Showing papers by "Heidelberg University published in 2007"
TL;DR: A large primary carebased anxiety study is analyzed to ascertain commonalities among anxiety diagnoses that are traditionally considered to be discrete and to determine whether a single measure can be used as a first step, common metric.
Abstract: Anxiety is as common as depression; however, it has received less attention and is often undetected and undertreated. The authors administered a 7-item anxiety scale to 965 primary care patients, w...
3,090 citations
TL;DR: Important vinylgold intermediates, the transmetalation from gold to other transition metals, the development of new ligands for gold catalysis, and significant contributions from computational chemistry are other crucial points for the field highlighted here.
Abstract: Although homogeneous gold catalysis was known previously, an exponential growth was only induced 12 years ago. The key findings which induce that rise of the field are discussed. This includes early reactions of allenes and furanynes and intermediates of these conversions as well as hydroarylation reactions. Other substrate types addressed are alkynyl epoxides and N-propargyl carboxamides. Important vinylgold intermediates, the transmetalation from gold to other transition metals, the development of new ligands for gold catalysis, and significant contributions from computational chemistry are other crucial points for the field highlighted here.
2,792 citations
TL;DR: The International Study Group of Pancreatic Surgery (ISGPS) developed an objective and generally applicable definition with grades of delayed gastric emptying (DGE) based primarily on severity and clinical impact as discussed by the authors.
2,150 citations
TL;DR: These data confirm that intravenous alteplase is safe and effective in routine clinical use when used within 3 h of stroke onset, even by centres with little previous experience of thrombolytic therapy for acute stroke.
1,861 citations
TL;DR: An objective, universally accepted definition and clinical grading of PPH is important for the appropriate management and use of interventions in PPH and would allow comparisons of results from future clinical trials.
1,790 citations
TL;DR: In patients with malignant MCA infarction, decompressive surgery undertaken within 48 h of stroke onset reduces mortality and increases the number of patients with a favourable functional outcome.
Abstract: Summary Background Malignant infarction of the middle cerebral artery (MCA) is associated with an 80% mortality rate. Non-randomised studies have suggested that decompressive surgery reduces this mortality without increasing the number of severely disabled survivors. To obtain sufficient data as soon as possible to reliably estimate the effects of decompressive surgery, results from three European randomised controlled trials (DECIMAL, DESTINY, HAMLET) were pooled. The trials were ongoing when the pooled analysis was planned. Methods Individual data for patients aged between 18 years and 60 years, with space-occupying MCA infarction, included in one of the three trials, and treated within 48 h after stroke onset were pooled for analysis. The protocol was designed prospectively when the trials were still recruiting patients and outcomes were defined without knowledge of the results of the individual trials. The primary outcome measure was the score on the modified Rankin scale (mRS) at 1 year dichotomised between favourable (0–4) and unfavourable (5 and death) outcome. Secondary outcome measures included case fatality rate at 1 year and a dichotomisation of the mRS between 0–3 and 4 to death. Data analysis was done by an independent data monitoring committee. Findings 93 patients were included in the pooled analysis. More patients in the decompressive-surgery group than in the control group had an mRS≤4 (75% vs 24%; pooled absolute risk reduction 51% [95% CI 34–69]), an mRS≤3 (43% vs 21%; 23% [5–41]), and survived (78% vs 29%; 50% [33–67]), indicating numbers needed to treat of two for survival with mRS≤4, four for survival with mRS≤3, and two for survival irrespective of functional outcome. The effect of surgery was highly consistent across the three trials. Interpretation In patients with malignant MCA infarction, decompressive surgery undertaken within 48 h of stroke onset reduces mortality and increases the number of patients with a favourable functional outcome. The decision to perform decompressive surgery should, however, be made on an individual basis in every patient.
1,502 citations
TL;DR: Imaging of collectively invading cocultures of carcinoma cells and stromal fibroblasts reveals that the leading cell is always a fibroblast and that carcinomas cells move within tracks in the extracellular matrix behind the fibro Blast.
Abstract: Imaging of collectively invading cocultures of carcinoma cells and stromal fibroblasts reveals that the leading cell is always a fibroblast and that carcinoma cells move within tracks in the extracellular matrix behind the fibroblast. The generation of these tracks by fibroblasts is sufficient to enable the collective invasion of the squamous cell carcinoma (SCC) cells and requires both protease- and force-mediated matrix remodelling. Force-mediated matrix remodelling depends on integrins alpha3 and alpha5, and Rho-mediated regulation of myosin light chain (MLC) activity in fibroblasts, but these factors are not required in carcinoma cells. Instead, carcinoma cells use Cdc42 and MRCK (myotonic dystrophy kinase-related CDC42-binding protein kinases) mediated regulation of MLC to follow the tracks generated by fibroblasts.
1,375 citations
TL;DR: HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9–MyD88 pathway involving the multivalent receptor RAGE.
Abstract: Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9-MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.
1,303 citations
TL;DR: A novel function of LDs is revealed in the assembly of infectious HCV and a new perspective on how viruses usurp cellular functions is provided.
Abstract: The lipid droplet (LD) is an organelle that is used for the storage of neutral lipids. It dynamically moves through the cytoplasm, interacting with other organelles, including the endoplasmic reticulum (ER). These interactions are thought to facilitate the transport of lipids and proteins to other organelles. The hepatitis C virus (HCV) is a causative agent of chronic liver diseases. HCV capsid protein (Core) associates with the LD, envelope proteins E1 and E2 reside in the ER lumen, and the viral replicase is assumed to localize on ER-derived membranes. How and where HCV particles are assembled, however, is poorly understood. Here, we show that the LD is involved in the production of infectious virus particles. We demonstrate that Core recruits nonstructural (NS) proteins and replication complexes to LD-associated membranes, and that this recruitment is critical for producing infectious viruses. Furthermore, virus particles were observed in close proximity to LDs, indicating that some steps of virus assembly take place around LDs. This study reveals a novel function of LDs in the assembly of infectious HCV and provides a new perspective on how viruses usurp cellular functions.
1,197 citations
TL;DR: Alcohol-related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility.
Abstract: Approximately 3.6% of cancers worldwide derive from chronic alcohol drinking, including those of the upper aerodigestive tract, the liver, the colorectum and the breast. Although the mechanisms for alcohol-associated carcinogenesis are not completely understood, most recent research has focused on acetaldehyde, the first and most toxic ethanol metabolite, as a cancer-causing agent. Ethanol may also stimulate carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. Alcohol-related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility.
940 citations
TL;DR: The underlying reaction based principles of transition-metal catalysis in multi-component syntheses of heterocycles, summarizes recent developments of palladium catalyzed MCR, and highlights the more recent contributions to MCR based heterocyclic synthesis by virtue of rhodium, ruthenium, and copper catalysis are outlined.
Abstract: For a long time multi-component syntheses of heterocycles have undeniably been a domain of classical carbonyl condensation chemistry. However, the advent of transition-metal catalysis not only has fertilized strategies in heterocyclic synthesis by uni- and bimolecular transformations but the past decade has also witnessed a rapid development of transition-metal catalysis in new multi-component reactions (MCR). Expectedly, palladium catalyzed processes have received a dominant position, yet, other transition-metal complexes are catching up implying organometallic elementary steps that reach even further than cross-coupling and carbometallation. Besides domino MCRs that are purely based upon organometallic catalysis the sequential and consecutive combination with condensation, addition and cycloaddition steps opens a vast playground for the invention of new sequences in heterocyclic synthesis. This tutorial review outlines the underlying reaction based principles of transition-metal catalysis in multi-component syntheses of heterocycles, summarizes recent developments of palladium catalyzed MCR, and highlights the more recent contributions to MCR based heterocyclic synthesis by virtue of rhodium, ruthenium, and copper catalysis.
TL;DR: This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.
Abstract: Background— Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. Methods and Results— Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Cavβ2b), CACNA2D1 (Cavα2δ1), and CACNA1C tagged with enhanced yellow fluorescent protein (Cav1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals ≤360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptati...
TL;DR: A step-by-step approach to percutaneous nephrolithotomy and its complications and management is focused on, with the most important consideration for achieving consistently successful outcomes in PNL with minimal major complications being the correct selection of patients.
Max Planck Society1, Centre national de la recherche scientifique2, Durham University3, North-West University4, Joseph Fourier University5, École Polytechnique6, Heidelberg University7, University of Erlangen-Nuremberg8, University of Hamburg9, University of Tübingen10, Humboldt University of Berlin11, Dublin Institute for Advanced Studies12, Charles University in Prague13, Yerevan Physics Institute14, Ruhr University Bochum15, University of Namibia16
TL;DR: In this paper, the average flux observed during an extreme gamma-ray outburst is I(>200 GeV) = (1.72$\pm$$0.05_{\rm stat}
Abstract: The high-frequency peaked BL Lac PKS 2155-304 at redshift z=0.116 is a well-known VHE (>100 GeV) gamma-ray emitter. Since 2002 its VHE flux has been monitored using the H.E.S.S. stereoscopic array of imaging atmospheric-Cherenkov telescopes in Namibia. During the July 2006 dark period, the average VHE flux was measured to be more than ten times typical values observed from the object. This article focuses solely on an extreme gamma-ray outburst detected in the early hours of July 28, 2006 (MJD 53944). The average flux observed during this outburst is I(>200 GeV) = (1.72$\pm$$0.05_{\rm stat}$$\pm$$0.34_{\rm syst}$) $\times$ 10$^{-9}$ cm$^{-2}$ s$^{-1}$, corresponding to ~7 times the flux, I(>200 GeV), observed from the Crab Nebula. Peak fluxes are measured with one-minute time scale resolution at more than twice this average value. Variability is seen up to ~600 s in the Fourier power spectrum, and well-resolved bursts varying on time scales of ~200 seconds are observed. There are no strong indications for spectral variability within the data. Assuming the emission region has a size comparable to the Schwarzschild radius of a ~10$^9 M_\odot$ black hole, Doppler factors greater than 100 are required to accommodate the observed variability time scales.
TL;DR: In this article, structural aspects of the functional renormalisation group are discussed, and a simple equation for the flow of these relations is provided, and the construction and analysis of truncation schemes in view of practical optimisation.
University of Texas MD Anderson Cancer Center1, University of Düsseldorf2, Sapienza University of Rome3, University of Bologna4, VU University Medical Center5, Royal Victoria Infirmary6, Mayo Clinic7, City of Hope National Medical Center8, Novartis9, Heidelberg University10, Humboldt University of Berlin11
TL;DR: Nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance and was effective in patients harboring BCR-ABL mutations associated with imatinIB resistance (except T315I), and also in Patients with a resistance mechanism independent of B CR-ABl mutations.
TL;DR: The transport of RNA molecules from the nucleus to the cytoplasm is fundamental for gene expression and understanding the mechanisms that connect RNP formation with export is a major challenge in the field.
Abstract: The transport of RNA molecules from the nucleus to the cytoplasm is fundamental for gene expression. The different RNA species that are produced in the nucleus are exported through the nuclear pore complexes via mobile export receptors. Small RNAs (such as tRNAs and microRNAs) follow relatively simple export routes by binding directly to export receptors. Large RNAs (such as ribosomal RNAs and mRNAs) assemble into complicated ribonucleoprotein (RNP) particles and recruit their exporters via class-specific adaptor proteins. Export of mRNAs is unique as it is extensively coupled to transcription (in yeast) and splicing (in metazoa). Understanding the mechanisms that connect RNP formation with export is a major challenge in the field.
Cleveland Clinic1, Heidelberg University2, New York University3, Women's College, Kolkata4, Brigham and Women's Hospital5, Brown University6, University of Western Australia7, University of California, San Francisco8, University of Rochester9, University of Kentucky10, SUNY Downstate Medical Center11, Case Western Reserve University12
TL;DR: In this analysis of the CHARISMA trial, the large number of patients with documented prior MI, ischemic stroke, or symptomatic PAD appeared to derive significant benefit from dual antiplatelet therapy with clopidogrel plus aspirin.
TL;DR: In this paper, Chandra measurements of the X-ray gas mass fraction (fgas )i n 42 hot (kT > 5 keV), Xray luminous, dynamically relaxed galaxy clusters spanning the redshift range 0.05 < z < 1.
Abstract: We present constraints on the mean matter density, � m, dark energy density, � DE, and the dark energy equation of state parameter, w, using Chandra measurements of the X-ray gas mass fraction (fgas )i n 42 hot (kT > 5 keV), X-ray luminous, dynamically relaxed galaxy clusters spanning the redshift range 0.05 < z < 1.1. Using only the fgas data for the six lowest redshift clusters at z < 0.15, for which dark energy has a negligible effect on the measurements, we measurem = 0.28 ± 0.06 (68 per cent confidence limits, using standard priors on the Hubble constant, H0, and mean baryon density, � b h 2 ). Analysing the data for all 42 clusters, employ- ing only weak priors on H0 andb h 2 , we obtain a similar result onm and a detection of the effects of dark energy on the distances to the clusters at ∼99.99 per cent confidence, with � DE = 0.86 ± 0.21 for a non-flatCDM model. The detection of dark energy is comparable in significance to recent type Ia supernovae (SNIa) studies and represents strong, independent evidence for cosmic acceleration. Systematic scatter remains undetected in the fgas data, despite a weighted mean statistical scatter in the distance measurements of only ∼5 per cent. For a flat cosmology with a constant dark energy equation of state, we measurem = 0.28 ± 0.06 and w =− 1.14 ± 0.31. Combining the fgas data with independent constraints from cosmic mi- crowave background and SNIa studies removes the need for priors onb h 2 and H0 and leads to tighter constraints: � m = 0.253 ± 0.021 and w =− 0.98 ± 0.07 for the same constant-w model. Our most general analysis allows the equation of state to evolve with redshift. Marginalizing over possible transition redshifts 0.05 < zt < 1, the combined fgas + CMB + SNIa data set constrains the dark energy equation of state at late and early times to be w0 =− 1.05 ± 0.29 and wet =− 0.83 ± 0.46, respectively, in agreement with the cosmological constant paradigm. Relaxing the assumption of flatness weakens the constraints on the equation of state by only a factor of ∼2. Our analysis includes conservative allowances for systematic uncertainties as- sociated with instrument calibration, cluster physics and data modelling. The measured small systematic scatter, tight constraint onm and powerful constraints on dark energy from the fgas data bode well for future dark energy studies using the next generation of powerful X-ray observatories, such as Constellation-X.
TL;DR: The experiments studying coherence dynamics show that 1D Bose gases are ideally suited for investigating one-dimensional systems, such as superconductors, quantum Hall systems, superfluid helium and spin systems.
Abstract: This paper reports a direct experimental study of the coherence dynamics in both isolated and coupled degenerate one-dimensional (1D) Bose gases. Completely isolated 1D Bose gases exhibit coherence decay in excellent agreement with recent predictions. The coherence of two coupled 1D Bose gases decays to a finite value, analogous to the phase locking of two lasers by injection. Low-dimensional systems provide beautiful examples of many-body quantum physics1. For one-dimensional (1D) systems2, the Luttinger liquid approach3 provides insight into universal properties. Much is known of the equilibrium state, both in the weakly4,5,6,7 and strongly8,9 interacting regimes. However, it remains a challenge to probe the dynamics by which this equilibrium state is reached10. Here we present a direct experimental study of the coherence dynamics in both isolated and coupled degenerate 1D Bose gases. Dynamic splitting is used to create two 1D systems in a phase coherent state11. The time evolution of the coherence is revealed through local phase shifts of the subsequently observed interference patterns. Completely isolated 1D Bose gases are observed to exhibit universal sub-exponential coherence decay, in excellent agreement with recent predictions12. For two coupled 1D Bose gases, the coherence factor is observed to approach a non-zero equilibrium value, as predicted by a Bogoliubov approach13. This coupled-system decay to finite coherence is the matter wave equivalent of phase-locking two lasers by injection. The non-equilibrium dynamics of superfluids has an important role in a wide range of physical systems, such as superconductors, quantum Hall systems, superfluid helium and spin systems14,15,16. Our experiments studying coherence dynamics show that 1D Bose gases are ideally suited for investigating this class of phenomena.
TL;DR: FGF23 is a novel independent predictor of progression of renal disease in patients with nondiabetic CKD after adjustment for age, gender, GFR, proteinuria, and serum levels of calcium, phosphate, and parathyroid hormone.
Abstract: It has not been firmly established whether disturbed calcium-phosphate metabolism affects progression of chronic kidney disease (CKD) in humans. In this cohort study of 227 nondiabetic patients with CKD, we assessed fibroblast growth factor 23 (FGF23) plasma concentrations in addition to other variables involved in calcium-phosphate metabolism, and we followed 177 of the patients prospectively for a median of 53 months to assess progression of renal disease. In the baseline cohort, we found a significant inverse correlation between glomerular filtration rate and both c-terminal and intact FGF23 levels (both P < 0.001). The 65 patients who experienced a doubling of serum creatinine and/or terminal renal failure were significantly older, had a significantly lower glomerular filtration rate at baseline, and significantly higher levels of intact parathormone, c-terminal and intact FGF23, and serum phosphate (all P < 0.001). Cox regression analysis revealed that both c-terminal and intact FGF23 independently predict progression of CKD after adjustment for age, gender, GFR, proteinuria, and serum levels of calcium, phosphate, and parathyroid hormone. The mean follow-up time to a progression end point was 46.9 (95% CI 40.2 to 53.6) months versus 72.5 (95% CI 67.7 to 77.3) months for patients with c-terminal FGF23 levels above or below the optimal cut-off level of 104 rU/mL (derived by receiver operator curve analysis), respectively. In conclusion, FGF23 is a novel independent predictor of progression of renal disease in patients with nondiabetic CKD. Its pathophysiological significance remains to be elucidated.
TL;DR: The results suggest that the observed activation is independent of the physiological states of hunger and satiation, and thus may contribute to pathological overeating and obesity.
TL;DR: The analysis of these various diseases suggests that IFs also have an important role in cell-type-specific physiological functions, and the nanomechanical properties of cell- type-specific IFs are central to the pathogenesis of diseases as diverse as muscular dystrophy and premature ageing.
Abstract: Intermediate filaments (IFs) constitute a major structural element of animal cells They build two distinct systems, one in the nucleus and one in the cytoplasm In both cases, their major function is assumed to be that of a mechanical stress absorber and an integrating device for the entire cytoskeleton In line with this, recent disease mutations in human IF proteins indicate that the nanomechanical properties of cell-type-specific IFs are central to the pathogenesis of diseases as diverse as muscular dystrophy and premature ageing However, the analysis of these various diseases suggests that IFs also have an important role in cell-type-specific physiological functions
TL;DR: The European Study Group on MRD detection in ALL (ESG-MRD-ALL), consisting of 30 MRD-PCR laboratories worldwide, has developed guidelines for the interpretation of real-time quantitative PCR-based MRD data.
Abstract: Most modern treatment protocols for acute lymphoblastic leukaemia (ALL) include the analysis of minimal residual disease (MRD). To ensure comparable MRD results between different MRD-polymerase chain reaction (PCR) laboratories, standardization and quality control are essential. The European Study Group on MRD detection in ALL (ESG-MRD-ALL), consisting of 30 MRD-PCR laboratories worldwide, has developed guidelines for the interpretation of real-time quantitative PCR-based MRD data. The application of these guidelines ensures identical interpretation of MRD data between different laboratories of the same MRD-based clinical protocol. Furthermore, the ESG-MRD-ALL guidelines will facilitate the comparison of MRD data obtained in different treatment protocols, including those with new drugs.
TL;DR: The finding that rhythmic mPer2 expression can be driven by both systemic cues and local oscillators suggests a plausible mechanism for the phase entrainment of subsidiary clocks in peripheral organs.
Abstract: The mammalian circadian timing system consists of a master pacemaker in neurons of the suprachiasmatic nucleus (SCN) and clocks of a similar molecular makeup in most peripheral body cells. Peripheral oscillators are self-sustained and cell autonomous, but they have to be synchronized by the SCN to ensure phase coherence within the organism. In principle, the rhythmic expression of genes in peripheral organs could thus be driven not only by local oscillators, but also by circadian systemic signals. To discriminate between these mechanisms, we engineered a mouse strain with a conditionally active liver clock, in which REV-ERBalpha represses the transcription of the essential core clock gene Bmal1 in a doxycycline-dependent manner. We examined circadian liver gene expression genome-wide in mice in which hepatocyte oscillators were either running or arrested, and found that the rhythmic transcription of most genes depended on functional hepatocyte clocks. However, we discovered 31 genes, including the core clock gene mPer2, whose expression oscillated robustly irrespective of whether the liver clock was running or not. By contrast, in liver explants cultured in vitro, circadian cycles of mPer2::luciferase bioluminescence could only be observed when hepatocyte oscillators were operational. Hence, the circadian cycles observed in the liver of intact animals without functional hepatocyte oscillators were likely generated by systemic signals. The finding that rhythmic mPer2 expression can be driven by both systemic cues and local oscillators suggests a plausible mechanism for the phase entrainment of subsidiary clocks in peripheral organs.
TL;DR: Recommendations for a stepped care approach that differentiates between uncomplicated and complicated FSS are given, and a balance between biomedical, organ-oriented, and cognitive interpersonal approaches is most appropriate at this truly psychosomatic interface.
TL;DR: It is demonstrated that clathrin-dependent endocytosis is operational in plants and constitutes the predominant pathway for the internalization of numerous plasma-membrane-resident proteins including PIN auxin efflux carriers.
TL;DR: The mechanism of action of imatinib in CML, the structural basis ofImatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance are described.
Abstract: Imatinib, a small-molecule ABL kinase inhibitor, is a highly effective therapy for early-phase chronic myeloid leukaemia (CML), which has constitutively active ABL kinase activity owing to the expression of the BCR-ABL fusion protein. However, there is a high relapse rate among advanced- and blast-crisis-phase patients owing to the development of mutations in the ABL kinase domain that cause drug resistance. Several second-generation ABL kinase inhibitors have been or are being developed for the treatment of imatinib-resistant CML. Here, we describe the mechanism of action of imatinib in CML, the structural basis of imatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance.
14 Mar 2007