Showing papers by "Heidelberg University published in 2004"
TL;DR: Recent findings indicate that network oscillations bias input selection, temporally link neurons into assemblies, and facilitate synaptic plasticity, mechanisms that cooperatively support temporal representation and long-term consolidation of information.
Abstract: Clocks tick, bridges and skyscrapers vibrate, neuronal networks oscillate. Are neuronal oscillations an inevitable by-product, similar to bridge vibrations, or an essential part of the brain’s design? Mammalian cortical neurons form behavior-dependent oscillating networks of various sizes, which span five orders of magnitude in frequency. These oscillations are phylogenetically preserved, suggesting that they are functionally relevant. Recent findings indicate that network oscillations bias input selection, temporally link neurons into assemblies, and facilitate synaptic plasticity, mechanisms that cooperatively support temporal representation and long-term consolidation of information.
5,512 citations
TL;DR: Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.
Abstract: background The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results. methods In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation. results The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors. conclusions Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.
2,436 citations
TL;DR: The study of iron biology has provided novel insights into gene regulation and unveiled remarkable links to the immune system.
1,687 citations
TL;DR: In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.
1,473 citations
TL;DR: Highly sensitive nanotubular structures formed de novo between cells that create complex networks facilitate the selective transfer of membrane vesicles and organelles but seem to impede the flow of small molecules are described.
Abstract: Cell-to-cell communication is a crucial prerequisite for the development and maintenance of multicellular organisms. To date, diverse mechanisms of intercellular exchange of information have been documented, including chemical synapses, gap junctions, and plasmodesmata. Here, we describe highly sensitive nanotubular structures formed de novo between cells that create complex networks. These structures facilitate the selective transfer of membrane vesicles and organelles but seem to impede the flow of small molecules. Accordingly, we propose a novel biological principle of cell-to-cell interaction based on membrane continuity and intercellular transfer of organelles.
1,471 citations
TL;DR: Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperative nausea and vomiting by about 26 percent, and the safest or least expensive antiemetic interventions should be used first.
Abstract: background Untreated, one third of patients who undergo surgery will have postoperative nausea and vomiting. Although many trials have been conducted, the relative benefits of prophylactic antiemetic interventions given alone or in combination remain unknown. methods We enrolled 5199 patients at high risk for postoperative nausea and vomiting in a randomized, controlled trial of factorial design that was powered to evaluate interactions among as many as three antiemetic interventions. Of these patients, 4123 were randomly assigned to 1 of 64 possible combinations of six prophylactic interventions: 4 mg of ondansetron or no ondansetron; 4 mg of dexamethasone or no dexamethasone; 1.25 mg of droperidol or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly assigned with respect to the first four interventions. The primary outcome was nausea and vomiting within 24 hours after surgery, which was evaluated blindly. results Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperative nausea and vomiting by about 26 percent. Propofol reduced the risk by 19 percent, and nitrogen by 12 percent; the risk reduction with both of these agents (i.e., total intravenous anesthesia) was thus similar to that observed with each of the antiemetics. All the interventions acted independently of one another and independently of the patients’ baseline risk. Consequently, the relative risks associated with the combined interventions could be estimated by multiplying the relative risks associated with each intervention. Absolute risk reduction, though, was a critical function of patients’ baseline risk. conclusions Because antiemetic interventions are similarly effective and act independently, the safest or least expensive should be used first. Prophylaxis is rarely warranted in low-risk patients, moderate-risk patients may benefit from a single intervention, and multiple interventions should be reserved for high-risk patients.
1,210 citations
TL;DR: The ability of the PHQ-9 to detect depression outcome and changes over time is demonstrated in three groups of patients whose depression status either improved, remained unchanged, or deteriorated over time.
1,207 citations
1,167 citations
TL;DR: Current ideas on the protein and DNA components of this transcriptional memory system are reviewed and how they interact dynamically with each other to orchestrate cellular memory for several hundred genes are reviewed.
Abstract: During the development of multicellular organisms, cells become different from one another by changing their genetic program in response to transient stimuli. Long after the stimulus is gone, "cellular memory" mechanisms enable cells to remember their chosen fate over many cell divisions. The Polycomb and Trithorax groups of proteins, respectively, work to maintain repressed or active transcription states of developmentally important genes through many rounds of cell division. Here we review current ideas on the protein and DNA components of this transcriptional memory system and how they interact dynamically with each other to orchestrate cellular memory for several hundred genes.
1,050 citations
TL;DR: The PHQ-9 has now proven to be a responsive and reliable measure of depression treatment outcomes and an attractive tool for gauging response to treatment in individual patient care as well as in clinical research.
Abstract: Background:Although effective treatment of depressed patients requires regular follow-up contacts and symptom monitoring, an efficient method for assessing treatment outcome is lacking. We investigated responsiveness to treatment, reproducibility, and minimal clinically important difference of the P
1,042 citations
Vanderbilt University1, University of Southern California2, University of Texas MD Anderson Cancer Center3, University of Wisconsin-Madison4, University of California, Los Angeles5, National Center for Genome Resources6, Portland VA Medical Center7, University of Colorado Boulder8, University of Pennsylvania9, Hannover Medical School10, Johns Hopkins University11, Oregon Health & Science University12, Cornell University13, University of Michigan14, University of Tennessee Health Science Center15, Washington University in St. Louis16, University of Toronto17, University of Memphis18, Medical Research Council19, University of Massachusetts Medical School20, Hebrew University of Jerusalem21, Université de Montréal22, Purdue University23, University of California, Davis24, Academy of Sciences of the Czech Republic25, University at Buffalo26, Emory University27, University of Cincinnati28, University of Texas Southwestern Medical Center29, New York University30, University of Groningen31, Rutgers University32, Stanford University33, Max Planck Society34, National Institutes of Health35, University of Alabama at Birmingham36, International Livestock Research Institute37, Heidelberg University38, Medical College of Wisconsin39, Icahn School of Medicine at Mount Sinai40, Oak Ridge National Laboratory41, Charité42, University of Antwerp43, RWTH Aachen University44, Paul Sabatier University45, University of California, San Francisco46, McGill University47, Pasteur Institute48, University of Western Australia49, Yale University50, University of Oxford51, Case Western Reserve University52, Roswell Park Cancer Institute53, University of Kentucky54, University of Helsinki55, University of Nebraska–Lincoln56, Harvard University57, Merck & Co.58, King's College London59, Northwestern University60, Shriners Hospitals for Children61, Thomas Jefferson University62, Novartis63, University of North Carolina at Chapel Hill64, Southern Illinois University Carbondale65, University of Rochester66
TL;DR: The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way the authors approach human health and disease.
Abstract: The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.
TL;DR: A new high-resolution structure is reported for bovine rhodopsin, the visual pigment in rod photoreceptor cells, and a theoretical study of the chromophore geometry has been carried out using combined quantum mechanics/force field molecular dynamics.
TL;DR: The continuing risk for lymphoma with time post‐transplantation, the contribution of immunosuppression to increased risk, and continuing poor outcomes in patients with post-transplant lymphoma are highlighted.
TL;DR: All three questionnaires performed well in depression screening, but significant differences in criterion validity existed; these results may be helpful in the selection of questionnaires and cut-off points.
TL;DR: This work investigated whether cells with MSC characteristics and multi‐lineage differentiation potential can be cultivated from UCB of healthy newborns and whether yields might be maximized by optimal culture conditions or by defining UCB quality criteria.
Abstract: Evidence has emerged that mesenchymal stem cells (MSCs) represent a promising population for supporting new clinical concepts in cellular therapy. However, attempts to isolate MSCs from umbilical cord blood (UCB) of full-term deliveries have previously either failed or been characterized by a low yield. We investigated whether cells with MSC characteristics and multi-lineage differentiation potential can be cultivated from UCB of healthy newborns and whether yields might be maximized by optimal culture conditions or by defining UCB quality criteria. Using optimized isolation and culture conditions, in up to 63% of 59 low-volume UCB units, cells showing a characteristic mesenchymal morphology and immune phenotype (MSC-like cells) were isolated. These were similar to control MSCs from adult bone marrow (BM). The frequency of MSC-like cells ranged from 0 to 2.3 clones per 1 x 10(8) mononuclear cells (MNCs). The cell clones proliferated extensively with at least 20 population doublings within eight passages. In addition, osteogenic and chondrogenic differentiation demonstrated a multi-lineage capacity comparable with BM MSCs. However, in contrast to MSCs, MSC-like cells showed a reduced sensitivity to undergo adipogenic differentiation. Crucial points to isolate MSC-like cells from UCB were a time from collection to isolation of less than 15 hours, a net volume of more than 33 ml, and an MNC count of more than 1 x 10(8) MNCs. Because MSC-like cells can be isolated at high efficacy from full-term UCB donations, we regard UCB as an additional stem cell source for experimental and potentially clinical purposes.
TL;DR: Observations from animal models and clinical trials that suggest benefit from an antihypertrophic strategy are summarized and signaling pathways that hold promise as potential targets for therapeutic intervention are focused on.
Abstract: Recent studies call into question the necessity of hypertrophic growth of the heart as a "compensatory" response to hemodynamic stress. These findings, coupled with recent progress in dissecting the molecular bases of hypertrophy, raise the prospect of suppressing hypertrophy without provoking circulatory insufficiency. In this article, we focus on signaling pathways that hold promise as potential targets for therapeutic intervention. We also summarize observations from animal models and clinical trials that suggest benefit from an antihypertrophic strategy.
TL;DR: Findings suggest that cytotoxic and vasogenic brain edema are two entities which can be targeted simultaneously or according to their temporal prevalence following traumatic brain injury.
TL;DR: A high-throughput RNA-interference screen of 19,470 double-stranded RNAs in cultured cells to characterize the function of nearly all predicted Drosophila genes in cell growth and viability found 438 dsRNAs that identified essential genes, among which 80% lacked mutant alleles.
Abstract: A crucial aim upon completion of whole genome sequences is the functional analysis of all predicted genes. We have applied a high-throughput RNA-interference (RNAi) screen of 19,470 double-stranded (ds) RNAs in cultured cells to characterize the function of nearly all (91%) predicted Drosophila genes in cell growth and viability. We found 438 dsRNAs that identified essential genes, among which 80% lacked mutant alleles. A quantitative assay of cell number was applied to identify genes of known and uncharacterized functions. In particular, we demonstrate a role for the homolog of a mammalian acute myeloid leukemia gene (AML1) in cell survival. Such a systematic screen for cell phenotypes, such as cell viability, can thus be effective in characterizing functionally related genes on a genome-wide scale.
TL;DR: Two novel structural concepts have emerged during the past two years which have led literally to an explosion of the field of chiral NHC catalysts for stereoselective transformations in organic synthesis.
Abstract: In recent years, N-heterocyclic carbenes (NHC) have proved to be a versatile class of spectator ligands in homogeneous catalysis. Being robust anchoring functions for late transition metals, their ligand donor capacity and their molecular shape is readily modified by variation of the substituents at the N-atoms and the structure of the cyclic backbone. After the first attempts to use chiral NHC ligands in asymmetric catalysis in the late 1990's, which initially met with limited success, several novel structural concepts have emerged during the past two years which have led literally to an explosion of the field. With a significant number of highly selective chiral catalysts based on chiral NHCs having been reported very recently, several general trends in the design of new NHC-containing molecular catalysts for stereoselective transformations in organic synthesis emerge.
TL;DR: In this paper, the authors focus on recent findings vis-a-vis titin's molecular spring segments in cardiac titins and discuss new insights regarding the role of titin as a biomechanical sensor and signaling molecule.
Abstract: The sarcomere contains, in addition to thin and thick filaments, a filament composed of the giant protein titin (also known as connectin). Titin molecules anchor in the Z-disc and extend to the M-line region of the sarcomere. The majority of titin’s I-band region functions as a molecular spring. This spring maintains the precise structural arrangement of thick and thin filaments, and gives rise to passive muscle stiffness; an important determinant of diastolic filling. Earlier work on titin has been reviewed before. In this study, our main focus is on recent findings vis-a-vis titin’s molecular spring segments in cardiac titins, including the discovery of fetal cardiac isoforms with novel spring elements. We also discuss new insights regarding the role of titin as a biomechanical sensor and signaling molecule. We will end with focusing on the rapidly growing knowledge regarding titinopathies.
TL;DR: Doppler ultrasound measurement for ABI determinations is a non-invasive, inexpensive, reliable tool in primary care and enables GPs to identify patients at risk of PAD, particularly with regard to other manifestations of atherothrombosis.
TL;DR: The basic theory required to understand and describe conical, and related, intersections is reviewed and an example is given using wavepacket dynamics simulations to demonstrate the prototypical features of how a molecular system passes through a conical intersection.
Abstract: Nonadiabatic effects play an important role in many areas of physics and chemistry. The coupling between electrons and nuclei may, for example, lead to the formation of a conical intersection between potential energy surfaces, which provides an efficient pathway for radiationless decay between electronic states. At such intersections the Born-Oppenheimer approximation breaks down, and unexpected dynamical processes result, which can be observed spectroscopically. We review the basic theory required to understand and describe conical, and related, intersections. A simple model is presented, which can be used to classify the different types of intersections known. An example is also given using wavepacket dynamics simulations to demonstrate the prototypical features of how a molecular system passes through a conical intersection.
TL;DR: The most important properties of 6-hydroxy-dopamine and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models are discussed.
Abstract: Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinson’s disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the human disease. PD is characterized by massive degeneration of dopaminergic neurons in the substantia nigra, the loss of striatal dopaminergic fibers and a dramatic reduction of the striatal dopamine levels. The formation of cytoplasmic inclusion bodies (Lewy bodies) in surviving dopaminergic neurons represents the most important neuropathological feature of PD. Furthermore, the massive striatal dopamine deficiency causes easily detectable motor deficits in PD patients, including bradykinesia, rigidity, and resting tremor, which are the cardinal symptoms of PD. Over the years, a broad variety of experimental models of PD were developed and applied in diverse species. This review focuses on the two most common “classical” toxin-induced PD models, the 6-hydroxy-dopamine (6-OHDA model) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models. This review discusses the most important properties of 6-OHDA and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models. The new genetic and environmental toxin models of PD (e.g. rotenone, paraquat, maneb) are discussed elsewhere in this “special issue.”
TL;DR: Novel insights are provided into the mechanisms of how pericytes may provide escape strategies to anti‐angiogenic therapies and novel concepts that target not only endothelial cells but also pericyte‐associated pathways involved in vascular stabilization and maturation exert potent anti‐vascular effects are provided.
Abstract: Destruction of existing tumor blood vessels may be achieved by targeting vascular endothelial growth factor (VEGF) signaling, which mediates not only endothelial cell proliferation but also endothelial cell survival. In this study, however, intravital microscopy failed to demonstrate that targeting of VEGFR-2 (by the tyrosine kinase inhibitor SU5416) induces significant regression of experimental tumor blood vessels. Immunohistochemistry, electron microscopy, expression analyses, and in situ hybridization provide evidence that this resistance of tumor blood vessels to VEGFR-2 targeting is conferred by pericytes that stabilize blood vessels and provide endothelial cell survival signals via the Ang-1/Tie2 pathway. In contrast, targeting VEGFR-2 plus the platelet-derived growth factor receptor (PDGFR)-beta system (PDGFR-beta) signaling (by SU6668) rapidly forced 40% of tumor blood vessels into regression, rendering these tumors hypoxic as shown by phosphorescence quenching. TUNEL staining, electron microscopy, and apoptosis blocking experiments suggest that VEGFR-2 plus PDGFR-beta targeting enforced tumor blood vessel regression by inducing endothelial cell apoptosis. We further show that this is achieved by an interference with pericyte-endothelial cell interaction. This study provides novel insights into the mechanisms of how 1) pericytes may provide escape strategies to anti-angiogenic therapies and 2) novel concepts that target not only endothelial cells but also pericyte-associated pathways involved in vascular stabilization and maturation exert potent anti-vascular effects.
TL;DR: This work considers how the protective function of NMD sometimes benefits heterozygous carriers and, in contrast, sometimes contributes to a clinical picture of protein deficiency by inhibiting expression of partially functional proteins.
Abstract: Nonsense-mediated decay (NMD) eliminates mRNAs containing premature termination codons and thus helps limit the synthesis of abnormal proteins. New results uncover a broader role of NMD as a pathway that also affects the expression of wild-type genes and alternative-splice products. Because the mechanisms by which NMD operates have received much attention, we discuss here the emerging awareness of the impact of NMD on the manifestation of human genetic diseases. We explore how an understanding of NMD accounts for phenotypic differences in diseases caused by premature termination codons. Specifically, we consider how the protective function of NMD sometimes benefits heterozygous carriers and, in contrast, sometimes contributes to a clinical picture of protein deficiency by inhibiting expression of partially functional proteins. Potential 'NMD therapeutics' will therefore need to strike a balance between the general physiological benefits of NMD and its detrimental effects in cases of specific genetic mutations.
TL;DR: This pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues.
Abstract: Animal experiments have provided evidence that the striatum and medial prefrontal cortex play a predominant role in the acquisition and maintenance of drug-seeking behavior. Alcohol-associated stimuli that were regularly paired with alcohol intake may become conditioned cues and elicit a motivational response that triggers relapse in alcohol-dependent patients. We used functional magnetic resonance imaging and visual alcohol-associated and control cues to assess brain activation in ten abstinent alcoholics and control subjects. Patients were followed for 3 months, and alcohol intake was recorded. Alcohol-related versus neutral visual stimuli activated the putamen, anterior cingulate and adjacent medial prefrontal cortex in alcoholics compared with healthy controls. Cue-induced activation of these brain areas was pronounced in the five alcoholics who subsequently relapsed during the observation period. A multiple regression analysis showed that, in alcoholics, the amount of subsequent alcohol intake was associated with the intensity of cue-induced brain activation but not the severity of alcohol craving, amount of previous alcohol intake or duration of abstinence before scanning. This pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues. Functional brain imaging may help to identify a group of alcoholics with an otherwise undetected high risk of relapse.
TL;DR: The first experimental observation of bright matter wavesolitons for 87Rb atoms with repulsive atom-atom interaction is reported, allowing the systematic investigation of gap solitons.
Abstract: We report on the first experimental observation of bright matter wave solitons for $^{87}\mathrm{Rb}$ atoms with repulsive atom-atom interaction. This counterintuitive situation arises inside a weak periodic potential, where anomalous dispersion can be realized at the Brillouin zone boundary. If the coherent atomic wave packet is prepared at the corresponding band edge, a bright soliton is formed inside the gap. The strength of our system is the precise control of preparation and real time manipulation, allowing the systematic investigation of gap solitons.
TL;DR: The consensus concludes that there is no need to ‘treat IMT values’ nor to monitor IMTvalues in individual patients apart from few exceptions and that IMT does not fulfill the characteristics of an accepted risk factor.
Abstract: Intima-media thickness (IMT) is increasingly used in clinical trials as a surrogate end point for determining the success of interventions that lower risk factors for atherosclerosis. The necessity for unified criteria to distinguish early atherosclerotic plaque formation from thickening of IMT and to standardize IMT measurements is addressed in this consensus statement. Plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness of > or =1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. Standard use of IMT measurements is recommended in all epidemiological and interventional trials dealing with vascular diseases to improve characterization of the population investigated. The consensus concludes that there is no need to 'treat IMT values' nor to monitor IMT values in individual patients apart from few exceptions. Although IMT has been suggested to represent an important risk marker, it does not fulfill the characteristics of an accepted risk factor. Standardized methods recommended in this consensus statement will foster homogenous data collection and analysis. This will help to improve the power of studies incorporating IMT measurements and to facilitate the merging of large databases for meta-analyses.
TL;DR: A proof-of-principle demonstration of five-photon entanglement and open-destination teleportation and can be used for investigations of measurement-based quantum computation and multi-party quantum communication.
Abstract: Quantum-mechanical entanglement of three or four particles has been achieved experimentally, and has been used to demonstrate the extreme contradiction between quantum mechanics and local realism. However, the realization of five-particle entanglement remains an experimental challenge. The ability to manipulate the entanglement of five or more particles is required for universal quantum error correction. Another key process in distributed quantum information processing, similar to encoding and decoding, is a teleportation protocol that we term 'open-destination' teleportation. An unknown quantum state of a single particle is teleported onto a superposition of N particles; at a later stage, this teleported state can be read out (for further applications) at any of the N particles, by a projection measurement on the remaining particles. Here we report a proof-of-principle demonstration of five-photon entanglement and open-destination teleportation (for N = 3). In the experiment, we use two entangled photon pairs to generate a four-photon entangled state, which is then combined with a single-photon state. Our experimental methods can be used for investigations of measurement-based quantum computation and multi-party quantum communication.
TL;DR: Using a battery of behavioral tests after termination of the stress procedure, it is found that anhedonia, but not chronic stress per se, is associated with key analogues of depressive symptoms, such as increased floating during forced swimming and decreased exploration of novelty.