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Gascoyne R.D.,British Columbia Cancer Agency | Rosenwald A.,University of Wrzburg | Poppema S.,University of Groningen | Lenz G.,Charité - Medical University of Berlin
Leukemia and Lymphoma | Year: 2010

There has recently been a rapid expansion in research aimed at identifying biomarkers that could improve the prognosis for patients with various subtypes of malignant lymphoma. Genomic and genetic studies have led to the identification of biological and clinical subgroups of diffuse large B-cell lymphomas with distinct underlying molecular features, divergent activation of oncogenetic pathways, and clinical course. Molecular studies of follicular lymphoma have suggested complex interactions between malignant cells and the surrounding immunological network that could affect disease progression. Moreover, the inflammatory cells of Hodgkin lymphoma have been shown to produce a complex network of cytokines and chemokines that provide a permissive microenvironment for tumor growth. Research into specific biomarkers and signaling pathways of malignant lymphomas might therefore result in the identification of novel targets for future therapeutic strategies. As gene expression profiling techniques are not yet feasible in the clinical laboratory, studies have aimed to translate the findings into more widely applicable techniques that might allow this research to be applied to routine clinical practice. This review focuses on recent advances in translational and clinical research on biomarkers in malignant lymphomas. © 2010 Informa UK, Ltd.

Drechsler C.,University of Wrzburg | Meinitzer A.,Medical University of Graz | Pilz S.,Medical University of Graz | Pilz S.,VU University Amsterdam | And 7 more authors.
European Journal of Heart Failure | Year: 2011

Aims Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients. Methods and results This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow-up, hazard ratios (HR) (95 CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95 CI 2.04.9), attenuating slightly in multivariate models (HR 2.4; 95 CI 1.53.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected. Conclusion Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact © Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email:

Ito H.,Kyushu Institute of Technology | Dashkovskiy S.,FH Erfurt | Wirth F.,University of Wrzburg
Automatica | Year: 2012

This paper addresses the problem of verifying stability of networks whose subsystems admit dissipation inequalities of integral input-to-state stability (iISS). We focus on two ways of constructing a Lyapunov function satisfying a dissipation inequality of a given network. Their difference from one another is elucidated from the viewpoint of formulation, relation, fundamental limitation and capability. One is referred to as the max-type construction resulting in a Lipschitz continuous Lyapunov function. The other is the sum-type construction resulting in a continuously differentiable Lyapunov function. This paper presents geometrical conditions under which the Lyapunov construction is possible for a network comprising n<2 subsystems. Although the sum-type construction for general n>2 has not yet been reduced to a readily computable condition, we obtain a simple condition of iISS small gain in the case of n=2. It is demonstrated that the max-type construction fails to offer a Lyapunov function if the network contains subsystems which are not input-to-state stable (ISS). © 2012 Elsevier Ltd. All rights reserved.

Shanmugam N.,St Georges Healthcare NHS Trust | Boerdlein A.,Biotronik SE and Co. KG | Proff J.,Biotronik SE and Co. KG | Ong P.,St Georges Healthcare NHS Trust | And 5 more authors.
Europace | Year: 2012

AimsUncertainty exists over the importance of device-detected short-duration atrial arrhythmias. Continuous atrial diagnostics, through home monitoring (HM) technology (BIOTRONIK, Berlin, Germany), provides a unique opportunity to assess frequency and quantity of atrial fibrillation (AF) episodes defined as atrial high-rate events (AHRE).Methods and resultsProspective data from 560 heart failure (HF) patients (age 67 ± 10 years, median ejection fraction 27) patients with a cardiac resynchronization therapy (CRT) device capable of HM from two multi-centre studies were analysed. Atrial high-rate events burden was defined as the duration of mode switch in a 24-h period with atrial rates of >180 beats for at least 1 or total of 14 min per day. The primary endpoint was incidence of a thromboembolic (TE) event. Secondary endpoints were cardiovascular death, hospitalization because of AF, or worsening HF. Over a median 370-day follow-up AHRE occurred in 40 of patients with 11 (2) patients developing TE complications and mortality rate of 4.3 (24 deaths, 16 with cardiovascular aetiology). Compared with patients without detected AHRE, patients with detected AHRE>3.8 h over a day were nine times more likely to develop TE complications (P 0.006). The majority of patients (73) did not show a temporal association with the detected atrial episode and their adverse event, with a mean interval of 46.7 ± 71.9 days (range 0194) before the TE complication.ConclusionIn a high-risk cohort of HF patients, device-detected atrial arrhythmias are associated with an increased incidence of TE events. A cut-off point of 3.8 h over 24 h was associated with significant increase in the event rate. Routine assessment of AHRE should be considered with other data when assessing stroke risk and considering anti-coagulation initiation and should also prompt the optimization of cardioprotective HF therapy in CRT patients.© The Author 2011.

Buchheim M.A.,University of Tulsa | Sutherland D.M.,University of Tulsa | Schleicher T.,University of Wrzburg | Forster F.,University of Wrzburg | Wolf M.,University of Wrzburg
Annals of Botany | Year: 2012

•Background and Aims: The green algal class Chlorophyceae comprises five orders (Chlamydomonadales, Sphaeropleales, Chaetophorales, Chaetopeltidales and Oedogoniales). Attempts to resolve the relationships among these groups have met with limited success. Studies of single genes (18S rRNA, 26S rRNA, rbcL or atpB) have largely failed to unambiguously resolve the relative positions of Oedogoniales, Chaetophorales and Chaetopeltidales (the OCC taxa). In contrast, recent genomics analyses of plastid data from OCC exemplars provided a robust phylogenetic analysis that supports a monophyletic OCC alliance.•Methods: An ITS2 data set was assembled to independently test the OCC hypothesis and to evaluate the performance of these data in assessing green algal phylogeny at the ordinal or class level. Sequence-structure analysis designed for use with ITS2 data was employed for phylogenetic reconstruction.•Key Results: Results of this study yielded trees that were, in general, topologically congruent with the results from the genomic analyses, including support for the monophyly of the OCC alliance.•Conclusions: Not all nodes from the ITS2 analyses exhibited robust support, but our investigation demonstrates that sequence-structure analyses of ITS2 provide a taxon-rich means of testing phylogenetic hypotheses at high taxonomic levels. Thus, the ITS2 data, in the context of sequence-structure analysis, provide an economical supplement or alternative to the single-marker approaches used in green algal phylogeny. © The Author 2011.

Segerer S.E.,University of Würzburg | Rieger L.,University of Würzburg | Kapp M.,University of Würzburg | Dombrowski Y.,Ludwig Maximilians University of Munich | And 3 more authors.
Human Reproduction | Year: 2012

BACKGROUND: Macrophage inhibitory cytokine-1 (MIC-1) is a multifunctional cytokine produced in high amounts by placental tissue. Inhibiting trophoblast invasion and suppressing inflammation through inhibition of macrophage activation, MIC-1 is thought to provide pleiotropic functions in the establishment and maintenance of pregnancy. So far, little is known about the decidual cell subsets producing MIC-1 and the effect of this cytokine on dendritic cells (DCs), which are known to play a distinct role in the development of pro-fetal tolerance in pregnancy. METHODS: To identify the decidual cell types expressing and secreting MIC-1, immunohistochemical staining, PCR experiments, western blot analysis and ELISAs were performed. Immature DCs (iDCs) were generated from peripheral blood-derived monocytes and differentiated in the presence of MIC-1 or dexamethasone (Dex) for control. Migratory and proliferative activity of DCs after MIC-1 exposure was investigated by migration and proliferation assay. Cytokine secretion after MIC-1 exposure was tested in isolated uNK cells, isolated CD14 monocytes, monocyte-derived iDCs and mature DCs. Subsequently, the phenotype of DCs was studied using FACS analysis. To test the T-cell stimulatory capacity of pre-incubated DCs, mixed lymphocyte reaction was applied. Finally, the expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) after the exposure of MIC-1 to maturing DCs was analysed by western blot. RESULTS: Immunohistochemical staining, PCR and western blot experiments demonstrated that MIC-1 is mainly expressed by trophoblast cells and decidual stromal cells. Analysis of the MIC-1 secretion of decidual cell types by ELISA again characterized trophoblast and stromal cells as main producers. The migratory activity of iDCs was significantly induced by MIC-1. No changes in proliferative activity of DCs were observed after MIC-1 pre-incubation. The secretion of pro- or anti-inflammatory cytokines was not affected significantly by MIC-1. Studying the phenotype of DCs after MIC-1 exposure by FACS analysis, we observed that MIC-1 suppresses the expression of typical maturation molecules such as CD25 and CD83 as well as of CD86 during cytokine-induced DC maturation similar to Dex. In addition, T-cell stimulatory capacity of DCs was significantly reduced after MIC-1 exposure. MIC-1 was also able to increase slightly the expression of IDO (a key immunomodulatory enzyme promoting periphereal tolerance) in maturing DCs. CONCLUSIONS: We have identified MIC-1 as a novel factor (secreted by decidual cells in early pregnancy) that could promote the increase of a tolerogenic subtype of DC in decidua. © The Author 2011.

Chen W.,University of Wrzburg | Gassner B.,University of Wrzburg | Brner S.,University of Wrzburg | Nikolaev V.O.,University of Wrzburg | And 5 more authors.
Cardiovascular Research | Year: 2012

Aims Cardiac atrial natriuretic peptide (ANP) participates in the maintenance of arterial blood pressure and intravascular volume homeostasis. The hypovolaemic effects of ANP result from coordinated actions in the kidney and systemic microcirculation. Hence, ANP, via its guanylyl cyclase-A (GC-A) receptor and intracellular cyclic GMP as second messenger, stimulates endothelial albumin permeability. Ultimately, this leads to a shift of plasma fluid into interstitial pools. Here we studied the role of caveolae-mediated transendothelial albumin transport in the hyperpermeability effects of ANP. Methods and Results Intravital microscopy studies of the mouse cremaster microcirculation showed that ANP stimulates the extravasation of fluorescent albumin from post-capillary venules and causes arteriolar vasodilatation. The hyperpermeability effect was prevented in mice with conditional, endothelial deletion of GC-A (EC GC-A KO) or with deleted caveolin-1 (cav-1), the caveolae scaffold protein. In contrast, the vasodilating effect was preserved. Concomitantly, the acute hypovolaemic action of ANP was abolished in EC GC-A KO and Cav-1 -/- mice. In cultured microvascular rat fat pad and mouse lung endothelial cells, ANP stimulated uptake and transendothelial transport of fluorescent albumin without altering endothelial electrical resistance. The stimulatory effect on albumin uptake was prevented in GC-A-or cav-1-deficient pulmonary endothelia. Finally, preparation of caveolin-enriched lipid rafts from mouse lung and western blotting showed that GC-A and cGMP-dependent protein kinase I partly co-localize with Cav-1 in caveolae microdomains. Conclusion ANP enhances transendothelial caveolae-mediated albumin transport via its GC-A receptor. This ANP-mediated cross-talk between the heart and the microcirculation is critically involved in the regulation of intravascular volume. © 2011 The Author.

A new species of Plagiotriptus is described from the Taita Hills of Kenya, East Africa. Data on habitat and co-occurring Saltatoria species are given and an updated key provided to the species of Plagiotriptus. .

Dietl J.,University of Wrzburg | Wischhusen J.,University of Wrzburg | Hausler S.F.M.,University of Wrzburg
Human Reproduction | Year: 2011

Recently, the distal Fallopian tube has attracted considerable attention not only as site of origin for serous cancer in women with BRCA mutations, but also as the anatomical location where the majority of serous ovarian cancers apparently develop. Consequently, the Fallopian tube may be the unique location where early 'ovarian' cancers can be foundwhich would contradict the long-standing impression that the ovaries and the Fallopian tubes are always simultaneously involved. Based on the dismal prognosis associated with ovarian cancer and our inability to screen for early-stage disease, we discuss the rationale for introducing salpinges-hysterectomy as new clinical standard for women in need of hysterectomy and further weigh the arguments for and against bilateral salpingectomy as a sterilization method. There is no known physiological benefit of retaining the post-reproductive Fallopian tube during hysterectomy or sterilization, especially as this does not affect ovarian hormone production. On the other hand, the consequences associated with a surgical menopause provide a rationale for preserving the ovaries in premenopausal women. Prophylactic removal of the Fallopian tubes during hysterectomy or sterilization would rule out any subsequent tubal pathology, such as hydrosalpinx, which is observed in up to 30 of women after hysterectomy. Moreover, this intervention is likely to offer considerable protection against later tumour development, even if the ovaries are retained. Thus, we recommend that any hysterectomy should be combined with salpingectomy. In addition, women over 35 years of age could also be offered bilateral salpingectomy as means of sterilization. © 2011 The Author.

Richter A.,University of Wrzburg | Wilbert J.,University of Wrzburg | Flentje M.,University of Wrzburg
Medical Physics | Year: 2011

Purpose: The aim of the work was to investigate the influence of intrafractional tumor motion to the accumulated (absorbed) dose. The accumulated dose was determined by means of calculations and measurements with a robot driven motion phantom. Methods: Different motion scenarios and compensation techniques were realized in a phantom study to investigate the influence of motion on image acquisition, dose calculation, and dose measurement. The influence of motion on the accumulated dose was calculated by employing two methods (a model based and a voxel based method). Results: Tumor motion resulted in a blurring of steep dose gradients and a reduction of dose at the periphery of the target. A systematic variation of motion parameters allowed the determination of the main influence parameters on the accumulated dose. The key parameters with the greatest influence on dose were the mean amplitude and the pattern of motion. Investigations on necessary safety margins to compensate for dose reduction have shown that smaller safety margins are sufficient, if the developed concept with optimized margins (OPT concept) was used instead of the standard internal target volume (ITV) concept. Both calculation methods were a reasonable approximation of the measured dose with the voxel based method being in better agreement with the measurements. Conclusions: Further evaluation of available systems and algorithms for dose accumulation are needed to create guidelines for the verification of the accumulated dose. © 2011 American Association of Physicists in Medicine.

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