Publications by authors named "Matthias Huber"

58 Publications

Dynamic Structural Changes and Thermodynamics in Phase Separation Processes of an Intrinsically Disordered-Ordered Protein Model.

Angew Chem Int Ed Engl 2022 Jan 6;61(3):e202112738. Epub 2021 Dec 6.

Zentrum für Biosystemanalyse (ZBSA), Albert-Ludwigs-Universität Freiburg, Habsburgerstrasse 49, 79104, Freiburg, Germany.

Elastin-like proteins (ELPs) are biologically important proteins and models for intrinsically disordered proteins (IDPs) and dynamic structural transitions associated with coacervates and liquid-liquid phase transitions. However, the conformational status below and above coacervation temperature and its role in the phase separation process is still elusive. Employing matrix least-squares global Boltzmann fitting of the circular dichroism spectra of the ELPs (VPGVG) , (VPGVG) , and (VPGVG) , we found that coacervation occurs sharply when a certain number of repeat units has acquired β-turn conformation (in our sequence setting a threshold of approx. 20 repeat units). The character of the differential scattering of the coacervate suspensions indicated that this fraction of β-turn structure is still retained after polypeptide assembly. Such conformational thresholds may also have a role in other protein assembly processes with implications for the design of protein-based smart materials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.202112738DOI Listing
January 2022

IMHOTEP: cross-professional evaluation of a three-dimensional virtual reality system for interactive surgical operation planning, tumor board discussion and immersive training for complex liver surgery in a head-mounted display.

Surg Endosc 2022 Jan 21;36(1):126-134. Epub 2021 Jan 21.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Virtual reality (VR) with head-mounted displays (HMD) may improve medical training and patient care by improving display and integration of different types of information. The aim of this study was to evaluate among different healthcare professions the potential of an interactive and immersive VR environment for liver surgery that integrates all relevant patient data from different sources needed for planning and training of procedures.

Methods: 3D-models of the liver, other abdominal organs, vessels, and tumors of a sample patient with multiple hepatic masses were created. 3D-models, clinical patient data, and other imaging data were visualized in a dedicated VR environment with an HMD (IMHOTEP). Users could interact with the data using head movements and a computer mouse. Structures of interest could be selected and viewed individually or grouped. IMHOTEP was evaluated in the context of preoperative planning and training of liver surgery and for the potential of broader surgical application. A standardized questionnaire was voluntarily answered by four groups (students, nurses, resident and attending surgeons).

Results: In the evaluation by 158 participants (57 medical students, 35 resident surgeons, 13 attending surgeons and 53 nurses), 89.9% found the VR system agreeable to work with. Participants generally agreed that complex cases in particular could be assessed better (94.3%) and faster (84.8%) with VR than with traditional 2D display methods. The highest potential was seen in student training (87.3%), resident training (84.6%), and clinical routine use (80.3%). Least potential was seen in nursing training (54.8%).

Conclusions: The present study demonstrates that using VR with HMD to integrate all available patient data for the preoperative planning of hepatic resections is a viable concept. VR with HMD promises great potential to improve medical training and operation planning and thereby to achieve improvement in patient care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00464-020-08246-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741674PMC
January 2022

Directed Assembly of Elastin-like Proteins into defined Supramolecular Structures and Cargo Encapsulation In Vitro.

J Vis Exp 2020 04 8(158). Epub 2020 Apr 8.

Center for Biological Systems Analysis, University of Freiburg; Faculty of Biology, University of Freiburg; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg; BIOSS Centre for Biological Signalling Studies, University of Freiburg; IMTEK Department of Microsystems Engineering, University of Freiburg; Cluster of Excellence livMatS at FIT - Freiburg Center for Interactive Materials and Bioinspired Technologies, University of Freiburg;

Tailored proteinaceous building blocks are versatile candidates for the assembly of supramolecular structures such as minimal cells, drug delivery vehicles and enzyme scaffolds. Due to their biocompatibility and tunability on the genetic level, Elastin-like proteins (ELP) are ideal building blocks for biotechnological and biomedical applications. Nevertheless, the assembly of protein based supramolecular structures with distinct physiochemical properties and good encapsulation potential remains challenging. Here we provide two efficient protocols for guided self-assembly of amphiphilic ELPs into supramolecular protein architectures such as spherical coacervates, fibers and stable vesicles. The presented assembly protocols generate Protein Membrane-Based Compartments (PMBCs) based on ELPs with adaptable physicochemical properties. PMBCs demonstrate phase separation behavior and reveal method dependent membrane fusion and are able to encapsulate chemically diverse fluorescent cargo molecules. The resulting PMBCs have a high application potential as a drug formulation and delivery platform, artificial cell, and compartmentalized reaction space.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3791/60935DOI Listing
April 2020

Adjustable Bioorthogonal Conjugation Platform for Protein Studies in Live Cells Based on Artificial Compartments.

ACS Synth Biol 2020 04 17;9(4):827-842. Epub 2020 Mar 17.

Zentrum für Biosystemanalyse (ZBSA), University of Freiburg, Habsburgerstraße 49, 79104 Freiburg, Germany.

The investigation of complex biological processes often requires defined multiple bioconjugation and positioning of functional entities on 3D structures. Prominent examples include spatially defined protein complexes in nature, facilitating efficient biocatalysis of multistep reactions. Mimicking natural strategies, synthetic scaffolds should comprise bioorthogonal conjugation reactions and allow for absolute stoichiometric quantification as well as facile scalability through scaffold reproduction. Existing scaffolding strategies often lack covalent conjugations on geometrically confined scaffolds or precise quantitative characterization. Addressing these shortcomings, we present a bioorthogonal dual conjugation platform based on genetically encoded artificial compartments comprising two distinct genetically encoded covalent conjugation reactions and their precise stoichiometric quantification. The SpyTag/SpyCatcher (ST/SC) bioconjugation and the controllable strain-promoted azide-alkyne cycloaddition (SPAAC) were implemented on self-assembled protein membrane-based compartments (PMBCs). The SPAAC reaction yield was quantified to be 23% ± 3% and a ST/SC surface conjugation yield of 82% ± 9% was observed, while verifying the compatibility of both chemical reactions as well as enhanced proteolytic stability. Using tandem mass spectrometry, absolute concentrations of the proteinaceous reactants were calculated to be 0.11 ± 0.05 attomol/cell for PMBC surface-tethered mCherry-ST-His and 0.22 ± 0.09 attomol/cell for PMBC-constituting pAzF-SC-E20F20-His. The established conjugation platform enables quantifiable protein-protein interaction studies on geometrically defined scaffolds and paves the road to investigate effects of scaffold-tethering on enzyme activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acssynbio.9b00494DOI Listing
April 2020

The toxic dinoflagellate Alexandrium minutum impairs the performance of oyster embryos and larvae.

Harmful Algae 2020 02 15;92:101744. Epub 2020 Feb 15.

Univ Brest, CNRS, IRD, Ifremer, LEMAR, F-29280, Plouzane, France. Electronic address:

The dinoflagellate genus Alexandrium comprises species that produce highly potent neurotoxins known as paralytic shellfish toxins (PST), and bioactive extracellular compounds (BEC) of unknown structure and ecological significance. The toxic bloom-forming species, Alexandrium minutum, is distributed worldwide and adversely affects many bivalves including the commercially and ecologically important Pacific oyster, Crassostrea gigas. In France, recurrent A. minutum blooms can co-occur with C. gigas spawning and larval development, and may endanger recruitment and population renewal. The present study explores how A. minutum affects oyster early development by exposing embryos and larvae, under controlled laboratory conditions, to two strains of A. minutum, producing only BEC or both PST and BEC. Results highlight the major role of BEC in A. minutum toxicity upon oyster development. The BEC strain caused lysis of embryos, the most sensitive stage to A. minutum toxicity among planktonic life stages. In addition, the non-PST-producing A. minutum strain inhibited hatching, disrupted larval swimming behavior, feeding, growth, and induced drastic decreases in survival and settlement of umbonate and eyed larvae (9 and 68 %, respectively). The findings indicated PST accumulation in oyster larvae (e.g. umbonate stages), possibly impairing development and settlement of larvae in response to the PST-producing strain. This work provides evidences that A. minutum blooms could hamper settlement of shellfish.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hal.2020.101744DOI Listing
February 2020

Prebiotic Protocell Model Based on Dynamic Protein Membranes Accommodating Anabolic Reactions.

Langmuir 2019 07 9;35(29):9593-9610. Epub 2019 Jul 9.

Zentrum für Biosystemanalyse (ZBSA) , Albert-Ludwigs-Universität Freiburg , 7 Habsburgerstrasse 49 , D-79104 Freiburg , Germany.

The nature of the first prebiotic compartments and their possible minimal molecular composition is of great importance in the origin of life scenarios. Current protocell model membranes are proposed to be lipid-based. This paradigm has several shortcomings such as limited membrane stability of monoacyl lipid-based membranes (e.g., fatty acids), missing pathways to synthesize protocell membrane components (e.g., phospholipids) under early earth conditions, and the requirement for different classes of molecules for the formation of compartments and the catalysis of reactions. Amino acids on the other hand are known to arise and persist with remarkable abundance under early earth conditions since the fundamental Miller-Urey experiments. They were also postulated early to form protocellular structures, for example, proteinoid capsules. Here, we present a protocell model constituted by membranes assembled from amphiphilic proteins based on prebiotic amino acids. Self-assembled dynamic protein membrane-based compartments (PMBCs) are impressively stable and compatible with prevalent cellular membrane constituents forming protein-only or protein-lipid hybrid membranes. They can embed processes essential for extant living cells, such as enclosure of molecules, membrane fusion, phase separation, and complex biosynthetic elements from modern cells demonstrating "upward" compatibility. Our findings suggest that prebiotic PMBCs represent a new type of protocell as a possible ancestor of current lipid-based cells. The presented prebiotic PMBC model can be used to design artificial cells, important for the study of structural, catalytic, and evolutionary pathways related to the emergence of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.langmuir.9b00445DOI Listing
July 2019

Minimalist Protocell Design: A Molecular System Based Solely on Proteins that Form Dynamic Vesicular Membranes Embedding Enzymatic Functions.

Chembiochem 2019 10 23;20(20):2618-2632. Epub 2019 Aug 23.

Zentrum für Biosystemanalyse (ZBSA), Albert-Ludwigs-Universität Freiburg, Habsburgerstrasse 49, 79104, Freiburg, Germany.

Life in its molecular context is characterized by the challenge of orchestrating structure, energy and information processes through compartmentalization and chemical transformations amenable to mimicry of protocell models. Here we present an alternative protocell model incorporating dynamic membranes based on amphiphilic elastin-like proteins (ELPs) rather than phospholipids. For the first time we demonstrate the feasibility of combining vesicular membrane formation and biocatalytic activity with molecular entities of a single class: proteins. The presented self-assembled protein-membrane-based compartments (PMBCs) accommodate either an anabolic reaction, based on free DNA ligase as an example of information transformation processes, or a catabolic process. We present a catabolic process based on a single molecular entity combining an amphiphilic protein with tobacco etch virus (TEV) protease as part of the enclosure of a reaction space and facilitating selective catalytic transformations. Combining compartmentalization and biocatalytic activity by utilizing an amphiphilic molecular building block with and without enzyme functionalization enables new strategies in bottom-up synthetic biology, regenerative medicine, pharmaceutical science and biotechnology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbic.201900283DOI Listing
October 2019

Self-Assembly Toolbox of Tailored Supramolecular Architectures Based on an Amphiphilic Protein Library.

Small 2019 07 7;15(30):e1900163. Epub 2019 Jun 7.

Center for Biological Systems Analysis, University of Freiburg, Habsburgerstrasse 49, 79104, Freiburg, Germany.

The molecular structuring of complex architectures and the enclosure of space are essential requirements for technical and living systems. Self-assembly of supramolecular structures with desired shape, size, and stability remains challenging since it requires precise regulation of physicochemical and conformational properties of the components. Here a general platform for controlled self-assembly of tailored amphiphilic elastin-like proteins into desired supramolecular protein assemblies ranging from spherical coacervates over molecularly defined twisted fibers to stable unilamellar vesicles is introduced. The described assembly protocols efficiently yield protein membrane-based compartments (PMBC) with adjustable size, stability, and net surface charge. PMBCs demonstrate membrane fusion and phase separation behavior and are able to encapsulate structurally and chemically diverse cargo molecules ranging from small molecules to naturally folded proteins. The ability to engineer tailored supramolecular architectures with defined fusion behavior, tunable properties, and encapsulated cargo paves the road for novel drug delivery systems, the design of artificial cells, and confined catalytic nanofactories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smll.201900163DOI Listing
July 2019

Targeted resequencing of a locus for heparin-induced thrombocytopenia on chromosome 5 identified in a genome-wide association study.

J Mol Med (Berl) 2018 08 22;96(8):765-775. Epub 2018 Jun 22.

Department of Genetic Epidemiology, Institute of Human Genetics, University Hospital Münster, Münster, Germany.

Immune-mediated heparin-induced thrombocytopenia (HIT) is the clinically most important adverse drug reaction (ADR) in response to heparin therapy characterized by a prothrombotic state despite a decrease in platelet count. We conducted a genome-wide association study in 96 suspected HIT cases and 96 controls to explore the genetic predisposition for HIT within a case-control pharmacovigilance study followed by replication in additional 86 cases and 86 controls from the same study. One single nucleotide polymorphism (SNP, rs1433265, P = 6.5 × 10, odds ratio (OR) 2.79) from 16 identified SNPs was successfully replicated (P = 1.5 × 10, OR 2.77; combined data set P = 2.7 × 10, OR 2.77) and remained the most strongly associated SNP after imputing locus genotypes. Fine mapping revealed a significantly associated risk-conferring haplotype (P = 4.9 × 10, OR 2.41). In order to find rare variants contributing to the association signals, we applied a targeted resequencing approach in a subgroup of 73 HIT patients and 23 controls for the regions with the 16 most strongly HIT-associated SNPs. C-alpha testing was applied to test for the impact of rare variants and we detected two candidate genes, the discoidin domain receptor tyrosine kinase 1 (DDR1, P = 3.6 × 10) and the multiple C2 and transmembrane domain containing 2 (MCTP2, P = 4.5 × 10). For the genes interactor of little elongation complex ELL subunit 1 (ICE1) and a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 16 (ADAMTS16) nearby rs1433265, we identified several missense variants. Although replication in an independent population is warranted, these findings provide a basis for future studies aiming to identify and characterize genetic susceptibility factors for HIT. KEY MESSAGES: We identified and validated a HIT-associated locus on chromosome 5. Targeted NGS analysis for rare variants identifies DDR1 and MCTP2 as novel candidates. In addition, missense variants for ADAMTS16 and ICE1 were identified in the locus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00109-018-1661-6DOI Listing
August 2018

IMHOTEP: virtual reality framework for surgical applications.

Int J Comput Assist Radiol Surg 2018 May 17;13(5):741-748. Epub 2018 Mar 17.

National Center for Tumor Diseases, Dresden, Germany.

Purpose: The data which is available to surgeons before, during and after surgery is steadily increasing in quantity as well as diversity. When planning a patient's treatment, this large amount of information can be difficult to interpret. To aid in processing the information, new methods need to be found to present multimodal patient data, ideally combining textual, imagery, temporal and 3D data in a holistic and context-aware system.

Methods: We present an open-source framework which allows handling of patient data in a virtual reality (VR) environment. By using VR technology, the workspace available to the surgeon is maximized and 3D patient data is rendered in stereo, which increases depth perception. The framework organizes the data into workspaces and contains tools which allow users to control, manipulate and enhance the data. Due to the framework's modular design, it can easily be adapted and extended for various clinical applications.

Results: The framework was evaluated by clinical personnel (77 participants). The majority of the group stated that a complex surgical situation is easier to comprehend by using the framework, and that it is very well suited for education. Furthermore, the application to various clinical scenarios-including the simulation of excitation propagation in the human atrium-demonstrated the framework's adaptability. As a feasibility study, the framework was used during the planning phase of the surgical removal of a large central carcinoma from a patient's liver.

Conclusion: The clinical evaluation showed a large potential and high acceptance for the VR environment in a medical context. The various applications confirmed that the framework is easily extended and can be used in real-time simulation as well as for the manipulation of complex anatomical structures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11548-018-1730-xDOI Listing
May 2018

pH controls spermatozoa motility in the Pacific oyster ().

Biol Open 2018 Mar 19;7(3). Epub 2018 Mar 19.

University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Vodnany 38925, Czech Republic.

Investigating the roles of chemical factors stimulating and inhibiting sperm motility is required to understand the mechanisms of spermatozoa movement. In this study, we described the composition of the seminal fluid (osmotic pressure, pH, and ions) and investigated the roles of these factors and salinity in initiating spermatozoa movement in the Pacific oyster, The acidic pH of the gonad (5.82±0.22) maintained sperm in the quiescent stage and initiation of flagellar movement was triggered by a sudden increase of spermatozoa external pH (pHe) when released in seawater (SW). At pH 6.4, percentage of motile spermatozoa was three times higher when they were activated in SW containing 30 mM NHCl, which alkalinizes internal pH (pHi) of spermatozoa, compared to NHCl-free SW, revealing the role of pHi in triggering sperm movement. Percentage of motile spermatozoa activated in Na-free artificial seawater (ASW) was highly reduced compared to ASW, suggesting that change of pHi triggering sperm motility was mediated by a Na/H exchanger. Motility and swimming speed were highest in salinities between 33.8 and 42.7‰ (within a range of 0 to 50 ‰), and pH values above 7.5 (within a range of 4.5 to 9.5).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/bio.031427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898264PMC
March 2018

Immobilization and high platelet count are associated with thromboembolic complications in heparin-induced thrombocytopenia.

Pharmacoepidemiol Drug Saf 2017 Oct 24;26(10):1149-1155. Epub 2017 May 24.

Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Purpose: Immune-mediated heparin-induced thrombocytopenia (HIT type II, HIT) is a potentially serious adverse drug reaction characterized by an increased risk of venous and arterial thrombosis. This study aimed to identify risk factors associated with the development of these complications.

Methods: Our study cohort included patients with HIT assembled in our pharmacovigilance center by reports from 51 collaborating hospitals in Berlin, Germany. To identify risk factors for thromboembolic complications, patients with thromboembolic events (cases) were compared to those without thromboembolic events (controls) in a case-control design. We applied univariable and multivariable logistic regression analysis to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for potential risk factors of thromboembolic complications.

Results: Our cohort comprised 209 HIT patients. Of those, 53 developed thromboembolic complications. Most HIT patients received heparin for medical indications (42.1%) or in the context of cardiovascular surgery (40.2%). Of the 78 thromboembolic complications, 49 (63%) and 29 (37%) were observed in the venous and arterial vascular bed, respectively. The main locations were deep vein thrombosis (39.7%), pulmonary embolism (16.7%), and limb artery thrombosis (16.7%). In multivariable analysis, immobilization prior to HIT (OR 4.6, 95% CI 1.2-18.0; P = .026) and higher platelet counts before initiation of heparin therapy (OR 1.004, 95% CI 1.000-1.008; P = .046) were independently associated with the occurrence of thromboembolic events.

Conclusions: Immobilization and a high platelet count (with a low effect size) are additional risk factors of thromboembolic complications in the course of HIT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pds.4235DOI Listing
October 2017

Automated detection of protein unfolding events in atomic force microscopy force curves.

Microsc Res Tech 2016 Nov 29;79(11):1105-1111. Epub 2016 Aug 29.

Institute for Biophysics, Department of Nanobiotechnology, University of Natural Resources and Life Sciences, Vienna, Austria.

Atomic force microscopy is not only a high-resolution imaging device but also a mechanical machine, which can be used either to indent or stretch (soft) biomaterials. Due to the statistical nature of such materials (i.e., hydrogels or polymers) hundreds of force-distance curves are required to describe their mechanical properties. In this manuscript, we present an automated system for polymer unfolding detection based on continuous wavelet analysis. We have tested the automated program on elastin, which is an important protein that provides elasticity to tissues and organs. Our results show that elastin changes its mechanical behavior in the presence of electrolytes. In particular, we show that NaCl has a different effect on the contour length than CaCl for similar unfolding forces. In addition, we provide the program in the supporting information for the researches facing such kind of problem.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jemt.22764DOI Listing
November 2016

Challenges and opportunities of power systems from smart homes to super-grids.

Ambio 2016 Jan;45 Suppl 1:S50-62

Institute for Renewable and Sustainable Energy Systems, Technische Universität München, Munich, Germany.

The world's power systems are facing a structural change including liberalization of markets and integration of renewable energy sources. This paper describes the challenges that lie ahead in this process and points out avenues for overcoming different problems at different scopes, ranging from individual homes to international super-grids. We apply energy system models at those different scopes and find a trade-off between technical and social complexity. Small-scale systems would require technological breakthroughs, especially for storage, but individual agents can and do already start to build and operate such systems. In contrast, large-scale systems could potentially be more efficient from a techno-economic point of view. However, new political frameworks are required that enable long-term cooperation among sovereign entities through mutual trust. Which scope first achieves its breakthrough is not clear yet.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13280-015-0733-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678120PMC
January 2016

Structure and assembly of the mouse ASC inflammasome by combined NMR spectroscopy and cryo-electron microscopy.

Proc Natl Acad Sci U S A 2015 Oct 13;112(43):13237-42. Epub 2015 Oct 13.

Biozentrum, University of Basel, 4056 Basel, Switzerland;

Inflammasomes are multiprotein complexes that control the innate immune response by activating caspase-1, thus promoting the secretion of cytokines in response to invading pathogens and endogenous triggers. Assembly of inflammasomes is induced by activation of a receptor protein. Many inflammasome receptors require the adapter protein ASC [apoptosis-associated speck-like protein containing a caspase-recruitment domain (CARD)], which consists of two domains, the N-terminal pyrin domain (PYD) and the C-terminal CARD. Upon activation, ASC forms large oligomeric filaments, which facilitate procaspase-1 recruitment. Here, we characterize the structure and filament formation of mouse ASC in vitro at atomic resolution. Information from cryo-electron microscopy and solid-state NMR spectroscopy is combined in a single structure calculation to obtain the atomic-resolution structure of the ASC filament. Perturbations of NMR resonances upon filament formation monitor the specific binding interfaces of ASC-PYD association. Importantly, NMR experiments show the rigidity of the PYD forming the core of the filament as well as the high mobility of the CARD relative to this core. The findings are validated by structure-based mutagenesis experiments in cultured macrophages. The 3D structure of the mouse ASC-PYD filament is highly similar to the recently determined human ASC-PYD filament, suggesting evolutionary conservation of ASC-dependent inflammasome mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1507579112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629351PMC
October 2015

Sequence-specific solid-state NMR assignments of the mouse ASC PYRIN domain in its filament form.

Biomol NMR Assign 2016 Apr 24;10(1):107-15. Epub 2015 Sep 24.

Institut de Biologie et Chimie des Protéines, Bases Moléculaires et Structurales des Systèmes Infectieux, Labex Ecofect, UMR 5086 CNRS, Université de Lyon, Lyon, France.

The apoptosis-associated speck-like protein (ASC protein) plays a central role in eukaryotic innate immune response. Upon infection, multiple ASC molecules assemble into long filaments, which are fundamental for triggering the cellular defense mechanism by starting an inflammatory cascade with the activation of caspase-1. ASC is composed of two domains, the C-terminal caspase-recruitment domain, which is involved in the recruitment of the caspase, and the N-terminal PYRIN domain (PYD), which is responsible for the formation of the filament. Here we present the (13)C and (15)N chemical shift assignment for filaments formed by the PYD of mouse ASC, a 91-residue protein. The backbone between residues 4 and 84 is assigned without interruption. Also, 86 % of the sidechain resonances for this stretch are assigned. Residues 1-3 and 85-91 show unfavorable dynamics and are not observed. Secondary chemical-shift analysis shows the presence of six α-helices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12104-015-9647-6DOI Listing
April 2016

A Single Nucleotide Polymorphism near the CYP17A1 Gene Is Associated with Left Ventricular Mass in Hypertensive Patients under Pharmacotherapy.

Int J Mol Sci 2015 Jul 30;16(8):17456-68. Epub 2015 Jul 30.

Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.

Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular mass. Notably, genome wide association studies supported the role of this enzyme in BP control. Against this background, we investigated associations between single nucleotide polymorphisms (SNPs) in or nearby the CYP17A1 gene with BP and left ventricular mass in patients with arterial hypertension and associated cardiovascular organ damage treated according to guidelines. Patients (n = 1007, mean age 58.0 ± 9.8 years, 83% men) with arterial hypertension and cardiac left ventricular ejection fraction (LVEF) ≥ 40% were enrolled in the study. Cardiac parameters of left ventricular mass, geometry and function were determined by echocardiography. The cohort comprised patients with coronary heart disease (n = 823; 81.7%) and myocardial infarction (n = 545; 54.1%) with a mean LVEF of 59.9% ± 9.3%. The mean left ventricular mass index (LVMI) was 52.1 ± 21.2 g/m2.7 and 485 (48.2%) patients had left ventricular hypertrophy. There was no significant association of any investigated SNP (rs619824, rs743572, rs1004467, rs11191548, rs17115100) with mean 24 h systolic or diastolic BP. However, carriers of the rs11191548 C allele demonstrated a 7% increase in LVMI (95% CI: 1%-12%, p = 0.017) compared to non-carriers. The CYP17A1 polymorphism rs11191548 demonstrated a significant association with LVMI in patients with arterial hypertension and preserved LVEF. Thus, CYP17A1 may contribute to cardiac hypertrophy in this clinical condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms160817456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581202PMC
July 2015

Molecular protein adaptor with genetically encoded interaction sites guiding the hierarchical assembly of plasmonically active nanoparticle architectures.

Nat Commun 2015 Mar 27;6:6705. Epub 2015 Mar 27.

Freiburg Institute for Advanced Studies (FRIAS), School of Soft Matter Research, University of Freiburg, Albertstrasse 19, Freiburg 79104, Germany.

The control over the defined assembly of nano-objects with nm-precision is important to create systems and materials with enhanced properties, for example, metamaterials. In nature, the precise assembly of inorganic nano-objects with unique features, for example, magnetosomes, is accomplished by efficient and reliable recognition schemes involving protein effectors. Here we present a molecular approach using protein-based 'adaptors/connectors' with genetically encoded interaction sites to guide the assembly and functionality of different plasmonically active gold nanoparticle architectures (AuNP). The interaction of the defined geometricaly shaped protein adaptors with the AuNP induces the self-assembly of nanoarchitectures ranging from AuNP encapsulation to one-dimensional chain-like structures, complex networks and stars. Synthetic biology and bionanotechnology are applied to co-translationally encode unnatural amino acids as additional site-specific modification sites to generate functionalized biohybrid nanoarchitectures. This protein adaptor-based nano-object assembly approach might be expanded to other inorganic nano-objects creating biohybrid materials with unique electronic, photonic, plasmonic and magnetic properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms7705DOI Listing
March 2015

Atomic-resolution three-dimensional structure of amyloid β fibrils bearing the Osaka mutation.

Angew Chem Int Ed Engl 2015 Jan 13;54(1):331-5. Epub 2014 Nov 13.

Physical Chemistry, ETH Zürich, Vladimir-Prelog-Weg 2, 8093 Zurich (Switzerland).

Despite its central importance for understanding the molecular basis of Alzheimer's disease (AD), high-resolution structural information on amyloid β-peptide (Aβ) fibrils, which are intimately linked with AD, is scarce. We report an atomic-resolution fibril structure of the Aβ1-40 peptide with the Osaka mutation (E22Δ), associated with early-onset AD. The structure, which differs substantially from all previously proposed models, is based on a large number of unambiguous intra- and intermolecular solid-state NMR distance restraints.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201408598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502972PMC
January 2015

Metamizole-induced agranulocytosis revisited: results from the prospective Berlin Case-Control Surveillance Study.

Eur J Clin Pharmacol 2015 Feb 8;71(2):219-27. Epub 2014 Nov 8.

Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Purpose: Treatment with metamizole (dipyrone) has steadily increased in Germany over the last decade. The consequences of this increase for metamizole-induced agranulocytosis (MIA) are unclear. The present study addressed this topic using data from the Berlin Case-Control Surveillance Study.

Methods: Adult patients (≥18 years of age) with acute nonchemotherapy-induced agranulocytosis were identified by active surveillance in all 51 Berlin hospitals between 2000 and 2010. Cases related to metamizole were ascertained applying the drug causality criteria of the World Health Organization. The incidence rate of MIA was calculated and standardised by age and sex based on the German standard population in 2010.

Results: Twenty-six MIA cases out of 88 (30 %) patients with validated agranulocytosis were ascertained. The incidence of MIA was 0.96 (95 % confidence interval (CI) 0.95-0.97) cases per million per year. The median age of MIA cases was 50 years (quartile (Q)1 31 years; Q3 68 years) and 19 (73 %) of them were women. In 17 (65 %) cases, neutrophil granulocytes dropped below the value of 0.1 × 10(9) cells/L with three patients suffering from sepsis. Headache and postoperative pain were the most frequent indications for metamizole in outpatients (n = 16) and inpatients (n = 10), respectively. The median treatment duration was 6 days (Q1 4 days; Q3 19 days).

Conclusions: MIA persists as a severe condition in current pharmacotherapy. The continuous increase of metamizole applications should be critically assessed, especially in regard to indications in the outpatient setting and with respect to metamizole treatment duration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00228-014-1777-8DOI Listing
February 2015

Designer amphiphilic proteins as building blocks for the intracellular formation of organelle-like compartments.

Nat Mater 2015 Jan 2;14(1):125-32. Epub 2014 Nov 2.

1] Institute for Macromolecular Chemistry, University of Freiburg, Stefan-Meier-Str. 31 D-79104 Freiburg, Germany [2] Institute for Pharmaceutical Sciences, University of Freiburg, Albertstr. 25 D-79104 Freiburg, Germany [3] Freiburg Institute for Advanced Studies (FRIAS), School of Soft Matter Research, University of Freiburg, Albertstr. 19 D-79104 Freiburg, Germany [4] Faculty of Chemistry and Pharmacy, University of Freiburg, Fahnenbergplatz D-79104 Freiburg, Germany [5] Faculty of Biology, University of Freiburg, Schänzlestrasse 1 D-79085 Freiburg, Germany [6] BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestrasse 18 D-79104 Freiburg, Germany [7] IMTEK Department of Microsystems Engineering, University of Freiburg, Georges-Köhler-Allee 103 D-79110 Freiburg, Germany [8] Center for Biosystems Analysis (ZBSA), University of Freiburg, Habsburger Str. 49 D-79104 Freiburg, Germany.

Nanoscale biological materials formed by the assembly of defined block-domain proteins control the formation of cellular compartments such as organelles. Here, we introduce an approach to intentionally 'program' the de novo synthesis and self-assembly of genetically encoded amphiphilic proteins to form cellular compartments, or organelles, in Escherichia coli. These proteins serve as building blocks for the formation of artificial compartments in vivo in a similar way to lipid-based organelles. We investigated the formation of these organelles using epifluorescence microscopy, total internal reflection fluorescence microscopy and transmission electron microscopy. The in vivo modification of these protein-based de novo organelles, by means of site-specific incorporation of unnatural amino acids, allows the introduction of artificial chemical functionalities. Co-localization of membrane proteins results in the formation of functionalized artificial organelles combining artificial and natural cellular function. Adding these protein structures to the cellular machinery may have consequences in nanobiotechnology, synthetic biology and materials science, including the constitution of artificial cells and bio-based metamaterials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nmat4118DOI Listing
January 2015

Introducing a combinatorial DNA-toolbox platform constituting defined protein-based biohybrid-materials.

Biomaterials 2014 Oct 27;35(31):8767-8779. Epub 2014 Jul 27.

Freiburg Institute for Advanced Studies (FRIAS), School of Soft Matter Research, University of Freiburg, Albertstr. 19, 79104, Germany; Institute for Macromolecular Chemistry, Univ. of Freiburg, Stefan-Meier-Str. 31, 79104 Freiburg, Germany; Faculty of Chemistry and Pharmacy, Univ. of Freiburg, Fahnenbergplatz, 79085 Freiburg, Germany; Faculty of Biology, Univ. of Freiburg, Schänzlestrasse 1, 79104 Freiburg, Germany; Institute for Pharmaceutical Sciences, Univ. of Freiburg, Albertstr. 25, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, Univ. of Freiburg, Schänzlestrasse 18, 79104 Freiburg, Germany. Electronic address:

The access to defined protein-based material systems is a major challenge in bionanotechnology and regenerative medicine. Exact control over sequence composition and modification is an important requirement for the intentional design of structure and function. Herein structural- and matrix proteins provide a great potential, but their large repetitive sequences pose a major challenge in their assembly. Here we introduce an integrative "one-vector-toolbox-platform" (OVTP) approach which is fast, efficient and reliable. The OVTP allows for the assembly, multimerization, intentional arrangement and direct translation of defined molecular DNA-tecton libraries, in combination with the selective functionalization of the yielded protein-tecton libraries. The diversity of the generated tectons ranges from elastine-, resilin, silk- to epitope sequence elements. OVTP comprises the expandability of modular biohybrid-materials via the assembly of defined multi-block domain genes and genetically encoded unnatural amino acids (UAA) for site-selective chemical modification. Thus, allowing for the modular combination of the protein-tecton library components and their functional expansion with chemical libraries via UAA functional groups with bioorthogonal reactivity. OVTP enables access to multitudes of defined protein-based biohybrid-materials for self-assembled superstructures such as nanoreactors and nanobiomaterials, e.g. for approaches in biotechnology and individualized regenerative medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2014.06.048DOI Listing
October 2014

Solid-state NMR sequential assignment of Osaka-mutant amyloid-beta (Aβ1-40 E22Δ) fibrils.

Biomol NMR Assign 2015 Apr 7;9(1):7-14. Epub 2014 Jan 7.

Laboratory of Physical Chemistry, ETH Zurich, Wolfgang Pauli Strasse 10, 8093, Zurich, Switzerland.

Alzheimer's disease (AD) is the most common form of dementia. Aggregation of amyloid β (Aβ), a peptide of 39-43 residues length, into insoluble fibrils is considered to initiate the disease. Determination of the molecular structure of Aβ fibrils is technically challenging and is a significant goal in AD research that may lead to design of effective therapeutical inhibitors of Aβ aggregation. Here, we present chemical-shift assignments for fibrils formed by highly pure recombinant Aβ1-40 with the Osaka E22Δ mutation that is found in familial AD. We show that that all regions of the peptide are rigid, including the N-terminal part often believed to be flexible in Aβ wt.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12104-013-9535-xDOI Listing
April 2015

Drug-induced agranulocytosis in the Berlin case-control surveillance study.

Eur J Clin Pharmacol 2014 Mar 3;70(3):339-45. Epub 2013 Dec 3.

Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Purpose: Drug-induced agranulocytosis (DIAG) is a rare but serious adverse drug reaction. The Berlin Case-Control Surveillance Study (FAKOS) aimed to identify pharmaceuticals with an increased risk for this condition.

Methods: Adult patients with acute non-chemotherapy-induced agranulocytosis, developed in hospital or in the outpatient setting, were ascertained by active surveillance in all 51 Berlin hospitals between the years 2000 and 2010. Applying the criteria of the World Health Organization, a standardized drug causality assessment was conducted for each agranulocytosis patient to determine possible drug aetiology. Drug risks were quantified in a case-control design with unconditional logistic regression analysis.

Results: Sixty-three out of 88 validated cases of agranulocytosis were identified as being at least probably drug-related. Drug causality assessment resulted in 36 pharmaceuticals with a certain or probable relationship to agranulocytosis. Drugs involved in ≥ 3 cases with a probable or certain causality were metamizole (dipyrone) (N = 10), clozapine (N = 6), sulfasalazine (N = 5), thiamazole (N = 5), and carbamazepine (N = 3). In case-control analysis, six drugs were identified with significant odds ratios for DIAG. The highest odds ratios were observed for clozapine, sulfasalazine, and thiamazole.

Conclusions: Our findings are generally in agreement with those of earlier case-control studies. The spectrum of drugs causing acute agranulocytosis has not changed considerably over recent years, despite many newly marketed drugs. Evidence for induction of agranulocytosis by some new pharmaceuticals is supported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00228-013-1618-1DOI Listing
March 2014

Dialysis-associated hypertension treated with Telmisartan--DiaTel: a pilot, placebo-controlled, cross-over, randomized trial.

PLoS One 2013 18;8(11):e79322. Epub 2013 Nov 18.

Department of Clinical Pharmacology and Toxicology, Charité Medical Centre Berlin, Germany.

Unlabelled: Treatment of hypertension in hemodialysis (HD) patients is characterised by lack of evidence for both the blood pressure (BP) target goal and the recommended drug class to use. Telmisartan, an Angiotensin receptor blocker (ARB) that is metabolised in the liver and not excreted via HD extracorporeal circuit might be particularly suitable for HD patients. We designed and conducted a randomised, placebo-controlled, double-blind and cross-over trial for treatment of dialysis-associated hypertension with telmisartan 80 mg once daily or placebo on top of standard antihypertensive treatment excluding other Renin-Angiotensin-System (RAS) blockers. In 29 patients after randomization we analysed BP after a treatment period of 8 weeks, while 13 started with telmisartan and 16 with placebo; after 8 weeks 11 continued with telmisartan and 12 with placebo after cross-over, respectively. Patients exhibited a significant reduction of systolic pre-HD BP from 141.9±21.8 before to 131.3±17.3 mmHg after the first treatment period with telmisartan or placebo. However, no average significant influence of telmisartan was observed compared to placebo. The latter may be due to a large inter-individual variability of BP responses reaching from a 40 mmHg decrease under placebo to 40 mmHg increase under telmisartan. Antihypertensive co-medication was changed for clinical reasons in 7 out of 21 patients with no significant difference between telmisartan and placebo groups. Our starting hypothesis, that telmisartan on top of standard therapy lowers systolic office BP in HD patients could not be confirmed. In conclusion, this small trial indicates that testing antihypertensive drug efficacy in HD patients is challenging due to complicated standardization of concomitant medication and other confounding factors, e.g. volume status, salt load and neurohormonal activation, that influence BP control in HD patients.

Trial Registration: Clinicaltrialsregister.eu 2005-005021-60.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0079322PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832496PMC
July 2014

Automated solid-state NMR resonance assignment of protein microcrystals and amyloids.

J Biomol NMR 2013 Jul 21;56(3):243-54. Epub 2013 May 21.

Center for Biomolecular Magnetic Resonance, Institute of Biophysical Chemistry, Goethe University Frankfurt am Main, Frankfurt am Main, Germany.

Solid-state NMR is an emerging structure determination technique for crystalline and non-crystalline protein assemblies, e.g., amyloids. Resonance assignment constitutes the first and often very time-consuming step to a structure. We present ssFLYA, a generally applicable algorithm for automatic assignment of protein solid-state NMR spectra. Application to microcrystals of ubiquitin and the Ure2 prion C-terminal domain, as well as amyloids of HET-s(218-289) and α-synuclein yielded 88-97 % correctness for the backbone and side-chain assignments that are classified as self-consistent by the algorithm, and 77-90 % correctness if also assignments classified as tentative by the algorithm are included.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10858-013-9742-xDOI Listing
July 2013

Genetics of melatonin receptor type 2 is associated with left ventricular function in hypertensive patients treated according to guidelines.

Eur J Intern Med 2013 Oct 21;24(7):650-5. Epub 2013 Apr 21.

Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

Background: Melatonin exerts multiple biological effects with potential impact on human diseases. This is underscored by genetic studies that demonstrated associations between melatonin receptor type 2 gene (MTNR1B) polymorphisms and characteristics of type 2 diabetes. We set out to test the hypothesis whether genetic variants at MTNR1B are also relevant for other disease phenotypes within the cardiovascular continuum. We thus investigated single nucleotide polymorphisms (SNPs) of MTNR1B in relation to blood pressure (BP) and cardiac parameters in hypertensive patients.

Methods: Patients (n=605, mean age 56.2±9.4years, 82.3% male) with arterial hypertension and cardiac ejection fraction (EF) ≥40% were studied. Cardiac parameters were assessed by echocardiography.

Results: The cohort comprised subjects with coronary heart disease (73.1%) and myocardial infarction (48.1%) with a mean EF of 63.7±8.9%. Analysis of SNPs rs10830962, rs4753426, rs12804291, rs10830963, and rs3781638 revealed two haplotypes 1 and 2 with frequencies of 0.402 and 0.277, respectively. Carriers with haplotype 1 (CTCCC) showed compared to non-carriers a higher mean 24-hour systolic BP (difference BP: 2.4mmHg, 95% confidence interval (CI): 0.3 to 4.5mmHg, p=0.023). Haplotype 2 (GCCGA) was significantly related to EF with an absolute increase of 1.8% (CI: 0.45 to 3.14%) in carriers versus non-carriers (p=0.009).

Conclusion: Genetics of MTNR1B point to impact of the melatonin signalling pathway for BP and left ventricular function. This may support the importance of the melatonin system as a potential therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejim.2013.03.015DOI Listing
October 2013

[The eye as target of adverse ocular drug reactions. Focus on systemic antiinfective therapy].

Med Monatsschr Pharm 2012 Dec;35(12):436-42; quiz 443-4

Charité - Universitäts-medizin Berlin, Institut für Klinische Pharmakologie und Toxikologie, Charitéplatz 1, 10117 Berlin.

The functions of the eye can be disturbed by pharmaceutical agents via various mechanisms. This review describes the complexity of ocular adverse drug reactions and underlines the need for a close interdisciplinary cooperation especially in this field to optimize drug safety. Antimicrobial agents will be used as examples to describe ocular adverse drug reactions. A recent case control study describes fluoroquinolones to be associated with the occurrence of retinal detachments. The high affinity of these agents to melanin may cause intraocular accumulation. Fluoroquinolones exert toxic effects on collagens which may destabilize the structure of the extracellular matrix. The ketolid telithromycin may cause impaired accommodation and binocular vision potentially due to its anticholinergic effect. Linezolid, an oxazolidinone, used against infections with methicillin resistant staphylococcus aureus (MRSA) may lead to progressive, potentially irreversible neuropathies of the optic nerve especially in long-time application. Treatment with rifabutin or the antiviral drug cidofovir may cause intraocular inflammation. In addition, cidofovir may impair the production of the aqueous fluid due to a toxic effect on ciliary epithelial cells. During therapy with voriconazol about one third of patients suffer from reversible visual disturbances. Liver dysfunction or pharmacogenetic variants in the cytochrome P450 system may contribute to a retarded metabolism with high intraocular drug levels. In summary, this review indicates the complexity of ocular adverse drug reactions and points out that an interdisciplinary approach is necessary to improve pharmacovigilance in this field.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2012

Ophthalmic drugs as part of polypharmacy in nursing home residents with glaucoma.

Drugs Aging 2013 Jan;30(1):31-8

Institute of Clinical Pharmacology and Toxicology, Charité, Universitätsmedizin Berlin, Berlin, Germany.

Background: Glaucoma comprises age-related neurodegenerative diseases of retinal ganglion cells, the worldwide prevalence of which is increasing. Local pharmacotherapy is the primary treatment option, especially in the elderly. But this therapeutic approach may include risks for adverse drug effects and drug-drug interactions, of particular importance in frail nursing home resident populations.

Objective: The aim of the present study was to investigate anti-glaucoma pharmacotherapy in nursing home residents in the context of multi-morbidity and related systemic co-medication.

Methods: Data for 8,685 nursing home residents with 88,695 drug prescriptions were analysed according to diagnosis and local or systemic pharmacotherapy. Data were provided in anonymous form by a German public health insurance company.

Results: The study cohort was characterized by a mean age of 83.6 ± 7.3 years (range: 65-106 years), 21 % of nursing home residents were at least 90 years old and 83.7 % were women. For each nursing home resident, an average of 6.0 ± 3.3 different drugs were registered. A diagnosis of glaucoma was recorded in 520 (6.0 %) nursing home residents; all subjects had co-existing medical conditions. Dementia was a frequent co-morbidity, diagnosed in 51.7 % of nursing home residents with glaucoma. Anti-glaucoma drugs contributed to 0.5 % of all prescriptions and were prescribed to 341 nursing home residents. The most frequently used anti-glaucoma ophthalmics were β-blockers (n = 219), followed by prostaglandin analogues (n = 101) and carbonic anhydrase inhibitors (n = 86). Local anti-glaucoma therapy was co-prescribed with a systemic pharmacotherapy in 338 nursing home residents. An ophthalmic agent was, on average, combined with 6.5 ± 3.2 prescriptions for systemic agents. Thus, 71.9 % of nursing home residents were prescribed ophthalmic β-blockers and a concomitant antihypertensive medication; local and systemic β-blockers were combined in 20.2 % of these patients. Co-treatment with cardiac glycosides or calcium antagonists was found in 13 % of nursing home residents prescribed ophthalmic parasympathomimetics, and in 14 % of those prescribed ophthalmic β-blockers, with the potential for drug-drug interactions to influence cardiac function.

Conclusions: Anti-glaucoma pharmacotherapy in nursing home residents is frequently prescribed in the context of polypharmacy. This may modify the efficacy and safety of local and systemic therapies. Therefore, individualized pharmacotherapy that integrates anti-glaucoma drug therapy into the overall treatment rationale in nursing home residents is necessary. However, to realize this concept, further clinical research in nursing home residents is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40266-012-0036-xDOI Listing
January 2013

Vitreous levels of proteins implicated in angiogenesis are modulated in patients with retinal or choroidal neovascularization.

Ophthalmologica 2012 4;228(3):188-93. Epub 2012 Aug 4.

Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Germany. matthias.huber @ charite.de

Aim: The aim of this study was to investigate the levels of pigment epithelium-derived factor (PEDF), angiopoietin 2, vascular endothelial growth factor (VEGF), and soluble VEGF receptor 1 (sVEGFR-1) in vitreous samples of patients suffering from age-related macular degeneration with choroidal neovascularization or from proliferative diabetic retinopathy (PDR).

Methods: Proteins in vitreous samples of 29 patients were quantified via enzyme-linked immunosorbent assays.

Results: Vitreous levels of sVEGFR-1 were significantly higher in age-related macular degeneration with choroidal neovascularization (p = 0.005) and in PDR (p = 0.003) versus controls. In analogue comparisons, PEDF was significantly decreased (p < 0.01). PDR was associated with significantly increased angiopoietin 2 and VEGF levels (p = 0.001 for both).

Conclusion: The vitreous in retinal or choroidal neovascularization revealed a pro-angiogenic potential indicated by decreased PEDF or increased angiopoietin 2 levels compared to controls. However, higher amounts of sVEGFR-1 were concomitant, pointing to activation of an endogenous anti-angiogenic system in the protein network.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000339952DOI Listing
March 2013
-->