of treatment effect. In 796 subjects, 77% to 88% were responders at rest, and 79% to 90% were responders at maximum frown. Onset was rapid; subjects reported effects in the first few days after treatment. No new tolerability or safety concerns were reported. IncobotulinumtoxinA injections were well tolerated and resulted in efficacy in the treatment of GFL for up to 2 years. © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.


Sibille J.,The Interdisciplinary Center | Sibille J.,University Paris Diderot | Pannasch U.,The Interdisciplinary Center | Pannasch U.,Charite - Medical University of Berlin | Rouach N.,The Interdisciplinary Center
Journal of Physiology | Year: 2014

Astroglial processes enclose ∼60% of CA1 hippocampal synapses to form the tripartite synapse. Although astrocytes express ionic channels, neurotransmitter receptors and transporters to detect neuronal activity, the nature, plasticity and impact of the currents induced by neuronal activity on short-term synaptic plasticity remain elusive in hippocampal astrocytes. Using simultaneous electrophysiological recordings of astrocytes and neurons, we found that single stimulation of Schaffer collaterals in hippocampal slices evokes in stratum radiatum astrocytes a complex prolonged inward current synchronized to synaptic and spiking activity in CA1 pyramidal cells. The astroglial current is composed of three components sensitive to neuronal activity, i.e. a long-lasting potassium current mediated by Kir4.1 channels, a transient glutamate transporter current and a slow residual current, partially mediated by GABA transporters and Kir4.1-independent potassium channels. We show that all astroglial membrane currents exhibit activity-dependent short-term plasticity. However, only the astroglial glutamate transporter current displays neuronal-like dynamics and plasticity. As Kir4.1 channel-mediated potassium uptake contributes to 80% of the synaptically evoked astroglial current, we investigated in turn its impact on short-term synaptic plasticity. Using glial conditional Kir4.1 knockout mice, we found that astroglial potassium uptake reduces synaptic responses to repetitive stimulation and post-tetanic potentiation. These results show that astrocytes integrate synaptic activity via multiple ionic channels and transporters and contribute to short-term plasticity in part via potassium clearance mediated by Kir4.1 channels. © 2013 The Physiological Society.


Sieper J.,Charite - Medical University of Berlin | Van Der Heijde D.,Leiden University | Dougados M.,University of Paris Descartes | Brown L.S.,Abbott Laboratories | And 2 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Objectives: To describe the efficacy and safety through 5 years of adalimumab treatment in patients with ankylosing spondylitis (AS), and to identify predictors of remission. Methods: Patients with active AS were followed up to 5 years during a 24-week randomised, controlled period, followed by an open-label extension. Disease activity and clinical improvement were evaluated by Assessment in Spondyloarthritis International Society (ASAS) responses, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS). Kaplan-Meier was used to identify patients with sustained ASAS partial remission (PR) or ASDAS inactive disease (ID) for three or more consecutive visits spanning ≥6 months. Logistic regression was used to identify factors associated with remission. Explanatory variables included baseline demographic and disease characteristics and week 12 responses. Results: Of the 311 patients who received at least one dose of adalimumab, 202 (65%) completed the 5-year study. Among 125 patients who received 5 years of adalimumab, 70%, 77%, 51% and 61% achieved ASAS40, BASDAI 50, ASAS PR and ASDAS ID, respectively. Of 311 adalimumab-treated patients, 45% and 55% achieved sustained ASAS PR and ASDAS ID at any time during study participation. The strongest predictor of remission at years 1 and 5 and of sustained remission was achieving remission at 12 weeks of treatment; baseline characteristics showed weaker associations. Adverse events were comparable with previous reports on adalimumab safety. Conclusions: In patients with active AS, the efficacy and safety of adalimumab were maintained through 5 years with about half of the patients experiencing sustained remission at any time during the study. Early achievement of remission was the best predictor of long-term and sustained remission.


Althoff T.F.,Charite - Medical University of Berlin | Offermanns S.,Max Planck Institute for Heart and Lung Research | Offermanns S.,Goethe University Frankfurt
Journal of Molecular Medicine | Year: 2015

Differentiated vascular smooth muscle cells (VSMCs) are critical determinants of vascular tone and blood pressure. However, during vascular remodeling processes, which occur in response to changing hemodynamics or vascular injury, VSMCs lose most of their contractile functions in a dedifferentiation process, which goes along with cell proliferation and cell migration. VSMCs are under the constant control of a variety of mediators with vasocontractile or vasodilatory properties. Most of these mediators act through G-protein-coupled receptors, which, via different downstream signaling pathways, regulate the phosphorylation of myosin light chain and thereby control vascular tone. Recent work indicates that procontractile G-protein-mediated signal transduction pathways are also critical regulators of vascular smooth muscle dedifferentiation and redifferentiation. This review describes some of the key G-protein-mediated signal transduction pathways regulating vascular tone and VSMC differentiation and their involvement in cardiovascular diseases. © 2015, Springer-Verlag Berlin Heidelberg.


Oestmann J.-W.,Charite - Medical University of Berlin
Deutsches Arzteblatt International | Year: 2012

Background: One quality parameter of medical theses is the number of articles published by the doctoral candidates. Over the course of the past decade the Charité- Universitätsmedizin Berlin has taken steps to improve the quality of the theses completed by its doctoral students in medicine and increase their publication activity. This study was designed to verify the efficacy of these measures and to detect general trends. Method: Medical theses completed in 1998, 2004 and 2008 (sample size >250 for each year) were retrospectively analyzed with regard to associated publications within a 7-year period (from 5 years before completion to 2 years thereafter). Quality and quantity were recorded. Publications found in the PubMed database were evaluated; the impact factor of the publishing journal was used as quality parameter. Results: The sample sizes were 264 for 1998, 316 for 2004, and 316 for 2008. The number of publications per doctoral student increased from 0.78 to 1.39 over the course of the study period, and the average impact factor rose from 2.42 to 3.62. Analysis using the current impact factors of the publishing journals showed an increase from 3.13 to 3.85. The proportion of case reports fell from 12.7% to 8%. The proportion of first authorships remained about the same. Conclusion: The past decade has seen an increase in the number of publications by doctoral students at the Charité and a rise in the aver age impact factor of the journals concerned.


Objective: The paradox of dissatisfaction means the phenomenon of patients being discontented with the outcome of a medical therapy despite impartial clinical improvement. This article aims at disclosing the typical features of deep brain stimulation (DBS) in movement disorders which predispose to the appearance of the paradox of dissatisfaction. Results: Due to its partly drastic and expansive effects in the subjective sense of individual patients deep brain stimulation implies the hazard of generating a paradox of dissatisfaction. Conclusions: To avoid the paradox of dissatisfaction in patients treated with DBS it is necessary to preoperatively inform them in a detailed and individually adjusted way as well as to pay attention to psychological problems evoking individual needs during the long-term care after DBS. Additionally it is needful to intensify the consideration of subjective indicators of well-being and quality of life in measuring the outcome of DBS. © Schattauer 2012.


Schlimme J.E.,Charite - Medical University of Berlin
Theoretical Medicine and Bioethics | Year: 2012

In this paper, I develop a phenomenological description of lived autonomy and describe possible alterations of lived autonomy associated with chronic depression as they relate to specific psychopathological symptoms. I will distinguish between two types of lived autonomy, a pre-reflective type and a reflective type, which differ with respect to the explicitness of the action that is willed into existence; and I will relate these types to the classical distinction between freedom of intentional action and freedom of the will. I will then describe how a chronically depressed person habitually discloses her experiential workspace with an impaired scope of perceivable action-properties, and pre-reflectively values many of these perceived action-properties as demanding or devalues these properties as well as her own abilities and drive to perform the respective actions ('depressive habituality'). These alterations, typically experienced in a passive manner, imply an impairment of both types of lived autonomy. Drawing on first-hand accounts, I will then argue that small islands of lived autonomy, even of the reflective type, are possible if the afflicted identifies with at least some of her 'depressive disabilities' (i.e., her levelled amount of daily activities, her social retreat in certain periods). Lastly, I will compare this manner of life-conduct with the constellation of includence (Inkludenz), as described by Tellenbach, and discuss the limitations of this study. © 2012 Springer Science+Business Media Dordrecht.


Hess D.C.,Georgia Regents University | Audebert H.J.,Charite - Medical University of Berlin
Nature Reviews Neurology | Year: 2013

This Review focuses on the application of telemedicine to the care of patients with acute stroke (telestroke), from the prehospital setting through hospitalization. Telestroke has grown remarkably in the past decade and has entered mainstream care for patients with acute stroke. Telestroke enables such patients to be remotely evaluated, thereby allowing optimal treatment and management even in clinically underserved areas and removing geographical disparities in access to expert care. Telestroke systems enable thrombolytic treatment to be administered in community and rural hospitals, and facilitate the appropriate transfer of patients with complex conditions (who require critical care services and neurosurgical or intra-arterial interventions) to a comprehensive stroke centre. Decision-analytic models show that telestroke is cost-effective from both a societal and a hospital perspective. Limitations to the use of telestroke in the USA include the need for state licensing and credentialling of physicians, and the technical requirements of a minimum network bandwidth (which is still lacking in some regions). However, the opportunity exists for telestroke to become the backbone of an electronic stroke unit and to be used to identify and enrol patients in clinical trials of acute stroke treatment. The use of telestroke in the prehospital setting has been hampered by limited telecommunication availability, but these problems might be mitigated by fourth-generation cellular data networks. © 2013 Macmillan Publishers Limited. All rights reserved.


Background: The length of the chromosome ends, telomeres, is widely accepted as a biomarker of aging. However, the dynamic of the relationship between telomere length and hematopoietic parameters in the normal aging process, which is of particular interest with respect to age-related anemia, is not well understood. Objective: We have analyzed the relationship between relative leukocyte telomere length (rLTL) and several hematological parameters in the older group of the Berlin Aging Study II (BASE-II) participants. This paper also compares rLTL between both BASE-II age groups (22-37 and 60-83 years). Methods: Genomic DNA was extracted from peripheral blood leukocytes of BASE-II participants and used to determine rLTL by a quantitative PCR protocol. Standard methods were used to determine blood parameters, and the WHO criteria were used to identify anemic participants. Results: Telomere length data were available for 444 younger participants (28.4 ± 3.1 years old; 52% women) and 1,460 older participants (68.2 ± 3.7 years old; 49.4% women). rLTL was significantly shorter in BASE-II participants of the older group (p = 3.7 × 10-12) and in women (p = 4.2 × 10-31). rLTL of older men exhibited a statistically significant, positive partial correlation with mean corpuscular hemoglobin (MCH; p = 0.012) and MCH concentration (p = 0.002). While these correlations were only observed in men, the rLTL of older women was negatively correlated with the number of thrombocytes (p = 0.015) in the same type of analysis. Among all older participants, 6% met the criteria to be categorized as ‘anemic'; however, there was no association between anemia and rLTL. Conclusion: In the present study, we have detected isolated correlations between rLTL and hematological parameters; however, in all cases, rLTL explained only a small part of the variation of the analyzed parameters. In disagreement with some other studies showing similar data, we interpret the association between rLTL and some of the hematological parameters studied here to be at most marginal. This applies also to the role of rLTL in anemia, at least in the age group investigated here. Since BASE-II is yet another large cohort in which women have on average shorter telomeres than men, this finding will be addressed in the discussion with respect to the ongoing debate on gender differences in telomere length. © 2016 S. Karger AG, Basel Copyright © 2016, S. Karger AG. All rights reserved.


Eckstein N.,Charite - Medical University of Berlin
Gerontology | Year: 2016

Background: Decreased bone mineral density (BMD) has been linked to metabolic disorders, such as type 2 diabetes. However, results regarding the metabolic syndrome (MetS), a cluster of at least 3 of 5 cardiovascular risk parameters with potentially contradictory effects on BMD are still inconclusive. Objective: We investigated the effect of MetS and its single parameters on BMD at 3 sites in community-dwelling older subjects. Methods: 1,402 subjects (51.1% female, 68 ± 4 years old) from the Berlin Aging Study II (BASE-II) were included. MetS was defined as suggested by IDF/NHLBI/AHA. Insulin resistance (IR) was assessed by the homeostasis model of IR. BMD (lumbar spine, femur neck, hip) and trunk fat were measured by dual-energy X-ray absorptiometry. Osteoporosis was defined by a T score of ≤-2.5. Results: MetS was present in 29.6% of women and 41.7% of men. In regression models, we observed a positive association of MetS with the BMD of the lumbar spine (p = 0.005) and hip (p = 0.028) in women even after adjustment for risk factors, but no effect of the single parameters apart from IR. In contrast, there was no association between MetS and BMD in men. However, higher trunk fat and higher waist circumference were associated with lower levels of BMD in men with or without MetS (p < 0.05). Conclusion: We obtained different results in men and women. In women, the positive though slight effect of MetS on BMD could not be explained by single MetS components apart from IR. In men, central obesity was negatively associated with BMD, suggesting that the metabolic effects driven by visceral fat have a negative impact. © 2016 S. Karger AG, Basel Copyright © 2016, S. Karger AG. All rights reserved.


Hailfinger S.,University of Tubingen | Lenz G.,Charite - Medical University of Berlin | Thome M.,University of Lausanne
Current Opinion in Chemical Biology | Year: 2014

The paracaspase MALT1 is an Arg-specific protease that cleaves multiple substrates to promote lymphocyte proliferation and survival. The catalytic activity of MALT1 is normally tightly regulated by antigen receptor triggering, which promotes MALT1 activation by its inducible monoubiquitination-dependent dimerization. Constitutive MALT1 activity is a hallmark of specific subsets of B-cell lymphomas, which are characterized by chromosomal translocations or point mutations that activate MALT1 or its upstream regulators. Recent findings suggest that such lymphomas may be sensitive to treatment with MALT1 inhibitors. Here we review recent progress in the understanding of MALT1 function and regulation, and the development of small molecule MALT1 inhibitors for therapeutic applications. © 2014 Elsevier Ltd.


Stengel A.,Charite - Medical University of Berlin | Tache Y.,University of California at Los Angeles | Tache Y.,Center for Neurobiology of Stress
Frontiers in Neuroscience | Year: 2014

Early on, corticotropin-releasing factor (CRF), a hallmark brain peptide mediating many components of the stress response, was shown to affect food intake inducing a robust anorexigenic response when injected into the rodent brain. Subsequently, other members of the CRF signaling family have been identified, namely urocortin (Ucn) 1, Ucn 2, and Ucn 3 which were also shown to decrease food intake upon central or peripheral injection. However, the kinetics of feeding suppression was different with an early decrease following intracerebroventricular injection of CRF and a delayed action of Ucns contrasting with the early onset after systemic injection. CRF and Ucns bind to two distinct G-protein coupled membrane receptors, the CRF1 and CRF2. New pharmacological tools such as highly selective peptide CRF1 or CRF2 agonists or antagonists along with genetic knock-in or knock-out models have allowed delineating the primary role of CRF2 involved in the anorexic response to exogenous administration of CRF and Ucns. Several stressors trigger behavioral changes including suppression of feeding behavior which are mediated by brain CRF receptor activation. The present review will highlight the state-of-knowledge on the effects and mechanisms of action of CRF/Ucns-CRF1/2 signaling under basal conditions and the role in the alterations of food intake in response to stress. © 2014 Stengel and Taché.


Stengel A.,Charite - Medical University of Berlin | Tache Y.,University of California at Los Angeles
Current Opinion in Pharmacology | Year: 2014

Postoperative ileus (POI) develops after abdominal surgery irrespective of the site of surgery. When prolonged, POI can lead to longer hospitalization times and higher healthcare costs. Moreover, it is associated with complaints for the patient. In order to develop new strategies to treat this condition, a deeper understanding of the pathophysiology of the POI is necessary. This review will focus on brain peptides (ghrelin, nesfatin-1, somatostatin, corticotropin-releasing factor, thyrotropin-releasing hormone and calcitoni