@article{HolzschuhDormannTscharntkeetal.2013, author = {Holzschuh, Andrea and Dormann, Carsten F. and Tscharntke, Teja and Steffan-Dewenter, Ingolf}, title = {Mass-flowering crops enhance wild bee abundance}, series = {Oecologia}, volume = {172}, journal = {Oecologia}, number = {2}, doi = {dx.doi.org/10.1007/s00442-012-2515-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126852}, pages = {447-484}, year = {2013}, abstract = {Although agricultural habitats can provide enormous amounts of food resources for pollinator species, links between agricultural and (semi-)natural habitats through dispersal and foraging movements have hardly been studied. In 67 study sites, we assessed the interactions between mass-flowering oilseed rape fields and semi-natural grasslands at different spatial scales, and their effects on the number of brood cells of a solitary cavity-nesting bee. The probability that the bee Osmia bicornis colonized trap nests in oilseed rape fields increased from 12 to 59 \% when grassland was nearby, compared to fields isolated from grassland. In grasslands, the number of brood cells of O. bicornis in trap nests was 55 \% higher when adjacent to oilseed rape compared to isolated grasslands. The percentage of oilseed rape pollen in the larval food was higher in oilseed rape fields and grasslands adjacent to oilseed rape than in isolated grasslands. In both oilseed rape fields and grasslands, the number of brood cells was positively correlated with the percentage of oilseed rape pollen in the larval food. We show that mass-flowering agricultural habitats—even when they are intensively managed—can strongly enhance the abundance of a solitary bee species nesting in nearby semi-natural habitats. Our results suggest that positive effects of agricultural habitats have been underestimated and might be very common (at least) for generalist species in landscapes consisting of a mixture of agricultural and semi-natural habitats. These effects might also have—so far overlooked—implications for interspecific competition and mutualistic interactions in semi-natural habitats.}, language = {en} } @article{SchartlWalterShenetal.2013, author = {Schartl, Manfred and Walter, Ronald B. and Shen, Yingjia and Garcia, Tzintzuni and Catchen, Julian and Amores, Angel and Braasch, Ingo and Chalopin, Domitille and Volff, Jean-Nicolas and Lesch, Klaus-Peter and Bisazza, Angelo and Minx, Pat and Hillier, LaDeana and Wilson, Richard K. and F{\"u}rstenberg, Susan and Boore, Jeffrey and Searle, Steve and Postlethwait, John H. and Warren, Wesley C.}, title = {The genome of the platyfish, Xiphophorus maculatus, provides insights into evolutionary adaptation and several complex traits}, series = {Nature Genetics}, volume = {45}, journal = {Nature Genetics}, number = {5}, doi = {10.1038/ng.2604}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132152}, pages = {567-572}, year = {2013}, abstract = {Several attributes intuitively considered to be typical mammalian features, such as complex behavior, live birth and malignant disease such as cancer, also appeared several times independently in lower vertebrates. The genetic mechanisms underlying the evolution of these elaborate traits are poorly understood. The platyfish, X. maculatus, offers a unique model to better understand the molecular biology of such traits. We report here the sequencing of the platyfish genome. Integrating genome assembly with extensive genetic maps identified an unexpected evolutionary stability of chromosomes in fish, in contrast to in mammals. Genes associated with viviparity show signatures of positive selection, identifying new putative functional domains and rare cases of parallel evolution. We also find that genes implicated in cognition show an unexpectedly high rate of duplicate gene retention after the teleost genome duplication event, suggesting a hypothesis for the evolution of the behavioral complexity in fish, which exceeds that found in amphibians and reptiles.}, language = {en} } @article{LehnenZechnerHaaf2013, author = {Lehnen, Harald and Zechner, Urlich and Haaf, Thomas}, title = {Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life}, series = {Molecular Human Reproduction}, volume = {19}, journal = {Molecular Human Reproduction}, number = {7}, doi = {10.1093/molehr/gat020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132165}, pages = {415-422}, year = {2013}, abstract = {The epidemic increase of type 2 diabetes and obesity in developed countries cannot be explained by overnutrition, physical inactivity and/or genetic factors alone. Epidemiologic evidence suggests that an adverse intrauterine environment, in particular a shortage or excess of nutrients is associated with increased risks for many complex diseases later in life. An impressive example for the 'fetal origins of adult disease' is gestational diabetes mellitus which usually presents in 1\% to >10\% of third trimester pregnancies. Intrauterine hyperglycemia is not only associated with increased perinatal morbidity and mortality, but also with increased lifelong risks of the exposed offspring for obesity, metabolic, cardiovascular and malignant diseases. Accumulating evidence suggests that fetal overnutrition (and similarly undernutrition) lead to persistent epigenetic changes in developmentally important genes, influencing neuroendocrine functions, energy homeostasis and metabolism. The concept of fetal programming has important implications for reproductive medicine. Because during early development the epigenome is much more vulnerable to environmental cues than later in life, avoiding adverse environmental factors in the periconceptional and intrauterine period may be much more important for the prevention of adult disease than any (i.e. dietetic) measures in infants and adults. A successful pregnancy should not primarily be defined by the outcome at birth but also by the health status in later life.}, language = {en} } @article{HerpinAdolfiNicoletal.2013, author = {Herpin, Amaury and Adolfi, Mateus C. and Nicol, Barbara and Hinzmann, Maria and Schmidt, Cornelia and Klughammer, Johanna and Engel, Mareen and Tanaka, Minoru and Guiguen, Yann and Schartl, Manfred}, title = {Divergent Expression Regulation of Gonad Development Genes in Medaka Shows Incomplete Conservation of the Downstream Regulatory Network of Vertebrate Sex Determination}, series = {Molecular Biology and Evolution}, volume = {30}, journal = {Molecular Biology and Evolution}, number = {10}, doi = {10.1093/molbev/mst130}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132262}, pages = {2328-2346}, year = {2013}, abstract = {Genetic control of male or female gonad development displays between different groups of organisms a remarkable diversity of "master sex-determining genes" at the top of the genetic hierarchies, whereas downstream components surprisingly appear to be evolutionarily more conserved. Without much further studies, conservation of sequence has been equalized to conservation of function. We have used the medaka fish to investigate the generality of this paradigm. In medaka, the master male sex-determining gene is dmrt1bY, a highly conserved downstream regulator of sex determination in vertebrates. To understand its function in orchestrating the complex gene regulatory network, we have identified targets genes and regulated pathways of Dmrt1bY. Monitoring gene expression and interactions by transgenic fluorescent reporter fish lines, in vivo tissue-chromatin immunoprecipitation and in vitro gene regulation assays revealed concordance but also major discrepancies between mammals and medaka, notably amongst spatial, temporal expression patterns and regulations of the canonical Hedgehog and R-spondin/Wnt/Follistatin signaling pathways. Examination of Foxl2 protein distribution in the medaka ovary defined a new subpopulation of theca cells, where ovarian-type aromatase transcriptional regulation appears to be independent of Foxl2. In summary, these data show that the regulation of the downstream regulatory network of sex determination is less conserved than previously thought.}, language = {en} } @article{MollReboredoSchwarzetal.2013, author = {Moll, Corinna and Reboredo, Jenny and Schwarz, Thomas and Appelt, Antje and Sch{\"u}rlein, Sebastian and Walles, Heike and Nietzer, Sarah}, title = {Tissue Engineering of a Human 3D in vitro Tumor Test System}, series = {Journal of Visualized Experiments}, volume = {78}, journal = {Journal of Visualized Experiments}, number = {e50460}, doi = {10.3791/50460}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132277}, year = {2013}, abstract = {Cancer is one of the leading causes of death worldwide. Current therapeutic strategies are predominantly developed in 2D culture systems, which inadequately reflect physiological conditions in vivo. Biological 3D matrices provide cells an environment in which cells can self-organize, allowing the study of tissue organization and cell differentiation. Such scaffolds can be seeded with a mixture of different cell types to study direct 3D cell-cell-interactions. To mimic the 3D complexity of cancer tumors, our group has developed a 3D in vitro tumor test system. Our 3D tissue test system models the in vivo situation of malignant peripheral nerve sheath tumors (MPNSTs), which we established with our decellularized porcine jejunal segment derived biological vascularized scaffold (BioVaSc). In our model, we reseeded a modified BioVaSc matrix with primary fibroblasts, microvascular endothelial cells (mvECs) and the S462 tumor cell line For static culture, the vascular structure of the BioVaSc is removed and the remaining scaffold is cut open on one side (Small Intestinal Submucosa SIS-Muc). The resulting matrix is then fixed between two metal rings (cell crowns). Another option is to culture the cell-seeded SIS-Muc in a flow bioreactor system that exposes the cells to shear stress. Here, the bioreactor is connected to a peristaltic pump in a self-constructed incubator. A computer regulates the arterial oxygen and nutrient supply via parameters such as blood pressure, temperature, and flow rate. This setup allows for a dynamic culture with either pressure-regulated pulsatile or constant flow. In this study, we could successfully establish both a static and dynamic 3D culture system for MPNSTs. The ability to model cancer tumors in a more natural 3D environment will enable the discovery, testing, and validation of future pharmaceuticals in a human-like model.}, language = {en} } @article{VolkmannAlbaneseAntoninietal.2013, author = {Volkmann, Jens and Albanese, Alberto and Antonini, Angelo and Chaudhuri, K. Ray and Clarke, Karl E. and de Bie, Rob M. A. and Deuschl, G{\"u}nther and Eggert, Karla and Houeto, Jean-Luc and Kulisevsky, Jaime and Nyholm, Dag and Odin, Per and Ostergaard, Karen and Poewe, Werner and Pollak, Pierre and Rabey, Jose Martin and Rascol, Olivier and Ruzicka, Evzen and Samuel, Michael and Speelman, Hans and Sydow, Olof and Valldeoriola, Francesc and van der Linden, Chris and Oertel, Wolfgang}, title = {Selecting deep brain stimulation or infusion therapies in advanced Parkinson's disease: an evidence-based review}, series = {Journal of Neurology}, volume = {260}, journal = {Journal of Neurology}, doi = {10.1007/s00415-012-6798-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132373}, pages = {2701-2714}, year = {2013}, abstract = {Motor complications in Parkinson's disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.}, language = {en} } @article{HornSchellerduPlessisetal.2013, author = {Horn, Anne and Scheller, Carsten and du Plessis, Stefan and Arendt, Gabriele and Nolting, Thorsten and Joska, John and Sopper, Sieghart and Maschke, Matthias and Obermann, Mark and Husstedt, Ingo W. and Hain, Johannes and Maponga, Tongai and Riederer, Peter and Koutsilieri, Eleni}, title = {Increases in CSF dopamine in HIV patients are due to the dopamine transporter 10/10-repeat allele which is more frequent in HIV-infected individuals}, series = {Journal of Neural Transmission}, volume = {120}, journal = {Journal of Neural Transmission}, doi = {10.1007/s00702-013-1086-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132385}, pages = {1411-1419}, year = {2013}, abstract = {Dysfunction of dopaminergic neurotransmission has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy-na{\"i}ve HIV patients and an inverse correlation between CSF DA and CD4 counts in the periphery, suggesting adverse effects of high levels of DA on HIV infection. In the current study including a total of 167 HIV-positive and negative donors from Germany and South Africa (SA), we investigated the mechanistic background for the increase of CSF DA in HIV individuals. Interestingly, we found that the DAT 10/10-repeat allele is present more frequently within HIV individuals than in uninfected subjects. Logistic regression analysis adjusted for gender and ethnicity showed an odds ratio for HIV infection in DAT 10/10 allele carriers of 3.93 (95 \% CI 1.72-8.96; p = 0.001, Fishers exact test). 42.6 \% HIV-infected patients harbored the DAT 10/10 allele compared to only 10.5 \% uninfected DAT 10/10 carriers in SA (odds ratio 6.31), whereas 68.1 versus 40.9 \%, respectively, in Germany (odds ratio 3.08). Subjects homozygous for the 10-repeat allele had higher amounts of CSF DA and reduced DAT mRNA expression but similar disease severity compared with those carrying other DAT genotypes. These intriguing and novel findings show the mutual interaction between DA and HIV, suggesting caution in the interpretation of CNS DA alterations in HIV infection solely as a secondary phenomenon to the virus and open the door for larger studies investigating consequences of the DAT functional polymorphism on HIV epidemiology and progression of disease.}, language = {en} } @article{KoutsilieriLutzScheller2013, author = {Koutsilieri, E. and Lutz, M. B. and Scheller, C.}, title = {Autoimmunity, dendritic cells and relevance for Parkinson's disease}, series = {Journal of Neural Transmission}, volume = {120}, journal = {Journal of Neural Transmission}, doi = {10.1007/s00702-012-0842-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132308}, pages = {75-81}, year = {2013}, abstract = {Innate and adaptive immune responses in neurodegenerative diseases have become recently a focus of research and discussions. Parkinson's disease (PD) is a neurodegenerative disorder without known etiopathogenesis. The past decade has generated evidence for an involvement of the immune system in PD pathogenesis. Both inflammatory and autoimmune mechanisms have been recognized and studies have emphasized the role of activated microglia and T-cell infiltration. In this short review, we focus on dendritic cells, on their role in initiation of autoimmune responses, we discuss aspects of neuroinflammation and autoimmunity in PD, and we report new evidence for the involvement of neuromelanin in these processes.}, language = {en} } @article{HuppFoertschWippeletal.2013, author = {Hupp, Sabrina and F{\"o}rtsch, Christina and Wippel, Carolin and Ma, Jiangtao and Mitchell, Timothy J. and Iliev, Asparouh I.}, title = {Direct Transmembrane Interaction between Actin and the Pore-Competent, Cholesterol-Dependent Cytolysin Pneumolysin}, series = {Journal of Molecular Biology}, volume = {425}, journal = {Journal of Molecular Biology}, number = {3}, doi = {10.1016/j.jmb.2012.11.034}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132297}, pages = {636-646}, year = {2013}, abstract = {The eukaryotic actin cytoskeleton is an evolutionarily well-established pathogen target, as a large number of bacterial factors disturb its dynamics to alter the function of the host cells. These pathogenic factors modulate or mimic actin effector proteins or they modify actin directly, leading to an imbalance of the precisely regulated actin turnover. Here, we show that the pore-forming, cholesterol-dependent cytolysin pneumolysin (PLY), a major neurotoxin of Streptococcus pneumoniae, has the capacity to bind actin directly and to enhance actin polymerisation in vitro. In cells, the toxin co-localised with F-actin shortly after exposure, and this direct interaction was verified by F{\"o}rster resonance energy transfer. PLY was capable of exerting its effect on actin through the lipid bilayer of giant unilamellar vesicles, but only when its pore competence was preserved. The dissociation constant of G-actin binding to PLY in a biochemical environment was 170-190 nM, which is indicative of a high-affinity interaction, comparable to the affinity of other intracellular actin-binding factors. Our results demonstrate the first example of a direct interaction of a pore-forming toxin with cytoskeletal components, suggesting that the cross talk between pore-forming cytolysins and cells is more complex than previously thought.}, language = {en} } @article{StotzMuellerZoelleretal.2013, author = {Stotz, Henrik U. and Mueller, Stefan and Zoeller, Maria and Mueller, Martin J. and Berger, Susanne}, title = {TGA transcription factors and jasmonate-independent COI1 signalling regulate specific plant responses to reactive oxylipins}, series = {Journal of Experimental Botany}, volume = {64}, journal = {Journal of Experimental Botany}, number = {4}, doi = {10.1093/jxb/ers389}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132318}, pages = {963-975}, year = {2013}, abstract = {Jasmonates and phytoprostanes are oxylipins that regulate stress responses and diverse physiological and developmental processes. 12-Oxo-phytodienoic acid (OPDA) and phytoprostanes are structurally related electrophilic cyclopentenones, which activate similar gene expression profiles that are for the most part different from the action of the cyclopentanone jasmonic acid (JA) and its biologically active amino acid conjugates. Whereas JA-isoleucine signals through binding to COI1, the bZIP transcription factors TGA2, TGA5, and TGA6 are involved in regulation of gene expression in response to phytoprostanes. Here root growth inhibition and target gene expression were compared after treatment with JA, OPDA, or phytoprostanes in mutants of the COI1/MYC2 pathway and in different TGA factor mutants. Inhibition of root growth by phytoprostanes was dependent on COI1 but independent of jasmonate biosynthesis. In contrast, phytoprostane-responsive gene expression was strongly dependent on TGA2, TGA5, and TGA6, but not dependent on COI1, MYC2, TGA1, and TGA4. Different mutant and overexpressing lines were used to determine individual contributions of TGA factors to cyclopentenone-responsive gene expression. Whereas OPDA-induced expression of the cytochrome P450 gene CYP81D11 was primarily regulated by TGA2 and TGA5, the glutathione S-transferase gene GST25 and the OPDA reductase gene OPR1 were regulated by TGA5 and TGA6, but less so by TGA2. These results support the model that phytoprostanes and OPDA regulate differently (i) growth responses, which are COI1 dependent but jasmonate independent; and (ii) lipid stress responses, which are strongly dependent on TGA2, TGA5, and TGA6. Identification of molecular components in cyclopentenone signalling provides an insight into novel oxylipin signal transduction pathways.}, language = {en} } @article{RoesslerBrill2013, author = {R{\"o}ssler, Wolfgang and Brill, Martin F.}, title = {Parallel processing in the honeybee olfactory pathway: structure, function, and evolution}, series = {Journal of Comparative Physiology A}, volume = {199}, journal = {Journal of Comparative Physiology A}, doi = {10.1007/s00359-013-0821-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132548}, pages = {981-996}, year = {2013}, abstract = {Animals face highly complex and dynamic olfactory stimuli in their natural environments, which require fast and reliable olfactory processing. Parallel processing is a common principle of sensory systems supporting this task, for example in visual and auditory systems, but its role in olfaction remained unclear. Studies in the honeybee focused on a dual olfactory pathway. Two sets of projection neurons connect glomeruli in two antennal-lobe hemilobes via lateral and medial tracts in opposite sequence with the mushroom bodies and lateral horn. Comparative studies suggest that this dual-tract circuit represents a unique adaptation in Hymenoptera. Imaging studies indicate that glomeruli in both hemilobes receive redundant sensory input. Recent simultaneous multi-unit recordings from projection neurons of both tracts revealed widely overlapping response profiles strongly indicating parallel olfactory processing. Whereas lateral-tract neurons respond fast with broad (generalistic) profiles, medial-tract neurons are odorant specific and respond slower. In analogy to "what-" and "where" subsystems in visual pathways, this suggests two parallel olfactory subsystems providing "what-" (quality) and "when" (temporal) information. Temporal response properties may support across-tract coincidence coding in higher centers. Parallel olfactory processing likely enhances perception of complex odorant mixtures to decode the diverse and dynamic olfactory world of a social insect.}, language = {en} } @article{DrechslerRitzTomaschitzetal.2013, author = {Drechsler, Christiane and Ritz, Eberhard and Tomaschitz, Andreas and Pilz, Stefan and Sch{\"o}nfeld, Stephan and Blouin, Katja and Bidlingmaier, Martin and Hammer, Fabian and Krane, Vera and M{\"a}rz, Winfried and Allolio, Bruno and Fassnacht, Martin and Wanner, Christoph}, title = {Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients}, series = {European Heart Journal}, volume = {34}, journal = {European Heart Journal}, doi = {10.1093/eurheartj/ehs361}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132562}, pages = {578-585}, year = {2013}, abstract = {Background: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients. Methods and results: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54\% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95\% CI: 1.06-2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95\% CI: 1.32-6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95\% CI: 1.01-2.62). Conclusions: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.}, language = {en} } @article{DrechslerSchmiedekeNiemannetal.2013, author = {Drechsler, Christiane and Schmiedeke, Benjamin and Niemann, Markus and Schmiedeke, Daniel and Kr{\"a}mer, Johannes and Turkin, Irina and Blouin, Katja and Emmert, Andrea and Pilz, Stefan and Obermayer-Pietsch, Barbara and Wiedemann, Frank and Breunig, Frank and Wanner, Christoph}, title = {Potential role of vitamin D deficiency on Fabry cardiomyopathy}, series = {Journal of Inherited Metabolic Disease}, volume = {37}, journal = {Journal of Inherited Metabolic Disease}, number = {2}, doi = {10.1007/s10545-013-9653-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132102}, pages = {289-295}, year = {2013}, abstract = {Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 ± 13 years (42 \% males), and a mean 25(OH)D of 23.5 ± 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D ≤ 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 ± 75 g in deficient, 154 ± 60 g in moderately deficient and 128 ± 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial.}, language = {en} } @article{FrantzKlaiberBabaetal.2013, author = {Frantz, Stefan and Klaiber, Michael and Baba, Hideo A. and Oberwinkler, Heinz and V{\"o}lker, Katharina and Gaßner, Birgit and Bayer, Barbara and Abeßer, Marco and Schuh, Kai and Feil, Robert and Hofmann, Franz and Kuhn, Michaela}, title = {Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I}, series = {European Heart Journal}, volume = {34}, journal = {European Heart Journal}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134693}, pages = {1233-1244}, year = {2013}, abstract = {Aims: Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism. Methods and results: To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the \([Ca^{2+}]_i\)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte \(Ca^{2+}_i\) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, \(Ca^{2+}_i\)-handling, and contractility via cGKI. Conclusion: These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte \(Ca^{2+}_i\) handling and contractility.}, language = {en} } @article{WetzelJablonkaBlum2013, author = {Wetzel, Andrea and Jablonka, Sibylle and Blum, Robert}, title = {Cell-autonomous axon growth of young motoneurons is triggered by a voltage-gated sodium channel}, series = {Channels (Austin)}, volume = {7}, journal = {Channels (Austin)}, number = {1}, doi = {10.4161/chan.23153}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132586}, pages = {51-56}, year = {2013}, abstract = {Spontaneous electrical activity preceding synapse formation contributes to the precise regulation of neuronal development. Examining the origins of spontaneous activity revealed roles for neurotransmitters that depolarize neurons and activate ion channels. Recently, we identified a new molecular mechanism underlying fluctuations in spontaneous neuronal excitability. We found that embryonic motoneurons with a genetic loss of the low-threshold sodium channel Na\(_V\)1.9 show fewer fluctuations in intracellular calcium in axonal compartments and growth cones than wild-type littermates. As a consequence, axon growth of Na\(_V\)1.9-deficient motoneurons in cell culture is drastically reduced while dendritic growth and cell survival are not affected. Interestingly, Na\(_V\)1.9 function is observed under conditions that would hardly allow a ligand- or neurotransmitter-dependent depolarization. Thus, Na\(_V\)1.9 may serve as a cell-autonomous trigger for neuronal excitation. In this addendum, we discuss a model for the interplay between cell-autonomous local neuronal activity and local cytoskeleton dynamics in growth cone function.}, language = {en} } @article{BonnSchmittLeschetal.2013, author = {Bonn, M. and Schmitt, A. and Lesch, K.-P. and Van Bockstaele, E. J. and Asan, E.}, title = {Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei}, series = {Brain Structure and Function}, volume = {218}, journal = {Brain Structure and Function}, number = {2}, doi = {10.1007/s00429-012-0406-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132591}, pages = {421-435}, year = {2013}, abstract = {Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 \%, and about 30-40 \% of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala.}, language = {en} } @article{BloemerPachelHofmannetal.2013, author = {Bl{\"o}mer, Nadja and Pachel, Christina and Hofmann, Urlich and Nordbeck, Peter and Bauer, Wolfgang and Mathes, Denise and Frey, Anna and Bayer, Barbara and Vogel, Benjamin and Ertl, Georg}, title = {5-Lipoxygenase facilitates healing after myocardial infarction}, series = {Basic Research in Cardiology}, volume = {108}, journal = {Basic Research in Cardiology}, number = {4}, doi = {10.1007/s00395-013-0367-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132602}, year = {2013}, abstract = {Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX\(^{-/-}\) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX\(^{-/-}\) bone marrow in 5-LOX\(^{-/-}\) animals), indicating that an altered function of 5-LOX\(^{-/-}\) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX\(^{-/-}\) mice in vivo after MI. This might be due to an impaired migration of 5-LOX\(^{-/-}\) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function.}, language = {en} } @article{HofmannFrantz2013, author = {Hofmann, Ulrich and Frantz, Stefan}, title = {How can we cure a heart "in flame"? A translational view on inflammation in heart failure}, series = {Basic Research in Cardiology}, volume = {108}, journal = {Basic Research in Cardiology}, number = {356}, doi = {10.1007/s00395-013-0356-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134497}, year = {2013}, abstract = {The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term "inflammation". Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-a led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective.}, language = {en} } @article{HolzapfelChhayaMelchelsetal.2013, author = {Holzapfel, Boris Michael and Chhaya, Mohit Prashant and Melchels, Ferry Petrus Wilhelmus and Holzapfel, Nina Pauline and Prodinger, Peter Michael and von Eisenhart-Rothe, R{\"u}diger and Griensven, Martijn van and Schantz, Jan-Thorsten and Rudert, Maximilian and Hutmacher, Dietmar Werner}, title = {Can Bone Tissue Engineering Contribute to Therapy Concepts after Resection of Musculoskeletal Sarcoma?}, series = {Sarcoma}, volume = {2013}, journal = {Sarcoma}, number = {Article ID 153640}, doi = {10.1155/2013/153640}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132465}, pages = {10 p.}, year = {2013}, abstract = {Resection of musculoskeletal sarcoma can result in large bone defects where regeneration is needed in a quantity far beyond the normal potential of self-healing. In many cases, these defects exhibit a limited intrinsic regenerative potential due to an adjuvant therapeutic regimen, seroma, or infection. Therefore, reconstruction of these defects is still one of the most demanding procedures in orthopaedic surgery. The constraints of common treatment strategies have triggered a need for new therapeutic concepts to design and engineer unparalleled structural and functioning bone grafts. To satisfy the need for long-term repair and good clinical outcome, a paradigm shift is needed from methods to replace tissues with inert medical devices to more biological approaches that focus on the repair and reconstruction of tissue structure and function. It is within this context that the field of bone tissue engineering can offer solutions to be implemented into surgical therapy concepts after resection of bone and soft tissue sarcoma. In this paper we will discuss the implementation of tissue engineering concepts into the clinical field of orthopaedic oncology.}, language = {en} } @article{HedrichHofmannPabliketal.2013, author = {Hedrich, Christian M. and Hofmann, Sigrun R. and Pablik, Jessica and Morbach, Henner and Girschick, Hermann J.}, title = {Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)}, series = {Pediatric Rheumatology}, volume = {11}, journal = {Pediatric Rheumatology}, number = {47}, doi = {10.1186/1546-0096-11-47}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132456}, year = {2013}, abstract = {Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear. Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.}, language = {en} }