Showing papers by "University of Erlangen-Nuremberg published in 2008"

Recommendations for the evaluation of left ventricular diastolic function by echocardiography

Abstract: The assessment of left ventricular (LV) diastolic function should be an integral part of a routine examination, particularly in patients presenting with dyspnea or heart failure. About half of patients with new diagnoses of heart failure have normal or near normal global ejection fractions (EFs). These patients are diagnosed with “diastolic heart failure” or “heart failure with preserved EF.”1 The assessment of LV diastolic function and filling pressures is of paramount clinical importance to distinguish this syndrome from other diseases such as pulmonary disease resulting in dyspnea, to assess prognosis, and to identify underlying cardiac disease and its best treatment. LV filling pressures as measured invasively include mean pulmonary wedge pressure or mean left atrial (LA) pressure (both in the absence of mitral stenosis), LV end-diastolic pressure (LVEDP; the pressure at the onset of the QRS complex or after A-wave pressure), and pre-A LV diastolic pressure (Figure 1).Although these pressures are different in absolute terms, they are closely related, and they change in a predictable progression with myocardial disease, such that LVEDP increases prior to the rise in mean LA pressure. Figure 1 The 4 phases of diastole are marked in relation to high-fidelity pressure recordings from the left atrium (LA) and left ventricle (LV) in anesthetized dogs. The first pressure crossover corresponds to the end of isovolumic relaxation and mitral valve opening. In the first phase, left atrial pressure exceeds left ventricular pressure, accelerating mitral flow. Peak mitral E roughly corresponds to the second crossover. Thereafter, left ventricular pressure exceeds left atrial pressure, decelerating mitral flow. These two phases correspond to rapid filling. This is followed by slow filling, with almost no pressure differences. During atrial contraction, left atrial pressure again exceeds left ventricular pressure. The solid arrow points to left ventricular minimal pressure, the dotted arrow to left ventricular …

Fcγ receptors as regulators of immune responses

Abstract: In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcgammaRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.

The genome of the model beetle and pest Tribolium castaneum.

Abstract: Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.

Predictive control in power electronics and drives

Abstract: The article consists of a Powerpoint presentation on predictive control in power electronics and drives. The areas discussed include: predictive control; power electronics; power drive; cascaded control structure; nonlinear control system; switching system; etc. etc.

Geometric error measurement and compensation of machines : an update

Abstract: For measuring machines and machine tools, geometrical accuracy is a key performance criterion. While numerical compensation is well established for CMMs, it is increasingly used on machine tools in addition to mechanical accuracy. This paper is an update on the CIRP keynote paper by Sartori and Zhang from 1995 [Sartori S, Zhang GX (1995) Geometric error measurement and compensation of machines, Annals of the CIRP 44(2):599–609]. Since then, numerical error compensation has gained immense importance for precision machining. This paper reviews the fundamentals of numerical error compensation and the available methods for measuring the geometrical errors of a machine. It discusses the uncertainties involved in different mapping methods and their application characteristics. Furthermore, the challenges for the use of numerical compensation for manufacturing machines are specified. Based on technology and market development, this work aims at giving a perspective for the role of numerical compensation in the future.

Interaction, growth, and ordering of epitaxial graphene on SiC{0001} surfaces: A comparative photoelectron spectroscopy study

Abstract: Thermally induced growth of graphene on the two polar surfaces of $6H\text{\ensuremath{-}}\mathrm{Si}\mathrm{C}$ is investigated with emphasis on the initial stages of growth and interface structure. The experimental methods employed are angle-resolved valence band photoelectron spectroscopy, soft x-ray induced core-level spectroscopy, and low-energy electron diffraction. On the Si-terminated (0001) surface, the $(6\sqrt{3}\ifmmode\times\else\texttimes\fi{}6\sqrt{3})R30\ifmmode^\circ\else\textdegree\fi{}$ reconstruction is the precursor of the growth of graphene and it persists at the interface upon the growth of few layer graphene (FLG). The $(6\sqrt{3}\ifmmode\times\else\texttimes\fi{}6\sqrt{3})R30\ifmmode^\circ\else\textdegree\fi{}$ structure is a carbon layer with graphene-like atomic arrangement covalently bonded to the substrate where it is responsible for the azimuthal ordering of FLG on SiC(0001). In contrast, the interaction between graphene and the C-terminated $(000\overline{1})$ surface is much weaker, which accounts for the low degree of order of FLG on this surface. A model for the growth of FLG on SiC{0001} is developed, wherein each new graphene layer is formed at the bottom of the existing stack rather than on its top. This model yields, in conjunction with the differences in the interfacial bonding strength, a natural explanation for the different degrees of azimuthal order observed for FLG on the two surfaces.

Recapitulation of IVIG Anti-Inflammatory Activity with a Recombinant IgG Fc

Abstract: It is well established that high doses of monomeric immunoglobulin G (IgG) purified from pooled human plasma [intravenous immunoglobulin (IVIG)] confer anti-inflammatory activity in a variety of autoimmune settings. However, exactly how those effects are mediated is not clear because of the heterogeneity of IVIG. Recent studies have demonstrated that the anti-inflammatory activity of IgG is completely dependent on sialylation of the N-linked glycan of the IgG Fc fragment. Here we determine the precise glycan requirements for this anti-inflammatory activity, allowing us to engineer an appropriate IgG1 Fc fragment, and thus generate a fully recombinant, sialylated IgG1 Fc with greatly enhanced potency. This therapeutic molecule precisely defines the biologically active component of IVIG and helps guide development of an IVIG replacement with improved activity and availability.

Energy Spectrum of Cosmic-Ray Electrons at TeV Energies

Abstract: The very large collection area of ground-based gamma-ray telescopes gives them a substantial advantage over balloon/satellite based instruments in the detection of very-high-energy (>600 GeV) cosmic-ray electrons. Here we present the electron spectrum derived from data taken with the H.E.S.S. system of imaging atmospheric Cherenkov telescopes. In this measurement, the first of this type, we are able to extend the measurement of the electron spectrum beyond the range accessible to direct measurements. We find evidence for a substantial steepening in the energy spectrum above 600 GeV compared to lower energies.

Phanerozoic trends in the global diversity of marine invertebrates.

Abstract: It has previously been thought that there was a steep Cretaceous and Cenozoic radiation of marine invertebrates. This pattern can be replicated with a new data set of fossil occurrences representing 3.5 million specimens, but only when older analytical protocols are used. Moreover, analyses that employ sampling standardization and more robust counting methods show a modest rise in diversity with no clear trend after the mid-Cretaceous. Globally, locally, and at both high and low latitudes, diversity was less than twice as high in the Neogene as in the mid-Paleozoic. The ratio of global to local richness has changed little, and a latitudinal diversity gradient was present in the early Paleozoic.

Psoriasis is associated with increased beta-defensin genomic copy number.

Abstract: Psoriasis is a common inflammatory skin disease with a strong genetic component. We analyzed the genomic copy number polymorphism of the beta-defensin region on human chromosome 8 in 179 Dutch individuals with psoriasis and 272 controls and in 319 German individuals with psoriasis and 305 controls. Comparisons in both cohorts showed a significant association between higher genomic copy number for beta-defensin genes and risk of psoriasis.

The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis.

Abstract: Autoantibody-mediated diseases like myasthenia gravis, autoimmune hemolytic anemia and systemic lupus erythematosus represent a therapeutic challenge. In particular, long-lived plasma cells producing autoantibodies resist current therapeutic and experimental approaches. Recently, we showed that the sensitivity of myeloma cells toward proteasome inhibitors directly correlates with their immunoglobulin synthesis rates. Therefore, we hypothesized that normal plasma cells are also hypersensitive to proteasome inhibition owing to their extremely high amount of protein biosynthesis. Here we show that the proteasome inhibitor bortezomib, which is approved for the treatment of multiple myeloma, eliminates both short- and long-lived plasma cells by activation of the terminal unfolded protein response. Treatment with bortezomib depleted plasma cells producing antibodies to double-stranded DNA, eliminated autoantibody production, ameliorated glomerulonephritis and prolonged survival of two mouse strains with lupus-like disease, NZB/W F1 and MRL/lpr mice. Hence, the elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases.

Cardiac computed tomography: Indications, applications, limitations, and training requirements - Report of a Writing Group deployed by the Working Group Nuclear Cardiology and Cardiac CT of the European Society of Cardiology and the European Council of Nuclear Cardiology

Abstract: As a consequence of improved technology, there is growing clinical interest in the use of multi-detector row computed tomography (MDCT) for non-invasive coronary angiography. Indeed, the accuracy of MDCT to detect or exclude coronary artery stenoses has been high in many published studies. This report of a Writing Group deployed by the Working Group Nuclear Cardiology and Cardiac CT (WG 5) of the European Society of Cardiology and the European Council of Nuclear Cardiology summarizes the present state of cardiac CT technology, as well as the currently available data concerning its accuracy and applicability in certain clinical situations. Besides coronary CT angiography, the use of CT for the assessment of cardiac morphology and function, evaluation of perfusion and viability, and analysis of heart valves is discussed. In addition, recommendations for clinical applications of cardiac CT imaging are given and limitations of the technique are described.

Induction of inflammatory and immune responses by HMGB1–nucleosome complexes: implications for the pathogenesis of SLE

Abstract: Autoantibodies against double-stranded DNA (dsDNA) and nucleosomes represent a hallmark of systemic lupus erythematosus (SLE). However, the mechanisms involved in breaking the immunological tolerance against these poorly immunogenic nuclear components are not fully understood. Impaired phagocytosis of apoptotic cells with consecutive release of nuclear antigens may contribute to the immune pathogenesis. The architectural chromosomal protein and proinflammatory mediator high mobility group box protein 1 (HMGB1) is tightly attached to the chromatin of apoptotic cells. We demonstrate that HMGB1 remains bound to nucleosomes released from late apoptotic cells in vitro. HMGB1–nucleosome complexes were also detected in plasma from SLE patients. HMGB1-containing nucleosomes from apoptotic cells induced secretion of interleukin (IL) 1β, IL-6, IL-10, and tumor necrosis factor (TNF) α and expression of costimulatory molecules in macrophages and dendritic cells (DC), respectively. Neither HMGB1-free nucleosomes from viable cells nor nucleosomes from apoptotic cells lacking HMGB1 induced cytokine production or DC activation. HMGB1-containing nucleosomes from apoptotic cells induced anti-dsDNA and antihistone IgG responses in a Toll-like receptor (TLR) 2–dependent manner, whereas nucleosomes from living cells did not. In conclusion, HMGB1–nucleosome complexes activate antigen presenting cells and, thereby, may crucially contribute to the pathogenesis of SLE via breaking the immunological tolerance against nucleosomes/dsDNA.

Anti-Inflammatory Actions of Intravenous Immunoglobulin

Abstract: The remarkable success story of the therapeutic application of pooled immunoglobulin G (IgG) preparations from thousands of donors, the so-called intravenous IgG (IVIG) therapy, to patients with a variety of hematological and immunological disorders began more than half a century ago. Since then, the use of this primary blood product has increased constantly, resulting in the serious danger of shortages in supply. Despite its widespread use and therapeutic success, the mechanisms of action, especially of the anti-inflammatory activity, are only beginning to be understood. In this review, we summarize the clinical use of IVIG for different diseases and discuss recent data on the molecular mechanisms that might explain how this potent drug mediates its activity in vivo.

Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism

Abstract: HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.

The Antiviral Activities of Artemisinin and Artesunate

Abstract: Traditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history. Our own interest in natural products from traditional Chinese medicine was triggered in the 1990s, by artemisinin-type sesquiterpene lactones from Artemisia annua L. As demonstrated in recent years, this class of compounds has activity against malaria, cancer cells, and schistosomiasis. Interestingly, the bioactivity of artemisinin and its semisynthetic derivative artesunate is even broader and includes the inhibition of certain viruses, such as human cytomegalovirus and other members of the Herpesviridae family (e.g., herpes simplex virus type 1 and Epstein-Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral diarrhea virus. Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile pharmacological tools from nature.

Supramolecular coordination chemistry: the synergistic effect of serendipity and rational design.

Abstract: Supramolecular coordination compounds bear exceptional advantages over their organic counterparts. They are available in one-pot reactions and in high yields and display physical properties that are generally inaccessible with organic species. Moreover, their weak, reversible, noncovalent bonding interactions facilitate error checking and self-correction. This Review emphasizes the achievements in supramolecular coordination chemistry initiated by serendipity and their materialization based on rational design. The recognition of similarities in the synthesis of different supramolecular assemblies allows prediction of potential results in related cases. Supramolecular synthesis obeys guidelines comparable to the "lead sheet" used by small jazz ensembles for improvisation and therefore more often leads to unpredicted results. The combination of detailed symmetry considerations with the basic rules of coordination chemistry has only recently allowed for the design of rational strategies for the construction of a variety of nanosized systems with specified size and shape.

Coherent Equalization and POLMUX-RZ-DQPSK for Robust 100-GE Transmission

Abstract: We discuss the use of a coherent digital receiver for the compensation of linear transmission impairments and polarization demultiplexing in a transmission system compatible with a future 100-Gb/s Ethernet standard. We present experimental results on the transmission performance of 111 Gbit/s POLMUX-RZ-DQPSK. For a dense WDM setup with channels carrying 111 Gbit/s with a 50 GHz channel spacing (2.0 bits/s/Hz), we show the feasibility of 2375 km transmission. This is enabled through coherent detection which results in excellent noise performance, and subsequent electronic equalization which provides the high tolerance to polarization mode dispersion and chromatic dispersion (CD). Furthermore, we discuss the impact of sampling and digital signal processing with either 1 or 2 samples/bit. We show that when combined with low-pass electrical filtering, 1 sample/bit signal processing is sufficient to obtain a large tolerance towards CD. The proposed modulation and detection techniques enable 111 Gbit/s transmission that is directly compatible with the existing 10 Gbit/s infrastructure.

Reversal of pathological pain through specific spinal GABAA receptor subtypes.

Abstract: Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.

Feast or famine: the global regulator DasR links nutrient stress to antibiotic production by Streptomyces

Abstract: Members of the soil‐dwelling prokaryotic genus Streptomyces produce many secondary metabolites, including antibiotics and anti‐tumour agents. Their formation is coupled with the onset of development, which is triggered by the nutrient status of the habitat. We propose the first complete signalling cascade from nutrient sensing to development and antibiotic biosynthesis. We show that a high concentration of N ‐acetylglucosamine—perhaps mimicking the accumulation of N ‐acetylglucosamine after autolytic degradation of the vegetative mycelium—is a major checkpoint for the onset of secondary metabolism. The response is transmitted to antibiotic pathway‐specific activators through the pleiotropic transcriptional repressor DasR, the regulon of which also includes all N ‐acetylglucosamine‐related catabolic genes. The results allowed us to devise a new strategy for activating pathways for secondary metabolite biosynthesis. Such ‘cryptic’ pathways are abundant in actinomycete genomes, thereby offering new prospects in the fight against multiple drug‐resistant pathogens and cancers.

Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism

Abstract: Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).