Heidelberg, Germany
Heidelberg, Germany

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Background: We study the relevance of diffusion for the dynamics of signaling pathways. Mathematical modeling of cellular diffusion leads to a coupled system of differential equations with Robin boundary conditions which requires a substantial knowledge in mathematical theory. Using our new developed analytical and numerical techniques together with modern experiments, we analyze and quantify various types of diffusive effects in intra- and inter-cellular signaling. The complexity of these models necessitates suitable numerical methods to perform the simulations precisely and within an acceptable period of time. Methods: The numerical methods comprise a Galerkin finite element space discretization, an adaptive time stepping scheme and either an iterative operator splitting method or fully coupled multilevel algorithm as solver. Results: The simulation outcome allows us to analyze different biological aspects. On the scale of a single cell, we showed the high cytoplasmic concentration gradients in irregular geometries. We found an 11 % maximum relative total STAT5-concentration variation in a fibroblast and a 70 % maximum relative pSTAT5-concentration variation in a fibroblast with an irregular cell shape. For pSMAD2 the maximum relative variation was 18 % in a hepatocyte with a box shape and 70 % in an irregular geometry. This result can be also obtained in a cell with a box shape if the molecules diffuse slowly (with D=1 μm2/s instead of D=15 μm2/s). On a scale of cell system in the lymph node, our simulations showed an inhomogeneous IL-2 pattern with an amount over three orders of magnitude (10-3-1 pM) and high gradients in face of its fast diffusivity. We observed that 20 out of 125 cells were activated after 9 h and 33 in the steady state. Our in-silico experiments showed that the insertion of 31 regulatory T cells in our cell system can completely downregulate the signal. Conclusions: We quantify the concentration gradients evolving from the diffusion of the molecules in several signaling pathways. For intracellular signaling pathways with nuclear accumulation the size of cytoplasmic gradients does not indicate the change in gene expression which has to be analyzed separately in future. For intercellular signaling the high cytokine concentration gradients play an essential role in the regulation of the molecular mechanism of the immune response. Furthermore, our simulation results can give the information on which signaling pathway diffusion may play a role. We conclude that a PDE model has to be considered for cells with an irregular shape or for slow diffusing molecules. Also the high gradients inside a cell or in a cell system can play an essential role in the regulation of the molecular mechanisms. © 2015 Friedmann.

Plaschke K.,Im Neuenheimer Feld | Kopitz J.,University of Heidelberg | Siegelin M.,University of Heidelberg | Schliebs R.,Paul Flechsig Institute for Brain Research | And 3 more authors.
Journal of Alzheimer's Disease | Year: 2010

For studying rare hereditary Alzheimer's disease (AD), transgenic (Tg) animal models overexpressing amyloid-β protein precursor (AβPP) followed by increased amyloid-β (Aβ) formation are used. In contrast, sporadic AD has been proposed to start with an insulin-resistant brain state (IRBS). We investigated the effect of IRBS induced by intracerebroventricularly (icv) administered streptozotocin (STZ) on behavior, glycogen synthase kinase-3 (GSK)α/β content, and the formation of AD-like morphological hallmarks Aβ and tau protein in AβPP Tg2576 mice. Nine-month-old Tg mice were investigated 6 months after a single icv injection of STZ or placebo. Spatial cognition was analyzed using the Morris water maze test. Soluble and aggregated Aβ -{40/42} fragments, total and phosphorylated tau protein, and GSK-3α/β were determined by ELISA. Cerebral (immuno)histological analyses were performed. In Tg mice, STZ treatment increased mortality, reduced spatial cognition, and increased cerebral aggregated Aβ fragments, total tau protein, and congophilic amyloid deposits. These changes were associated with decreased GSK-3α/β ratio (phosphorylated/total). A linear negative correlation was detected between Aβ -{42} and cognition, and between GSK-3α/β ratio and aggregated Aβ -{40+42}. No marked necrotic and apoptotic changes were observed. In conclusion, IRBS may aggravate AD-like changes such as behavioral and increase the formation of pathomorphological AD hallmarks via GSK-3α/β pathway in AβPP-overexpressing mice. © 2010 - IOS Press and the authors. All rights reserved.

Marten A.,Im Neuenheimer Feld | Buchler M.W.,Im Neuenheimer Feld | Werft W.,German Cancer Research Institute | Wente M.N.,Im Neuenheimer Feld | And 2 more authors.
Journal of Immunotherapy | Year: 2010

Pancreatic adenocarcinoma as an aggressive tumor still lacks specific markers. Resection offers the only potential cure, and earlier diagnosis could benefit many patients. Here, we analyzed siC3b as a potential diagnostic marker. Soluble iC3b is generated in the fluid phase after binding of autoantibodies to tumor cells and subsequent inactivation of the complement cascade by interaction with complement regulatory proteins. Two hundred thirty-two plasma samples from patients with adjuvant treatment after resection, from healthy volunteers, and from vulnerable patients were collected prospectively and analyzed for siC3b. Every 3 months, the patients underwent imaging and the results from siC3b enzyme-linked immunosorbent assay were categorized according to radiologically defined recurrence within 4 months after blood withdrawal. Furthermore, the regulatory factors of the complement system were analyzed in tumor cells and in urine. The most important finding was that up to 4 months before radiologically defined recurrence, siC3b plasma level is increased with a sensitivity and specificity resulting in an area under the curve of 0.85, which could be further increased by combining it with CA19.9 (area under the curve=0.92). Complement regulatory proteins are highly expressed in pancreatic carcinoma cells and detectable in the patient's urine. In summary, screening for siC3b in patients with an increased risk for pancreatic ductal adenocarcinoma (patients with chronic pancreatitis, hereditary pancreatitis, after curative resection, and patients with a variety of familial cancer syndromes) allows for early detection with high sensitivity, as siC3b plasma levels are increased up to 4 months before radiologic evidence. Sensitivity could be further increased by combining this approach with CA19.9. Copyright © 2010 by Lippincott Williams & Wilkins.

Tielborger K.,University of Tübingen | Fleischer A.,Hebrew University of Jerusalem | Menzel L.,Im Neuenheimer Feld | Metz J.,University of Tübingen | Sternberg M.,Tel Aviv University
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2010

The eastern Mediterranean faces a severe water crisis: water supply decreases due to climate change, while demand increases due to rapid population growth. The GLOWA Jordan River project generates science-based management strategies for maximizing water productivity under global climate change. We use a novel definition of water productivity as the full range of services provided by landscapes per unit blue (surface) and green (in plants and soil) water. Our combined results from climatological, ecological, economic and hydrological studies suggest that, in Israel, certain landscapes provide high returns as ecosystem services for little input of additional blue water. Specifically, cultural services such as recreation may by far exceed that of food production. Interestingly, some highly valued landscapes (e.g. rangeland) appear resistant to climate change, making them an ideal candidate for adaptive land management. Vice versa, expanding irrigated agriculture is unlikely to be sustainable under global climate change. We advocate the inclusion of a large range of ecosystem services into integrated land and water resources management. The focus on cultural services and integration of irrigation demand will lead to entirely different but productive water and land allocation schemes that may be suitable for withstanding the problems caused by climate change. © 2010 The Royal Society.

Feireisl E.,Academy of Sciences of the Czech Republic | Friedmann E.,Im Neuenheimer Feld
Journal of Mathematical Fluid Mechanics | Year: 2012

We consider a mathematical model of a rigid body immersed in a viscous, compressible fluid moving with a velocity prescribed on the boundary of a large channel containing the body. We assume that the Mach number is proportional to a small parameter ε and that the general boundary of the body contains small asperities of amplitude proportional to εα for a certain α > 0 and suppose the Navier's slip condition on this rough boundary. We show that time averages of the drag functional converge, as ε → 0, to the corresponding time averages of the drag for the limit system, whereas the limit system is turning out to be the incompressible Navier-Stokes system with no-slip condition on the smooth limit body. © 2012 Springer Basel AG.

Hankey G.J.,Royal Perth Hospital | Hacke W.,Im Neuenheimer Feld | Easton J.D.,Brown University | Johnston S.C.,University of California at San Francisco | And 5 more authors.
Stroke | Year: 2010

Background and Purpose-: Disabling stroke is costly and considered by some patients a fate worse than death. We aimed to determine whether clopidogrel reduces the rate and functional severity of stroke among high vascular risk patients, including patients with previous transient ischemic attack or ischemic stroke, who were enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial. Methods-: We randomly assigned 15 603 high vascular risk patients to receive clopidogrel (75 mg daily) or placebo in addition to background acetylsalicylic acid and followed them for a median of 28 months. The main outcome of this prespecified substudy was the functional severity of stroke outcome events as measured by the modified Rankin Scale (mRS) score at 3 months after the stroke outcome. Results-: During follow-up, 436 (2.8%) patients had a definite adjudicated stroke and a follow-up assessment of the mRS at 3 months poststroke, of whom 202 had been randomly assigned clopidogrel and 234 placebo (relative risk reduction 14%, 95% CI:-4% to 29%, P=0.12). There was no significant difference between the mean mRS scores at 3 months after stroke among patients assigned clopidogrel compared with placebo (mean mRS 3.6 [SD 2.4] clopidogrel versus 3.3 [SD 2.1] placebo; P=0.15). There was also no significant difference between the various categories of the mRS score at 3 months after stroke among patients assigned to clopidogrel compared with placebo. Among 4320 patients with a qualifying diagnosis of transient ischemic attack or ischemic stroke, 233 (5.4%) experienced a stroke during follow-up, of whom 103 were randomly assigned clopidogrel and 130 placebo (relative risk reduction 20%, 95% CI:-3% to 38%). There was no significant difference between the mean mRS scores at 3 months after stroke among patients with a qualifying transient ischemic attack or ischemic stroke who were assigned clopidogrel compared with placebo (3.4 [SD 2.1] clopidogrel versus 3.3 [SD 1.9] placebo; P=0.48). Conclusion-: The addition of clopidogrel to acetylsalicylic acid did not significantly alter the rate and functional severity of stroke outcome events among high vascular risk patients enrolled in the CHARISMA trial. © 2010 American Heart Association, Inc.

Susal C.,Im Neuenheimer Feld | Opelz G.,Im Neuenheimer Feld | Morath C.,University of Heidelberg
Transfusion Medicine and Hemotherapy | Year: 2013

The complement-dependent lymphocytotoxicity (CDC) method has been the classical technique to detect human leukocyte antigen (HLA) antibodies in sera of patients who are listed for kidney transplantation. Because of the drawbacks of CDC, such as low sensitivity and low resolution in characterizing antibody specificities, the more specific ELISA technology was introduced in the 1990s which utilizes solubilized HLA molecules instead of lymphocytes. During the last 10 years, the introduction of the Luminex-based single antigen bead (L-SAB) technology, which uses recombinant single HLA molecules, allows detection and characterization of HLA antibodies at greater sensitivity than CDC and ELISA. A drawback associated with this technique is that the interpretation of results is demanding and requires comprehensive experience in HLA antibody diagnostics. Herein we discuss the current role and value of L-SAB technology in the clinical management of sensitized kidney transplant recipients. © 2013 S. Karger GmbH, Freiburg.

Santos E.,Im Neuenheimer Feld | Sanchez-Porras R.,Im Neuenheimer Feld | Dohmen C.,University of Cologne | Hertle D.,Im Neuenheimer Feld | And 2 more authors.
Cephalalgia | Year: 2012

Background: Cortical spreading depolarization (CSD) has been implicated in the pathophysiology of migraine with aura. Patients that suffer from this type of migraine have shown a higher risk of developing an ischaemic stroke.Case: A 42-year-old female exhibited reoccurring migraine attacks for the first time 1 month before suffering an ischaemic infarction. Imaging studies revealed an occlusion in the right middle cerebral artery. Other possible disorders were excluded. It was possible to register 20 CSDs, of which 12 coincided with high levels of glutamate and lactate/pyruvate ratio. Loss of electrocorticographic activity was observed for 89 hours after the 8th depolarization.Conclusions: Migraine with aura symptoms may be induced by CSDs triggered by hypoperfusion states. Our case supports the idea of the migraine with aura-stroke continuum. © International Headache Society 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Hoffmann K.,University of Heidelberg | Hinz U.,University of Heidelberg | Hillebrand N.,University of Heidelberg | Ganten T.,Im Neuenheimer Feld | And 4 more authors.
Langenbeck's Archives of Surgery | Year: 2014

Purpose: Liver transplantation (LT) is well established in patients with autoimmune liver disease. Despite excellent outcomes, organ scarcity demands careful patients’ selection and timing of transplantation.Methods: This retrospective study analyzes data of 79 consecutive patients with primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and overlap syndrome, undergoing LT between 2001 and 2012. Overall survival (OS) and graft survival were assessed using Kaplan-Meier estimate. Multivariate survival analysis was performed to identify prognostic factors by using Cox regression model.Results: After 59.6-month median follow-up, the 5-year OS and graft survival were 75.3 and 68.8 %, respectively. The 5-year survival rates for patients with PSC (n = 57), AIH (n = 17), and overlap syndrome (n = 5) were 76.3, 76.0, and 60.0 %. The 90-day mortality rate of 70.0 % was significantly higher in patients with a labMELD score ≥20 (n = 10) compared to 26.1 % in 69 patients with a labMELD <20 (p = 0.009). A lab Model for End-Stage Liver Disease (MELD) score ≥20 was an independent predictor of impaired OS (p = 0.050, hazard ratio 2.5). The 5-year OS was 55.7 % in patients with a labMELD score ≥20 compared to 84.7 % in patients with a labMELD score <20.Conclusion: The recipients’ MELD score is a predictor for the short-term outcome after LT in patients with autoimmune liver disease. Meticulous selection for transplant listing remains necessary to safe scarce donor organs. © 2014, Springer-Verlag Berlin Heidelberg.

Habermehl D.,Im Neuenheimer Feld | Habermehl D.,University of Heidelberg | Kessel K.,Im Neuenheimer Feld | Welzel T.,Im Neuenheimer Feld | And 10 more authors.
Radiation Oncology | Year: 2012

Introduction: To evaluate efficacy and secondary resectability in patients with locally advanced pancreatic cancer (LAPC) treated with neoadjuvant chemoradiotherapy (CRT).Patients and methods: A total of 215 patients with locally advanced pancreatic cancer were treated with chemoradiation at a single institution. Radiotherapy was delivered with a median dose of 52.2 Gy in single fractions of 1.8 Gy. Chemotherapy was applied concomitantly as gemcitabine (GEM) at a dose of 300 mg/m 2weekly, followed by adjuvant cycles of full-dose GEM (1000 mg/m 2). After neoadjuvant CRT restaging was done to evaluate secondary resectability. Overall and disease-free survival were calculated and prognostic factors were estimated.Results: After CRT a total of 26% of all patients with primary unresectable LAPC were chosen to undergo secondary resection. Tumour free resection margins could be achieved in 39.2% (R0-resection), R1-resections were seen in 41.2%, residual macroscopic tumour in 11.8% (R2) and in 7.8% resection were classified as Rx. Patients with complete resection after CRT showed a significantly increased median overall survival (OS) with 22.1 compared to 11.9 months in non-resected patients. Median OS and disease-free survival (DFS) of all patients were 12.3 and 8.1 months respectively. In most cases the first site of disease progression was systemic with hepatic (52%) and peritoneal (36%) metastases.Discussion: A high percentage of patients with locally advanced pancreatic cancer can undergo secondary resection after gemcitabine-based chemoradiation and has a relative long-term prognosis after complete resection. © 2012 Habermehl et al; licensee BioMed Central Ltd.

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