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  • SpringerLink  (18)
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  • 1
    Language: English
    In: Current Neurology and Neuroscience Reports, 2011, Vol.11(3), pp.305-312
    Description: Antiangiogenic treatment has recently become an integral part of modern cancer therapy targeting the vasculature of numerous aggressive malignancies including glioblastoma. There is preclinical evidence that antiangiogenic therapies promote glioma cell invasiveness. In clinical series, upon progression on antiangiogenic therapy with the vascular endothelial growth factor–directed antibody bevacizumab (BEV), glioblastoma has been reported to display a more infiltrative pattern of recurrence. This distant spread at recurrence or progression and a gliomatosis cerebri-like growth pattern is best detectable on fluid-attenuated inversion recovery MRI. The frequency of up to 20% to 30% of such a pattern in BEV-treated patients is higher than expected to occur without BEV. Older reports and common clinical knowledge estimate the frequency of diffuse or distant spread in recurrent glioblastoma at 10%. This observation stimulated two streams of research. One is to overcome this often insidious adverse effect of antiangiogenic treatment, to optimize antiangiogenic therapies and to face this major challenge, integrating antiangiogenic with anti-invasive mechanisms into one combined treatment concept. The second is questioning a specific property of antiangiogenic therapy to induce diffuse or distant spread. Here, alternative hypotheses of increased awareness and better imaging as well as invasiveness being part of the natural course of the disease have been tested. Without doubt, migration and invasiveness are major obstacles to successful glioma therapy, notably local therapies, both in the natural course of the disease and in the concept of “evasive resistance.” However, clinical analyses of case series, matched pairs analyses, and follow-up on the BRAIN trial (A Study to Evaluate Bevacizumab Alone or in Combination with Irinotecan for Treatment of Glioblastoma Multiforme), which led to accelerated approval of BEV for recurrent glioblastoma in the United States, have not supported a specific propensity of BEV to induce diffuse growth or distant spread at recurrence.
    Keywords: Evasive resistance ; Recurrence pattern ; MRI ; Bevacizumab
    ISSN: 1528-4042
    E-ISSN: 1534-6293
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  • 2
    Language: English
    In: Environmental Earth Sciences, 2012, Vol.65(8), pp.2377-2389
    Description: For water management purposes, information about an entire aquifer system is generally more important than information about a specific spring. Since a karstic aquifer system might drain to several outlets, conclusions derived from a single spring can be misleading for characterization and modeling. In this study we apply a conceptual model to an Alpine dolomite karst system in Austria. The particular challenge was that several small springs with strongly varying hydrological behavior and diffuse flow into surrounding streams drain this system. Instead of applying the model to a single spring, it was calibrated simultaneously to several observations within the system aiming to identify the karst system’s intrinsic hydrodynamic parameters. Parameter identification is supported by modeling the transport of water isotopes (δ 18 O). The parameters were transferred to the whole system with a simple upscaling procedure and a sensitivity analysis was performed to unfold influence of isotopic information on parameter sensitivity and simulation uncertainty. The results show that it is possible to identify system intrinsic parameters. But the sensitivity analysis revealed that some are hardly identifiable. Only by considering uncertainty reasonable predictions can be provided for the whole system. Including isotopic information increases the sensitivity of some intrinsic parameters, but it goes along with a sensitivity decrease for others. However, a possible reduction of prediction uncertainty by isotopic information is compensated by deficiencies in the transport modeling routines.
    Keywords: Karst aquifer ; Karst modeling ; Water isotopes ; Solute transport modeling ; Upscaling ; Rainfall-runoff modeling
    ISSN: 1866-6280
    E-ISSN: 1866-6299
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  • 3
    Language: English
    In: Theoretical and Applied Climatology, 2018, Vol.131(1), pp.259-270
    Description: Estimation of drought in a certain temporal and spatial scale is crucial in climate change studies. The current study targets on three agricultural areas widespread in Greece, Ardas River Basin in Northeastern Greece, Sperchios River Basin in Central Greece, and Geropotamos River Basin in Crete Island in South Greece that are characterized by diverse climates as they are located in various regions. The objective is to assess the spatiotemporal variation of drought conditions prevailing in these areas. The Standardized Precipitation Index (SPI) was used to identify and assess the present and future drought conditions. Future simulated data were derived from a number of Regional Climatic Models (RCMs) from the ENSEMBLES European Project. The analysis was performed for the future periods of 2021–2050 and 2071–2100, implementing A1B and B1 scenarios. The spatial analysis of the drought conditions was performed using a combined downscaling technique and the Ordinary Kriging. The Mann-Kendall test was implemented for trend investigation. During both periods and scenarios, drought conditions will tend to be more severe in the upcoming years. The decrease of the SPI values in the Sperchios River Basin is expected to be the strongest, as it is the only study area that will show a negative balance (in SPI values), regarding the drought conditions. For the Ardas and the Geropotamos River Basins, a great increase of the drought conditions will occur during the 2021–2050 period, while for 2071–2100 period, the decrease will continue but it will be tempered. Nevertheless, the situation in all study areas according to the SPI classification is characterized as “Near-normal”, in terms of drought conditions.
    Keywords: Drought analysis ; Standardized precipitation index ; IPCC emission scenarios ; Multi-linear regression ; Spatial interpolation ; Greece
    ISSN: 0177-798X
    E-ISSN: 1434-4483
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  • 4
    Language: English
    In: Trees, 2018, Vol.32(5), pp.1443-1455
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00468-018-1725-9 Byline: Jakob Sohrt (1), Cornelia Herschbach (2), Markus Weiler (1) Keywords: Nitrogen; Phosphorus; Foliar resorption efficiency; Foliar N:P ratio; Coniferous; Deciduous Abstract: Key message While there is evidence that foliar P concentration controls foliar P resorption efficiency, this is not found for N. Likewise, the foliar N:P ratio affects P, but not N resorption. Abstract This study focuses on foliar nutrient resorption efficiency, which describes the proportion of foliar nutrients that is resorbed before abscission. The two main tree types of temperate forests--deciduous and coniferous--are compared in this context. The aim of this meta-analysis is to describe the foliar resorption efficiency of N and P as a function of absolute and relative concentrations of these nutrients in mature foliage, which may serve as a proxy for the plants nutritional status. In addition to prior work on this subject which has focused mainly on single-nutrient resorption efficiency, the effects of relative- and absolute foliar N and P levels are decoupled and analyzed separately. P resorption efficiency was significantly higher at lower absolute foliar P concentration and strongly tied to the original foliar P concentration for both deciduous trees and conifers. In addition, a significant correlation between P resorption efficiency and the foliar N:P ratio was found for deciduous but not for coniferous trees. In contrast, the N resorption efficiency did not relate to the foliar N concentration, nor to the foliar N:P ratio for deciduous and coniferous trees. The results of this study provide strong evidence, that the decoupling of absolute and relative N- and P concentrations in mature foliage is a critical factor for assessing the effect of relative N:P nutrition on nutrient resorption from foliage. If the statistical dependency among absolute and relative foliar N and P concentrations is not considered, the effect of relative N:P nutrition on single nutrient resorption efficiency is likely over-estimated. Overall the results point towards trees of temperate forests being P limited rather than N limited. Author Affiliation: (1) grid.5963.9, Albert Ludwigs University of Freiburg, Friedrichstra[sz]e 39, 79098, Freiburg, Germany (2) grid.5963.9, Albert Ludwigs University of Freiburg, Georges-Kohler-Allee 53/54, 79110, Freiburg, Germany Article History: Registration Date: 16/06/2018 Received Date: 17/02/2018 Accepted Date: 15/06/2018 Online Date: 21/06/2018 Article note: Communicated by H. Rennenberg. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00468-018-1725-9) contains supplementary material, which is available to authorized users.
    Keywords: Nitrogen ; Phosphorus ; Foliar resorption efficiency ; Foliar N:P ratio ; Coniferous ; Deciduous
    ISSN: 0931-1890
    E-ISSN: 1432-2285
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  • 5
    Language: English
    In: Environmental Earth Sciences, 2016, Vol.75(21), pp.1-16
    Description: Heavy precipitation-induced flash floods are still a serious hazard and generate high damages. In the context of climate change, an increase of the occurrence of flash floods is very likely. To improve flash-flood predictions and allow measures to reduce damage in vulnerable catchments, the spatial dynamics of runoff generation at a high spatial resolution during extreme rainfall events need to be better predicted. The results of these models can then be included into hydraulic models to predict the surface water level and flow dynamics based on high-resolution topographic data. Long-term discharge data does generally not exist in the small headwaters mostly influenced by flash floods, which would allow to calibrate conventional rainfall-runoff models. But hydrological models predicting runoff generation processes without calibration based on available spatially distributed data sets are still lacking. Such a model [Runoff Generation Research (RoGeR)] was developed for the state of Baden-Württemberg. It is based on an extensive collection of spatial data, including a digital elevation model of 1 × 1 m 2 resolution, degree of sealing of the earth surface for the same resolution, and soil properties and geology at the scale of 1:50,000. Within the state of Baden-Württemberg, different regions were selected encompassing distinct environmental characteristics regarding climate, soil properties, land use, topography and geology. RoGeR was tested and validated by simulating 33 observed flood events in 13 mesoscale catchments without calibration and by modelling seven 60-m² artificial rainfall experiments on five different hillslopes in different regions of Switzerland. The results showed that the model was able to reproduce the temporal runoff dynamics as well as the peak discharge and the runoff volume in the mesoscale catchments as well as the 60-m² hillslope plots. The model could reproduce processes and hydrological response under different antecedent soil moisture and precipitation characteristics without any calibration, despite applying it to different regions and different scales. This suggests that RoGeR is predestinated to quantify runoff generation processes during heavy rainfall events at different scales without the typical model calibration procedure allowing to better quantify input and model uncertainty.
    Keywords: Runoff generation ; Uncalibrated model ; Infiltration ; Preferential flow ; Subsurface flow ; Flash floods
    ISSN: 1866-6280
    E-ISSN: 1866-6299
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  • 6
    Language: English
    In: European Radiology, 2015, Vol.25(5), pp.1497-1503
    Description: Byline: Daniel Schwarz (1), Markus Weiler (2,3), Mirko Pham (1), Sabine Heiland (4), Martin Bendszus (1), Philipp Baumer (1) Keywords: MR neurography; Polyneuropathy; MRI; Muscle denervation; Nerve lesion Abstract: Objective To investigate the diagnostic contribution of T2-w nerve lesions and of muscle denervation in peripheral motor neuropathies by magnetic resonance neurography (MRN). Methods Fifty-one patients with peripheral motor neuropathies underwent high-resolution MRN by large coverage axial T2-w sequences of the upper arm, elbow, and forearm. Images were evaluated by two blinded readers for T2-w signal alterations of median, ulnar, and radial nerves, and for denervation in respective target muscle groups. Results All 51 patients displayed nerve lesions in at least one of three nerves, and 43 out of 51 patients showed denervation in at least one target muscle group of these nerves. In 21 out of 51 patients, the number of affected nerves matched the number of affected target muscle groups. In the remaining 30 patients, T2-w lesions were encountered more frequently than target muscle group denervation. In 153 nerve-muscle pairs, 72 showed denervation, but only one had increased muscle signal without a lesion in the corresponding nerve. Conclusions MRN-based diagnosis of peripheral motor neuropathies is more likely by visualization of peripheral nerve lesions than by denervation in corresponding target muscles. Increased muscular T2-w signal without concomitant nerve lesions should raise suspicion of an etiology other than peripheral neuropathy. Key Points acents In peripheral neuropathy, T2-w nerve lesions are more frequent than muscle denervation. acents Muscle denervation almost never occurs without detectable lesions in corresponding nerves. acents MRN-aided diagnosis of peripheral motor neuropathy should focus primarily on nerve lesions. acents Increased muscular T2-w signal intensity without concomitant nerve lesions indicates other aetiology. Author Affiliation: (1) Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany (2) Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany (3) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany (4) Section of Experimental Radiology, Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany Article History: Registration Date: 11/11/2014 Received Date: 28/05/2014 Accepted Date: 11/11/2014 Online Date: 30/11/2014 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00330-014-3498-x) contains supplementary material, which is available to authorized users.
    Keywords: MR neurography ; Polyneuropathy ; MRI ; Muscle denervation ; Nerve lesion
    ISSN: 0938-7994
    E-ISSN: 1432-1084
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  • 7
    Language: German
    In: Onkopipeline, 2009, Vol.2(1), pp.23-29
    Description: Trotz ermutigender Daten in der Primärtherapie von Glioblastompatienten mit Methylierung des Promotors der O 6 -Methylguanyl-Methyltransferase (MGMT) ist neben der weiteren Optimierung dieser Therapie vor allem die Entwicklung von effektiven Rezidivtherapien vordringlich. In Analogie zu präklinischen Ergebnissen wurde vermutet, dass das Verständnis molekularer prognostischer und insbesondere für eine spezifische Therapie prädiktiver Parameter eine verbesserte Patientenselektion vor Therapie- oder Studienbeginn ermögliche und damit den unselektiven Einsatz selektiv wirkender Therapien verhindere. Aktuell verfügbare molekulare Parameter sind allerdings vor allem prognostisch und nicht prädiktiv. Aktuelle multinationale Studienkonzepte bei malignen Gliomen schließen dennoch erstmals Patienten nach vorhergehender molekularer Untersuchung des 1p/19q-Status oder der Methylierung des MGMT-Promotors ein. Eine Herausforderung für neue Studien ist neben der unmittelbaren Verbesserung der Therapie die Etablierung molekularer prädiktiver Signaturen. Aufgrund der drängenden klinischen Situation und der biologischen Spezifika von hirneigenen Tumoren werden aktuell auch neuartige Konzepte wie die Entwicklung zellulärer Vehikel für die Therapie oder die Verwendung von lentiviral tranduziertem, alkylanzienresistentem Knochenmark untersucht. Classic chemo- or radiotherapy alone are not going to make significant impact in the future treatment of malignant glioma. A better understanding of molecular prognostic or preferentially predictive molecular markers enables an improved patient selection prior to radio- or chemotherapy and reduces the risk of unselective administration of targeted therapies. Over the past years, loss of heterozygosity on chromosomes 1p/19q in anaplastic oligodendro - glial tumors as well as analysis of promoter methylation of the O-methylguanine-DNA methyltransferase harbored important prognostic and the latter even predictive information on the sensitivity toward an alkylating chemotherapy. Newly developed multinational studies on malignant glioma for the first time ever include patients according to molecular parameters. Novel molecular signatures as well as targeted therapeutics ask for new studies, preferentially in combination with cytotoxic chemotherapeutics or radiotherapy.
    Keywords: Brain tumors ; Bevacizumab ; Enzastaurin ; Temsirolimus
    ISSN: 1866-5861
    E-ISSN: 1866-587X
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  • 8
    Language: English
    In: Knee Surgery, Sports Traumatology, Arthroscopy, 2012, Vol.20(5), pp.889-895
    Description: Byline: Markus Weiss (1), Frank N. Unterhauser (2), Andreas Weiler (3) Keywords: Tendon; ACL; Crimp; [alpha]-smooth muscle actin; Myofibroblast Abstract: Purpose Collagen crimp is essential for maintaining viscoelastic properties of normal ligament and tendon tissue. The actin isoform [alpha]-smooth muscle actin (ASMA) has been identified in fibroblastic cells of these tissues. These highly differentiated cells, so-called myofibroblasts may transmit tensile forces to the extracellular matrix, thus it has been suggested that they are responsible for the wrinkling of the extracellular matrix and the formation of crimp. During anterior cruciate ligament (ACL) graft remodeling, crimp formation plays an integral role. Thus, it was our purpose to determine the relationship between myofibroblast density and crimp frequency in human tendon graft tissue and the ACL. Methods Different tendon grafts and ACLs were harvested from young human multi-organ donors immediately after death. Myofibroblasts were immunostained with a monoclonal antibody, and histomorphometry was performed using a digital imaging system. Crimp length was measured, and data were correlated. Results All tendons and ACLs showed a significant correlation of myofibroblast density and crimp frequency (R .sup.2 0.81--0.43). The strongest correlation was found for the patellar tendon, the poorest for the gracilis tendon. There is also evidence that the phenotype respectively the shape of myofibroblasts might be responsible for different stages of crimp formation. Conclusion With the present investigation, we found that myofibroblasts might be involved in crimp formation and should be viewed as an integral part of normal tendon and ligament tissue. Furthermore, the shape of myofibroblasts may further indicate the contractile potency of the extracellular matrix, thus presenting a dynamic and variable crimp rather than a static situation. This study is an experimental study. In terms of clinical relevance all the mentioned tendons can be used as auto- or allografts for ACL reconstruction, nevertheless their microscopic structure and cellular population have yet not been adequately investigated and compared. Author Affiliation: (1) Klinik fur Arthroskopische Chirurgie und Sporttraumatologie, Krankenhaus St. Josef, Bergstr. 6 - 12, 42105, Wuppertal, Germany (2) From Center for Musculoskeletal Surgery, Charite, Humboldt-University of Berlin, Berlin, Germany (3) Sporthopaedicum Berlin, Oranienburgerstr. 70, 13437, Berlin, Germany Article History: Registration Date: 04/08/2011 Received Date: 22/12/2010 Accepted Date: 04/08/2011 Online Date: 31/08/2011
    Keywords: Tendon ; ACL ; Crimp ; α-smooth muscle actin ; Myofibroblast
    ISSN: 0942-2056
    E-ISSN: 1433-7347
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  • 9
    Language: English
    In: Naunyn-Schmiedeberg's Archives of Pharmacology, 1989, Vol.340(6), pp.752-759
    Description: Benzothiazinones represent a novel class of drugs which block voltage-dependent L -type calcium channels in different tissues. [ 3 H]HOE166 (R-(±)-3,4-dihydro-2-isopro-opyl-4-methyl-2-[2-[4-[4-[2-(3, 4, 5-trimethoxyphenyl)ethyl]piperazinyl]butoxy]phenyl]-2H -1, 4-benzothiazin-3-on-dihydrochloride; ≈ 57 Ci/mmol) a potent optically pure benzothiazinone was employed to characterize receptors associated with skeletal muscle transverse tubule calcium channels. [ 3 H]HOE166 reversibly labels the membrane-bound calcium channels with high affinity (K d = 0.36 ± 0.05 nM; B max = 18.2 ± 3.3 pmol/mg of membrane protein; means ± SD, n = 13), HOE166 (K i = 0.76 nM) is 29-fold more potent than the respective (S)-enantiomer (K i = 22.1 nM). Binding is inhibited by divalent and trivalent cations (Cd 2+ and La 3+ being most potent) and other calcium channel drugs (1,4 dihydropyridines, phenylalkylamines, benzothiazepines). High affinity [ 3 H]HOE166 binding activity is maintained (Kd = 4.5–9.0 nM) after solubilization and purification (554–1350 pmoles/mg of protein) of the calcium channel complex from transverse-tubule membranes. The following data support our recent claim (Striessnig et al. 1985, 1988) that HOE166 labels a domain on L -type calcium channels which is distinct from that defined by 1,4 dihydropyridines, phenylalkylamines or benzothiazepines: (1) All 1,4 dihydropyridine-, phenylalkylamine-and benzothiazepine-receptor-selective drugs tested are only very weak inhibitors of [ 3 H]HOE166 binding. (2) (+)-PN200-110 only partially inhibits [ 3 H]HOE166 binding to the purified calcium. channel complex. (3) The decay of the [ 3 H]HOE166-receptor complex is monoexponential but the dissociation rate constants depend on the ligand concentration; (+)-PN200-100 accelerates the dissociation in the presence of unlabelled HOE166. (4) Nanomolar concentrations of HOE166 and HOE167 completely inhibit (−)-[ 3 H]desmethoxyverapamil binding to a Drosophila phenylalkylamine receptor (which lacks a 1,4 dihydropyridine binding domain). Taken together, these results are incompatible with the view that [ 3 H]HOE166 binds competitively to the calcium channel linked 1,4 dihydropyridine drug receptors.
    Keywords: Benzothiazinones ; Purified calcium channels ; Drosophila ; Calcium channel blockers ; Skeletal muscle
    ISSN: 0028-1298
    E-ISSN: 1432-1912
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  • 10
    Language: English
    In: Intensive Care Medicine, 2003, Vol.29(10), pp.1656-1665
    Description: Byline: Matthias David (1), Norbert Weiler (2), Wolfgang Heinrichs (1), Markus Neumann (1), Thilo Joost (1), Klaus Markstaller (1), Balthasar Eberle (1) Keywords: Adult respiratory distress syndrome; High-frequency oscillatory ventilation; Respiratory therapy; Ventilator-associated lung injury; Human Abstract: Objective This study examined whether ARDS patients in whom predefined ventilator settings fail to maintain oxygenation and CO.sub.2 removal can be safely transitioned to high-frequency oscillatory ventilation (HFOV), and whether HFOV use is efficacious. Design and setting Prospective observational study in the 14-bed intensive care unit of a university hospital. Patients and participants 42 patients with ARDS (APACHE II score 28 (IQR 24--37) and ventilation time prior HFOV 3.0 days (0.7--9.1). Measurements and results Gas exchange parameters and ventilator data were recorded before and during HFOV treatment (-12 h, -6 h, baseline, 10 min, 1 h, 6 h, 12 h, 24 h). Primary endpoints included: (a) [P.sub.a]O.sub.2/FIO.sub.2 ratio 24 h after start of HFOV treatment or the last point of measurement if HFOV ended within the first 24 h (b) HFOV-related complications. Post hoc analysis assessed the relationship between outcome and the response to HFOV, and between outcome and time of mechanical ventilation prior to HFOV. At baseline the median [P.sub.a]O.sub.2/FIO.sub.2 ratio was 95 (IQR 62--129) after 24 h of HFOV the [P.sub.a]O.sub.2/FIO.sub.2 ratio had increased significantly to 165 (88--225) only one patient developed a unilateral pneumothorax. Of the 42 patients 18 (43%) had died by day 30. Subset analyses showed a significantly higher 30-day mortality rate in patients with at least 3 days of mechanical ventilation prior to HFOV (64%) and in patients without oxygenation improvement after 24 h on HFOV (71%). Conclusions HFOV is an effective and safe method to ventilate ARDS patients. Failure to improve oxygenation within 24 h of HFOV is associated with high mortality. Author Affiliation: (1) Department of Anesthesiology, Johannes Gutenberg University, Langenbeckstrasse 1, Mainz, Germany (2) Department of Anesthesiology and Intensive Care Medicine, Christian Albrecht University, Schwanenweg 21, 24105, Kiel, Germany Article History: Received Date: 27/08/2002 Accepted Date: 03/06/2003 Online Date: 25/07/2003 Article note: An editorial regarding this article can be found in the same issue http://dx.doi.org/10.1007/s00134-003-1939-z
    Keywords: Adult respiratory distress syndrome ; High-frequency oscillatory ventilation ; Respiratory therapy ; Ventilator-associated lung injury ; Human
    ISSN: 0342-4642
    E-ISSN: 1432-1238
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