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Showing papers by "University of Marburg published in 2016"


Journal ArticleDOI
TL;DR: The ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatics with Functional and non-functional tumours is published.
Abstract: Only advances that occurred from 2011–2014 that either strengthen the previous 2011 guidelines [1;2] or lead to changes or additional guidelines are reviewed here. Advances and modifications in the treatment of advanced metastatic disease is only briefly dealt with here as it is covered in a separate chapter, similar to the 2011 guideline format [3]. The format used here is the same as used in the 2011 guidelines with page references to the appropriate section inserted [1;2] and this document is meant as a supplement to these guidelines and does not reiterate all of the points made in the previous guidelines, only changes, supporting findings or modifications of the 2011 guidelines are thus covered here. As in the previous F-p-NET guidelines [1], the F-p-NETs will be considered in three groups: the more frequent gastrinomas and insulinomas considered independently and all the rare functional p-NETs (RFTs) considered together and as a separate category (Annex 1 and Table 1). Table 1 Functional Pancreatic endocrine tumors [F-p-NET] syndromes

988 citations


Journal ArticleDOI
TL;DR: Three-dimensional brain magnetic resonance imaging data was meta-analyzed to identify subcortical brain volumes that robustly discriminate major depressive disorder patients from healthy controls and showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
Abstract: The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

759 citations


Journal ArticleDOI
TL;DR: This Perspective proposes a precision medicine strategy for chronic airway diseases in general, and asthma and COPD in particular, and a discussion of the concept of “treatable traits” as a way towards precision medicine of chronicAirway diseases.
Abstract: Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent chronic airway diseases that have a high personal and social impact. They likely represent a continuum of different diseases that may share biological mechanisms (i.e. endotypes), and present similar clinical, functional, imaging and/or biological features that can be observed (i.e. phenotypes) which require individualised treatment. Precision medicine is defined as "treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations". In this Perspective, we propose a precision medicine strategy for chronic airway diseases in general, and asthma and COPD in particular.

709 citations


Journal ArticleDOI
TL;DR: Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year and showed not only noninferiority but also superiority in reducing the annual rate of all COPd exacerbations.
Abstract: BackgroundMost guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations The role of treatment with a LABA–LAMA regimen in these patients is unclear MethodsWe conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily The primary outcome was the annual rate of all COPD exacerbations ResultsA total of 1680 patients were assigned to the indacaterol–glycopyrronium group, and 1682 to the salmeterol–fluticasone group Indacaterol–glycopyrronium showed not onl

680 citations


Journal ArticleDOI
TL;DR: A detailed assessment of the chemistry of Mn oxides by considering how their bulk and nanoscale properties contribute to their effectiveness as water-oxidizing catalysts and the issue of Mn complexes decomposing to Mn oxide is provided.
Abstract: All cyanobacteria, algae, and plants use a similar water-oxidizing catalyst for water oxidation. This catalyst is housed in Photosystem II, a membrane-protein complex that functions as a light-driven water oxidase in oxygenic photosynthesis. Water oxidation is also an important reaction in artificial photosynthesis because it has the potential to provide cheap electrons from water for hydrogen production or for the reduction of carbon dioxide on an industrial scale. The water-oxidizing complex of Photosystem II is a Mn–Ca cluster that oxidizes water with a low overpotential and high turnover frequency number of up to 25–90 molecules of O2 released per second. In this Review, we discuss the atomic structure of the Mn–Ca cluster of the Photosystem II water-oxidizing complex from the viewpoint that the underlying mechanism can be informative when designing artificial water-oxidizing catalysts. This is followed by consideration of functional Mn-based model complexes for water oxidation and the issue of Mn com...

513 citations


Journal ArticleDOI
TL;DR: The tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.
Abstract: Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic β-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.

500 citations


Journal ArticleDOI
TL;DR: High REC and RLC, low LDH, and absence of metastasis other than soft-tissue/lung are independent baseline characteristics associated with favorable OS of patients with melanoma treated with pembrolizumab, indicating a subgroup with excellent prognosis.
Abstract: Purpose: Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) following pembrolizumab treatment in melanoma patients. Experimental design: Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following pembrolizumab. Kaplan-Meier analysis and Cox regression were applied for survival analysis. Results: Relative eosinophil count (REC) {greater than or equal to}1.5%, relative lymphocyte count (RLC) {greater than or equal to}17.5%, {less than or equal to}2.5-fold elevation of LDH, and the absence of metastasis other than soft-tissue/lung were associated with favorable OS in the discovery (n=177) and the confirmation (n=182) cohort and had independent positive impact (all P<0.001). Their independent role was subsequently confirmed in the validation cohort (n=257; all P<0.01). The number of favorable factors was strongly associated with prognosis. One-year-OS probabilities of 83.9% vs 14.7% and response rates of 58.3% vs 3.3% were observed in patients with four out of four compared to those with none out of four favorable baseline factors present, respectively. Conclusions: High REC and RLC, low LDH, and absence of metastasis other than soft-tissue/lung are independent baseline characteristics associated with favorable OS of patients with melanoma treated with pembrolizumab. Presence of four favorable factors in combination identifies a subgroup with excellent prognosis. In contrast, patients with no favorable factors present have a poor prognosis, despite pembrolizumab, and additional treatment advances are still needed. A potential predictive impact needs to be further investigated.

451 citations


Journal ArticleDOI
01 Jul 2016-Pain
TL;DR: The redefinition of neuropathic pain,23 which specifically excludes the concept of “dysfunction,” has left a large group of patients without a valid pathophysiological descriptor for their experience of pain.
Abstract: 1. IntroductionThe redefinition of neuropathic pain,23 which specifically excludes the concept of “dysfunction,” has left a large group of patients without a valid pathophysiological descriptor for their experience of pain. This group comprises people who have neither obvious activation of nocicepto

442 citations


Journal ArticleDOI
Claudio L. Afonso1, Gaya K. Amarasinghe2, Krisztián Bányai3, Yīmíng Bào4, Christopher F. Basler5, Sina Bavari6, Nicolás Bejerman, Kim R. Blasdell7, François Xavier Briand, Thomas Briese8, Alexander Bukreyev9, Charles H. Calisher10, Kartik Chandran11, Jiāsēn Chéng12, Anna N. Clawson4, Peter L. Collins4, Ralf G. Dietzgen13, Olga Dolnik14, Leslie L. Domier15, Ralf Dürrwald, John M. Dye6, Andrew J. Easton16, Hideki Ebihara4, Szilvia L. Farkas3, Juliana Freitas-Astúa17, Pierre Formenty18, Ron A. M. Fouchier19, Yanping Fu12, Elodie Ghedin20, Michael M. Goodin21, Roger Hewson22, Masayuki Horie23, Timothy H. Hyndman24, Dàohóng Jiāng12, E. W. Kitajima25, Gary P. Kobinger26, Hideki Kondo27, Gael Kurath28, Robert A. Lamb29, Sergio Lenardon, Eric M. Leroy, C. Li, Xian Dan Lin30, Lìjiāng Liú12, Ben Longdon31, Szilvia Marton3, Andrea Maisner14, Elke Mühlberger32, Sergey V. Netesov33, Norbert Nowotny34, Norbert Nowotny35, Jean L. Patterson36, Susan Payne37, Janusz T. Paweska, Richard E. Randall38, Bertus K. Rima39, Paul A. Rota30, Dennis Rubbenstroth40, Martin Schwemmle40, Mang Shi41, Sophie J. Smither42, Mark D. Stenglein10, David M. Stone, Ayato Takada43, Calogero Terregino, Robert B. Tesh9, Jun Hua Tian30, Keizo Tomonaga44, Noël Tordo45, Jonathan S. Towner30, Nikos Vasilakis9, Martin Verbeek46, Viktor E. Volchkov47, Victoria Wahl-Jensen, John A. Walsh16, Peter J. Walker7, David Wang2, Lin-Fa Wang48, Thierry Wetzel, Anna E. Whitfield49, Jiǎtāo Xiè12, Kwok-Yung Yuen50, Yong-Zhen Zhang41, Jens H. Kuhn4 
United States Department of Agriculture1, Washington University in St. Louis2, Hungarian Academy of Sciences3, National Institutes of Health4, Georgia State University5, United States Army Medical Research Institute of Infectious Diseases6, Commonwealth Scientific and Industrial Research Organisation7, Columbia University8, University of Texas Medical Branch9, Colorado State University10, Yeshiva University11, Huazhong Agricultural University12, University of Queensland13, University of Marburg14, University of Illinois at Urbana–Champaign15, University of Warwick16, Empresa Brasileira de Pesquisa Agropecuária17, World Health Organization18, Erasmus University Rotterdam19, New York University20, University of Kentucky21, Public Health England22, Kagoshima University23, Murdoch University24, University of São Paulo25, Public Health Agency of Canada26, Okayama University27, United States Geological Survey28, Northwestern University29, Centers for Disease Control and Prevention30, University of Cambridge31, Boston University32, Novosibirsk State University33, University of Veterinary Medicine Vienna34, University of Medicine and Health Sciences35, Texas Biomedical Research Institute36, Texas A&M University37, University of St Andrews38, Queen's University Belfast39, University of Freiburg40, Chinese Center for Disease Control and Prevention41, Defence Science and Technology Laboratory42, Hokkaido University43, Kyoto University44, Pasteur Institute45, Wageningen University and Research Centre46, University of Lyon47, National University of Singapore48, Kansas State University49, University of Hong Kong50
TL;DR: The updated taxonomy of the order Mononegavirales is presented as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
Abstract: In 2016, the order Mononegavirales was emended through the addition of two new families (Mymonaviridae and Sunviridae), the elevation of the paramyxoviral subfamily Pneumovirinae to family status (Pneumoviridae), the addition of five free-floating genera (Anphevirus, Arlivirus, Chengtivirus, Crustavirus, and Wastrivirus), and several other changes at the genus and species levels. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).

404 citations


Journal ArticleDOI
TL;DR: A stoichiometric and thermodynamic model is delved into that sheds light on the effect of substrate ratios and environmental conditions on product formation and was reviewed to bring together research from different fields.
Abstract: Chain elongation into medium-chain carboxylates, such as n-caproate and n-caprylate, with ethanol as an electron donor and with open cultures of microbial consortia (i.e., reactor microbiomes) under anaerobic conditions is being developed as a biotechnological production platform. The goal is to use the high thermodynamic efficiency of anaerobic fermentation to convert organic biomass or organic wastes into valuable biochemicals that can be extracted. Several liter-scale studies have been completed and a first pilot-plant study is underway. However, the underlying microbial pathways are not always well understood. In addition, an interdisciplinary approach with knowledge from fields ranging from microbiology and chemical separations to biochemistry and environmental engineering is required. To bring together research from different fields, we reviewed the literature starting with the microbiology and ending with the bioprocess engineering studies that already have been performed. Because understanding the microbial pathways is so important to predict and steer performance, we delved into a stoichiometric and thermodynamic model that sheds light on the effect of substrate ratios and environmental conditions on product formation. Finally, we ended with an outlook.

388 citations


Journal ArticleDOI
TL;DR: The present overview focuses on a systematic description and reasonable classification of the most relevant types of fluorescent nanodots according to their nature, quantum confinement and crystalline structure, starting with a clear distinction between semiconductor and carbon-based dots.


Journal ArticleDOI
TL;DR: Data indicate that NPs in vivo should no longer be considered as homogeneous entities, but should be seen as inorganic/organic/biological nano-hybrids with complex and intricately linked distribution and degradation pathways.
Abstract: What happens to inorganic nanoparticles (NPs), such as plasmonic gold or silver, superparamagnetic iron oxide, or fluorescent quantum dot NPs after they have been administrated to a living being? This review discusses the integrity, biodistribution, and fate of NPs after in vivo administration. The hybrid nature of the NPs is described, conceptually divided into the inorganic core, the engineered surface coating comprising of the ligand shell and optionally also bio-conjugates, and the corona of adsorbed biological molecules. Empirical evidence shows that all of these three compounds may degrade individually in vivo and can drastically modify the life cycle and biodistribution of the whole heterostructure. Thus, the NPs may be decomposed into different parts, whose biodistribution and fate would need to be analyzed individually. Multiple labeling and quantification strategies for such a purpose will be discussed. All reviewed data indicate that NPs in vivo should no longer be considered as homogeneous entities, but should be seen as inorganic/organic/biological nano-hybrids with complex and intricately linked distribution and degradation pathways.

Journal ArticleDOI
15 Jan 2016-Science
TL;DR: It is found that RNA hydroxymethylation can favor mRNA translation and is found to be most abundant in the Drosophila brain, and Tet-deficient fruitflies suffer impaired brain development, accompanied by decreased RNA hydroxyethylation.
Abstract: Hydroxymethylcytosine, well described in DNA, occurs also in RNA. Here, we show that hydroxymethylcytosine preferentially marks polyadenylated RNAs and is deposited by Tet in Drosophila. We map the transcriptome-wide hydroxymethylation landscape, revealing hydroxymethylcytosine in the transcripts of many genes, notably in coding sequences, and identify consensus sites for hydroxymethylation. We found that RNA hydroxymethylation can favor mRNA translation. Tet and hydroxymethylated RNA are found to be most abundant in the Drosophila brain, and Tet-deficient fruitflies suffer impaired brain development, accompanied by decreased RNA hydroxymethylation. This study highlights the distribution, localization, and function of cytosine hydroxymethylation and identifies central roles for this modification in Drosophila.

Journal ArticleDOI
TL;DR: Physicians in charge of older patients should be aware that malnutrition, dehydration, and pneumonia are frequently caused by (unrecognized) dysphagia, and the diagnosis is particularly difficult in the case of silent aspiration.
Abstract: Oropharyngeal dysphagia (OD) is a highly prevalent and growing condition in the older population. Although OD may cause very severe complications, it is often not detected, explored, and treated. Older patients are frequently unaware of their swallowing dysfunction which is one of the reasons why the consequences of OD, ie, aspiration, dehydration, and malnutrition, are regularly not attributed to dysphagia. Older patients are particularly vulnerable to dysphagia because multiple age-related changes increase the risk of dysphagia. Physicians in charge of older patients should be aware that malnutrition, dehydration, and pneumonia are frequently caused by (unrecognized) dysphagia. The diagnosis is particularly difficult in the case of silent aspiration. In addition to numerous screening tools, videofluoroscopy was the traditional gold standard of diagnosing OD. Recently, the fiberoptic endoscopic evaluation of swallowing is increasingly utilized because it has several advantages. Besides making a diagnosis, fiberoptic endoscopic evaluation of swallowing is applied to evaluate the effectiveness of therapeutic maneuvers and texture modification of food and liquids. In addition to swallowing training and nutritional interventions, newer rehabilitation approaches of stimulation techniques are showing promise and may significantly impact future treatment strategies.

Journal ArticleDOI
TL;DR: The chimpanzee adenovirus 3 (ChAd3) vaccine boosted with MVA elicited B-cell and T-cell immune responses to ZEBOV that were superior to those induced by the ChAd3 vaccine alone.
Abstract: Background The West African outbreak of Ebola virus disease has caused more than 8500 deaths. A vaccine could contribute to outbreak control in the region. We assessed a monovalent formulation of a chimpanzee adenovirus 3 (ChAd3)-vectored vaccine encoding the surface glycoprotein of Zaire ebolavirus (EBOV), matched to the outbreak strain. Methods After expedited regulatory and ethics approvals, 60 healthy adult volunteers in Oxford, United Kingdom, received a single dose of the ChAd3 vaccine at one of three dose levels: 1×10(10) viral particles, 2.5×10(10) viral particles, and 5×10(10) viral particles (with 20 participants per group). Safety was assessed over the next 4 weeks. Antibodies were measured on enzyme-linked immunosorbent assay (ELISA) and T-cell responses on enzyme-linked immunospot (ELISpot) and flow-cytometry assays. Results No safety concerns were identified at any of the dose levels studied. Fever developed in 2 of the 59 participants who were evaluated. Prolonged activated partial-thromboplastin times and transient hyperbilirubinemia were observed in 4 and 8 participants, respectively. Geometric mean antibody responses on ELISA were highest (469 units; range, 58 to 4051; 68% response rate) at 4 weeks in the high-dose group, which had a 100% response rate for T cells on ELISpot, peaking at day 14 (median, 693 spot-forming cells per million peripheral-blood mononuclear cells). Flow cytometry revealed more CD4+ than CD8+ T-cell responses. At the vaccine doses tested, both antibody and T-cell responses were detected but at levels lower than those induced in macaques protected by the same vaccine. Conclusions The ChAd3 monovalent vaccine against EBOV was immunogenic at the doses tested. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875 .).

Journal ArticleDOI
TL;DR: Investigations funded by the Deutsche Forschungsgemeinschaft on the anaerobic microbial degradation of hydrocarbons ranged from isolation and enrichment of hitherto unknown hydrocarbon-degrading anaerobe microorganisms, discovery of novel reactions, detailed studies of enzyme mechanisms and structures to process-oriented in situ studies.
Abstract: Hydrocarbons are abundant in anoxic environments and pose biochemical challenges to their anaerobic degradation by microorganisms. Within the framework of the Priority Program 1319, investigations fun

Journal ArticleDOI
TL;DR: The need to intensify therapeutic PD research is stressed and reasons why the translation of basic research to disease‐modifying therapies has been unsuccessful so far are pointed out.
Abstract: Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain stimulation, and physiotherapy. The arsenal of pharmacotherapies includes L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine. In the later course of the disease, motor complications occur, at which stage different oral formulations of L-Dopa or dopamine agonists with long half-life, a transdermal application or parenteral pumps for continuous drug supply can be subscribed. Alternatively, the patient is offered deep brain stimulation of the subthalamic nucleus (STN) or the internal part of the globus pallidus (GPi). For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials, and some of them already yielding positive results in phase 3 trials. In addition, non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia, including adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) and modulators of the metabolic glutamate receptor 5 (mGluR5 - mavoglurant) and serotonin (eltoprazine) receptors. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, inosine (a precursor of urate), and isradipine (a dihydropyridine calcium channel blocker), as well as active and passive immunization against α-synuclein and inhibitors or modulators of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available. We here review the current status of treatment options for motor and non-motor symptoms, and discuss current investigative strategies for disease modification. This review provides basic insights, mainly addressing basic scientists and non-specialists. It stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials. Non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, and isradipine – a dihydropyridine calcium channel blocker – as well as active and passive immunization against α-synuclein and inhibitors of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available for PD. We here review the current status of treatment options and investigative strategies for both motor and non-motor symptoms. This review stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. This article is part of a special issue on Parkinson disease.

Journal ArticleDOI
TL;DR: The concept of the cerebellar syndrome is revisited in the light of recent advances in the understanding of Cerebellar operations and the key symptoms and signs of cerebellars dysfunction are discussed.
Abstract: The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor region in lobule VIII, and (c) cognitive and limbic regions located in the posterior lobe (lobule VI, lobule VIIA which includes crus I and crus II, and lobule VIIB). The limbic cerebellum is mainly represented in the posterior vermis. The cortico-ponto-cerebellar and cerebello-thalamo-cortical loops establish close functional connections between the cerebellum and the supratentorial motor, paralimbic and association cortices, and cerebellar symptoms are associated with a disruption of these loops.

Journal ArticleDOI
22 Sep 2016-Cell
TL;DR: A conserved mechanism emerges whereby epithelia use organ-specific BTNL/Btnl genes to shape local T cell compartments in murine enterocytes, evoking the developmental selection of TCRαβ+ repertoires.

Journal ArticleDOI
TL;DR: A relatively small degree of structural impairment in the subgenual cingulate cortex before therapy seems to be associated with successful treatment with ECT, and neuroimaging techniques could prove to be promising tools for predicting the individual therapeutic effectiveness of ECT.
Abstract: Importance Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, biomarkers that accurately predict a response to ECT remain unidentified. Objective To investigate whether certain factors identified by structural magnetic resonance imaging (MRI) techniques are able to predict ECT response. Design, Setting, and Participants In this nonrandomized prospective study, gray matter structure was assessed twice at approximately 6 weeks apart using 3-T MRI and voxel-based morphometry. Patients were recruited through the inpatient service of the Department of Psychiatry, University of Muenster, from March 11, 2010, to March 27, 2015. Two patient groups with acute major depressive disorder were included. One group received an ECT series in addition to antidepressants (n = 24); a comparison sample was treated solely with antidepressants (n = 23). Both groups were compared with a sample of healthy control participants (n = 21). Main Outcomes and Measures Binary pattern classification was used to predict ECT response by structural MRI that was performed before treatment. In addition, univariate analysis was conducted to predict reduction of the Hamilton Depression Rating Scale score by pretreatment gray matter volumes and to investigate ECT-related structural changes. Results One participant in the ECT sample was excluded from the analysis, leaving 67 participants (27 men and 40 women; mean [SD] age, 43.7 [10.6] years). The binary pattern classification yielded a successful prediction of ECT response, with accuracy rates of 78.3% (18 of 23 patients in the ECT sample) and sensitivity rates of 100% (13 of 13 who responded to ECT). Furthermore, a support vector regression yielded a significant prediction of relative reduction in the Hamilton Depression Rating Scale score. The principal findings of the univariate model indicated a positive association between pretreatment subgenual cingulate volume and individual ECT response (Montreal Neurological Institute [MNI] coordinates x = 8, y = 21, z = −18; Z score, 4.00; P r = 0.73). Furthermore, the analysis of treatment effects revealed a increase in hippocampal volume in the ECT sample (MNI coordinates x = −28, y = −9, z = −18; Z score, 7.81; P Conclusions and Relevance A relatively small degree of structural impairment in the subgenual cingulate cortex before therapy seems to be associated with successful treatment with ECT. In the future, neuroimaging techniques could prove to be promising tools for predicting the individual therapeutic effectiveness of ECT.

Journal ArticleDOI
12 May 2016-Nature
TL;DR: Lightwave-driven charge transport is exploited, the foundation of attosecond science, to explore ultrafast quasiparticle collisions directly in the time domain and suggests a promising new way of generating sub-femtosecond pulses.
Abstract: Ever since Ernest Rutherford scattered α-particles from gold foils1, collision experiments have revealed insights into atoms, nuclei and elementary particles2 In solids, many-body correlations lead to characteristic resonances3—called quasiparticles—such as excitons, dropletons4, polarons and Cooper pairs The structure and dynamics of quasiparticles are important because they define macroscopic phenomena such as Mott insulating states, spontaneous spin- and charge-order, and high-temperature superconductivity5 However, the extremely short lifetimes of these entities6 make practical implementations of a suitable collider challenging Here we exploit lightwave-driven charge transport7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, the foundation of attosecond science9, 10, 11, 12, 13, to explore ultrafast quasiparticle collisions directly in the time domain: a femtosecond optical pulse creates excitonic electron–hole pairs in the layered dichalcogenide tungsten diselenide while a strong terahertz field accelerates and collides the electrons with the holes The underlying dynamics of the wave packets, including collision, pair annihilation, quantum interference and dephasing, are detected as light emission in high-order spectral sidebands17, 18, 19 of the optical excitation A full quantum theory explains our observations microscopically This approach enables collision experiments with various complex quasiparticles and suggests a promising new way of generating sub-femtosecond pulses

Journal ArticleDOI
TL;DR: This work quantifies cross-taxon consensus in diversity gradients and evaluates predictors of diversity from single taxa to a multi-taxa community level and points to the importance of temperature for diversification and species coexistence in plant and animal communities.
Abstract: The factors determining gradients of biodiversity are a fundamental yet unresolved topic in ecology. While diversity gradients have been analysed for numerous single taxa, progress towards general explanatory models has been hampered by limitations in the phylogenetic coverage of past studies. By parallel sampling of 25 major plant and animal taxa along a 3.7 km elevational gradient on Mt. Kilimanjaro, we quantify cross-taxon consensus in diversity gradients and evaluate predictors of diversity from single taxa to a multi-taxa community level. While single taxa show complex distribution patterns and respond to different environmental factors, scaling up diversity to the community level leads to an unambiguous support for temperature as the main predictor of species richness in both plants and animals. Our findings illuminate the influence of taxonomic coverage for models of diversity gradients and point to the importance of temperature for diversification and species coexistence in plant and animal communities.


Journal ArticleDOI
TL;DR: This work demonstrates how photoredox-mediated C(sp3 )-H activation through radical translocation can be combined with asymmetric catalysis to provide a C-C bond-formation product with high enantioselectivity.
Abstract: This work demonstrates how photoredox-mediated C(sp3)−H activation through radical translocation can be combined with asymmetric catalysis. Upon irradiation with visible light, α,β-unsaturated N-acylpyrazoles react with N-alkoxyphthalimides in the presence of a rhodium-based chiral Lewis acid catalyst and the photosensitizer fac-[Ir(ppy)3] to provide a C−C bond-formation product with high enantioselectivity (up to 97 % ee) and, where applicable, with some diastereoselectivity (3.0:1 d.r.). Mechanistically, the synthetic strategy exploits a radical translocation (1,5-hydrogen transfer) from an oxygen-centered to a carbon-centered radical with a subsequent stereocontrolled radical alkene addition.

Journal ArticleDOI
TL;DR: The findings suggest that the PMH-Scale indeed measures a single concept and allows us to compare scores over groups and over time, and is a brief and easy to interpret instrument for measuring PMH across a large variety of relevant groups.
Abstract: In recent years, it has been increasingly recognized that the absence of mental disorder is not the same as the presence of positive mental health (PMH). With the PMH-scale we propose a short, unidimensional scale for the assessment of positive mental health. The scale consists of 9 Likert-type items. The psychometric properties of the PMH-scale were tested in a series of six studies using samples from student (n = 5406), patient (n = 1547) and general (n = 3204) populations. Factorial structure and measurement equivalence were tested with the measurement invariance testing. The factor models were analysed with the maximum likelihood procedure. Internal consistency was examined using Cronbach’s alpha, test-retest reliability, convergent and divergent validity was examined by Pearson correlation. Sensitivity to (therapeutic) change was examined with the t-test. Results confirmed unidimensionality, scalar invariance across samples and over time, high internal consistency, good retest-reliability, good convergent and discriminant validity as well as sensitivity to therapeutic change. These findings suggest that the PMH-Scale indeed measures a single concept and allows us to compare scores over groups and over time. The PMH-scale thus is a brief and easy to interpret instrument for measuring PMH across a large variety of relevant groups.

Journal ArticleDOI
TL;DR: A quantum yield of <1 supports the proposed catalytic cycle in which at least one photon is needed for each asymmetric C-C bond formation mediated by single electron transfer.
Abstract: Combining single electron transfer between a donor substrate and a catalyst-activated acceptor substrate with a stereocontrolled radical-radical recombination enables the visible-light-driven catalytic enantio- and diastereoselective synthesis of 1,2-amino alcohols from trifluoromethyl ketones and tertiary amines. With a chiral iridium complex acting as both a Lewis acid and a photoredox catalyst, enantioselectivities of up to 99% ee were achieved. A quantum yield of <1 supports the proposed catalytic cycle in which at least one photon is needed for each asymmetric C-C bond formation mediated by single electron transfer.

Journal ArticleDOI
TL;DR: As canopy openness and habitat heterogeneity seem to be the major drivers of saproxylic beetle diversity in temperate forests, it is recommended that managers aim to increase the heterogeneity of dead-wood substrates under both sunny and shady forest conditions.
Abstract: Summary Resource availability and habitat heterogeneity are principle drivers of biodiversity, but their individual roles often remain unclear since both factors are usually correlated. The biodiversity of species dependent on dead wood could be driven by either resource availability represented by dead-wood amount or habitat heterogeneity characterized by dead-wood diversity or both. Understanding their roles is crucial for improving evidence-based conservation strategies for saproxylic species in managed forests. To disentangle the effects of dead-wood amount and dead-wood diversity on biodiversity relative to canopy openness (microclimate), we experimentally exposed different amounts of logs and branches of two different tree species representing a gradient of dead-wood diversity in 190 sunny and shady forest plots. During the 3 years after exposing dead wood, we sampled saproxylic beetles, which are together with fungi the most diverse and important taxonomic group involved in decomposition of wood. The composition of saproxylic beetle assemblages differed clearly between shady and sunny forest plots, with higher richness in sunny plots. Both dead-wood amount and dead-wood diversity positively and independently affected species richness of saproxylic beetles, but these effects were mediated by canopy openness. In sunny forest, species richness increased with increasing amount of dead wood, whereas in shady forest, dead-wood diversity was the prevailing factor. The stepwise analysis of abundance and species richness, however, indicated that effects of both factors supported only the habitat-heterogeneity hypothesis, as the positive effect of high amounts of dead wood could be explained by cryptic variability of dead-wood quality within single objects. Synthesis and applications. As canopy openness and habitat heterogeneity seem to be the major drivers of saproxylic beetle diversity in temperate forests, we recommend that managers aim to increase the heterogeneity of dead-wood substrates under both sunny and shady forest conditions. Intentional opening of the canopy should be considered in anthropogenically homogenized, dense forests. Specifically in temperate mixed montane forests, dead wood should be provided in the form of large logs in sunny habitats and a high diversity of different dead-wood substrates should be retained or created in shady forests.

Book ChapterDOI
TL;DR: The most common strategy and the golden standard for the prevention of caries, gingivitis and periodontitis is the mechanical removal of this biofilms from teeth, restorations or dental prosthesis by regular toothbrushing.
Abstract: The oral microbiota represents an important part of the human microbiota, and includes several hundred to several thousand diverse species. It is a normal part of the oral cavity and has an important function to protect against colonization of extrinsic bacteria which could affect systemic health. On the other hand, the most common oral diseases caries, gingivitis and periodontitis are based on microorganisms. While (medical) research focused on the planktonic phase of bacteria over the last 100 years, it is nowadays generally known, that oral microorganisms are organised as biofilms. On any non-shedding surfaces of the oral cavity dental plaque starts to form, which meets all criteria for a microbial biofilm and is subject to the so-called succession. When the sensitive ecosystem turns out of balance – either by overload or weak immune system – it becomes a challenge for local or systemic health. Therefore, the most common strategy and the golden standard for the prevention of caries, gingivitis and periodontitis is the mechanical removal of this biofilms from teeth, restorations or dental prosthesis by regular toothbrushing.

Journal ArticleDOI
TL;DR: There is limited evidence suggesting that i.v. lidocaine may be a useful adjuvant during general anaesthesia because of its beneficial impact on several outcomes after surgery.
Abstract: Background Improvement of postoperative pain and other perioperative outcomes remain a significant challenge and a matter of debate among perioperative clinicians. This systematic review aims to evaluate the effects of perioperative i.v. lidocaine infusion on postoperative pain and recovery in patients undergoing various surgical procedures. Methods CENTRAL, MEDLINE, EMBASE, and CINAHL databases and ClinicalTrials.gov, and congress proceedings were searched for randomized controlled trials until May 2014, that compared patients who did or did not receive continuous perioperative i.v. lidocaine infusion. Results Forty-five trials (2802 participants) were included. Meta-analysis suggested that lidocaine reduced postoperative pain (visual analogue scale, 0 to 10 cm) at 1–4 h (MD −0.84, 95% CI −1.10 to −0.59) and at 24 h (MD −0.34, 95% CI −0.57 to −0.11) after surgery, but not at 48 h (MD −0.22, 95% CI −0.47 to 0.03). Subgroup analysis and trial sequential analysis suggested pain reduction for patients undergoing laparoscopic abdominal surgery or open abdominal surgery, but not for patients undergoing other surgeries. There was limited evidence of positive effects of lidocaine on postoperative gastrointestinal recovery, opioid requirements, postoperative nausea and vomiting, and length of hospital stay. There were limited data available on the effect of systemic lidocaine on adverse effects or surgical complications. Quality of evidence was limited as a result of inconsistency (heterogeneity) and indirectness (small studies). Conclusions There is limited evidence suggesting that i.v. lidocaine may be a useful adjuvant during general anaesthesia because of its beneficial impact on several outcomes after surgery.