TY - JOUR A1 - Montelius, Mikael A1 - Ljungberg, Maria A1 - Horn, Michael A1 - Forssell-Aronsson, Eva T1 - Tumour size measurement in a mouse model using high resolution MRI JF - BMC Medical Imaging N2 - Background Animal models are frequently used to assess new treatment methods in cancer research. MRI offers a non-invasive in vivo monitoring of tumour tissue and thus allows longitudinal measurements of treatment effects, without the need for large cohorts of animals. Tumour size is an important biomarker of the disease development, but to our knowledge, MRI based size measurements have not yet been verified for small tumours (10−2–10−1 g). The aim of this study was to assess the accuracy of MRI based tumour size measurements of small tumours on mice. Methods 2D and 3D T2-weighted RARE images of tumour bearing mice were acquired in vivo using a 7 T dedicated animal MR system. For the 3D images the acquired image resolution was varied. The images were exported to a PC workstation where the tumour mass was determined assuming a density of 1 g/cm3, using an in-house developed tool for segmentation and delineation. The resulting data were compared to the weight of the resected tumours after sacrifice of the animal using regression analysis. Results Strong correlations were demonstrated between MRI- and necropsy determined masses. In general, 3D acquisition was not a prerequisite for high accuracy. However, it was slightly more accurate than 2D when small (<0.2 g) tumours were assessed for inter- and intraobserver variation. In 3D images, the voxel sizes could be increased from 1603 μm3 to 2403 μm3 without affecting the results significantly, thus reducing acquisition time substantially. Conclusions 2D MRI was sufficient for accurate tumour size measurement, except for small tumours (<0.2 g) where 3D acquisition was necessary to reduce interobserver variation. Acquisition times between 15 and 50 minutes, depending on tumour size, were sufficient for accurate tumour volume measurement. Hence, it is possible to include further MR investigations of the tumour, such as tissue perfusion, diffusion or metabolic composition in the same MR session. KW - cancer KW - magnetic resonance KW - animal model KW - volume determination Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124049 VL - 12 IS - 12 ER - TY - JOUR A1 - Dorsch, Oliver A1 - Krieter, Detlef H. A1 - Lemke, Horst-Dieter A1 - Fischer, Stefan A1 - Melzer, Nima A1 - Sieder, Christian A1 - Bramlage, Peter A1 - Harenberg, Job T1 - A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis – the membrane study JF - BMC Nephrology N2 - Background Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results 120 patients were screened, 109 enrolled (median age 71; range 26–90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9% (n = 2/106; 95% confidence interval [CI] 0.23–6.65%); no major bleeding. 1.9% had moderate/severe clotting in the lines/bubble catcher and 2.8% in the dialyser at week 8. 15.7 ± 14.3% of the dialysis filters’ visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 ± 0, 3000 (2400–6000) and 4200 (3000–6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [95%CI 0.21–0.27], 0.33 [0.27–0.40] and 0.38 [0.33–0.45] aXa IU/ml at 2 h. \(C_{48h}\) was 0.01 [0.01–0.02] aXa IU at all visits. At baseline and 4 weeks \(AUC_{0-48h}\) was 2.66 [2.19–3.24] and 3.66 [3.00–4.45] aXa IU*h/ml. In 3.0% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34%) had at least one episode of minor bleeding. 4) 85.3% of patients had any adverse event, 9.2% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis. KW - hemodialysis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124052 VL - 13 IS - 50 ER - TY - JOUR A1 - Nass, Maximilian A1 - Weissbrich, Benedikt A1 - Huber, Moritz A1 - Schneider, Elisabeth Marion A1 - Weiss, Manfred T1 - BK viremia in critically ill surgical patients with hemorrhagic or septic shock JF - BMC Research Notes N2 - Background Infections with polyomavirus BK virus (BKV) are a common cause of renal dysfunction after renal transplantation and may also be harmful in surgical patients with shock. The aim of the present study was to determine the frequency of BKV viremia in critically ill surgical patients with septic or hemorrhagic shock, and, if viremia is detectable, whether viremia may be associated with renal dysfunction. Findings A total of 125 plasma samples from 44 critically ill surgical patients with septic or hemorrhagic shock were tested by real-time polymerase chain reaction (PCR) for BKV DNA during their stay on the intensive care unit (ICU). BKV viremia occurred in four patients, i.e. in three of the septic and in one of the hemorrhagic shock group. There was no association between viremia and renal dysfunction. All positive samples contained a low viral load (< 500 copies/ml). Conclusions Since BK viremia was rarely found and with low viral load only in critically ill surgical patients with shock, it is very unlikely that BK viremia results in BK nephropathy later on. KW - acute kidney injury KW - BK virus KW - polyomavirus KW - critically ill KW - sepsis KW - shock Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124136 VL - 5 IS - 100 ER - TY - JOUR A1 - Nolte, Thomas A1 - Zadeh-Khorasani, Maryam A1 - Safarov, Orkhan A1 - Rueff, Franziska A1 - Varga, Rita A1 - Herbach, Nadja A1 - Wanke, Rüdiger A1 - Wollenberg, Andreas A1 - Mueller, Thomas A1 - Gropp, Roswitha A1 - Wolf, Eckhard A1 - Siebeck, Matthias T1 - Induction of oxazolone-mediated features of atopic dermatitis in NOD-scid \(IL2Rγ^{null}\) mice engrafted with human peripheral blood mononuclear cells JF - Disease Models and Mechanisms N2 - Animal models mimicking human diseases have been used extensively to study the pathogenesis of autoimmune diseases and the efficacy of potential therapeutics. They are, however, limited with regard to their similarity to the human disease and cannot be used if the antagonist and its cognate receptor require high similarity in structure or binding. Here, we examine the induction of oxazolone-mediated features of atopic dermatitis (AD) in NOD-scid IL2Rγnull mice engrafted with human peripheral blood mononuclear cells (PBMC). The mice developed the same symptoms as immunocompetent BALB/c mice. Histological alterations induced by oxazolone were characterized by keratosis, epithelial hyperplasia and influx of inflammatory cells into the dermis and epidermis. The cellular infiltrate was identified as human leukocytes, with T cells being the major constituent. In addition, oxazolone increased human serum IgE levels. The response, however, required the engraftment of PBMC derived from patients suffering from AD, which suggests that this model reflects the immunological status of the donor. Taken together, the model described here has the potential to evaluate the efficacy of therapeutics targeting human lymphocytes in vivo and, in addition, might be developed further to elucidate molecular mechanisms inducing and sustaining flares of the disease. KW - human diseases Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124150 VL - 6 ER - TY - JOUR A1 - Franke, B. A1 - Faraone, S. V. A1 - Asherson, P. A1 - Buitelaar, J. A1 - Bau, C. H. D. A1 - Ramos-Quiroga, J. A. A1 - Mick, E. A1 - Grevet, E. H. A1 - Johansson, S. A1 - Haavik, J. A1 - Lesch, K.-P. A1 - Cormand, B. A1 - Reif, A. T1 - The genetics of attention deficit/hyperactivity disorder in adults, a review JF - Molecular Psychiatry N2 - The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30–40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood. KW - IMpACT KW - persistent ADHD KW - molecular genetics KW - heritability KW - endophenotype Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124677 VL - 17 ER - TY - JOUR A1 - Dietz, U. A. A1 - Wichelmann, C. A1 - Wunder, C. A1 - Kauczok, J. A1 - Spor, L. A1 - Strauß, A. A1 - Wildenauer, R. A1 - Jurowich, C. A1 - Germer, C. T. T1 - Early repair of open abdomen with a tailored two-component mesh and conditioning vacuum packing: a safe alternative to the planned giant ventral hernia JF - Hernia N2 - Purpose Once open abdomen therapy has succeeded, the problem of closing the abdominal wall must be addressed. We present a new four-stage procedure involving the application of a two-component mesh and vacuum conditioning for abdominal wall closure of even large defects. The aim is to prevent the development of a giant ventral hernia and the eventual need for the repair of the abdominal wall. Methods Nineteen of 62 patients treated by open abdomen over a two-year period could not receive primary abdominal wall closure. To achieve closure in these patients, we applied the following four-stage procedure: stage 1: abdominal damage control and conditioning of the abdominal wall; stage 2: attachment of a tailored two-component mesh of polyglycolic acid (PGA) and large pore polypropylene (PP) in intraperitoneal position (IPOM) plus placement of a vacuum bandage; stage 3: vacuum therapy for 3–4 weeks to allow granulation of the mesh and optimization of dermatotraction; stage 4: final skin suture. During stage 3, eligible patients were weaned from respirator and mobilized. Results The abdominal wall gap in the 19 patients ranged in size from 240 cm2 to more than 900 cm2. An average of 3.44 vacuum dressing changes over 19 days were required to achieve 60–100 % granulation of the surface area, so final skin suture could be made. Already in stage 3, 14 patients (73.68 %) could be weaned from respirator an average of 6.78 days after placement of the two-component mesh; 6 patients (31.57 %) could be mobilized on the edge of the bed and/or to a bedside chair after an average of 13 days. No mesh-related hematomas, seromas, or intestinal fistulas were observed. Conclusion The four-stage procedure presented here is a viable option for achieving abdominal wall closure in patients treated with open abdomen, enabling us to avoid the development of planned giant ventral hernias. It has few complications and has the special advantage of allowing mobilization of the patients before final skin closure. Long-term course in a large number of patients must still confirm this result. KW - synthetic mesh KW - open abdomen KW - laparostomy KW - giant ventral hernia KW - vacuum conditioning Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124686 VL - 16 IS - 4 ER - TY - JOUR A1 - Radermacher, Kim A. A1 - Wingler, Kirstin A1 - Kleikers, Pamela A1 - Altenhöfer, Sebastian A1 - Hermans, Johannes J. R. A1 - Kleinschnitz, Christoph A1 - Schmidt, Harald H. H. W. T1 - The 1027th target candidate in stroke: Will NADPH oxidase hold up? JF - Experimental and Translational Stroke Medicine N2 - As recently reviewed, 1026 neuroprotective drug candidates in stroke research have all failed on their road towards validation and clinical translation, reasons being quality issues in preclinical research and publication bias. Quality control guidelines for preclinical stroke studies have now been established. However, sufficient understanding of the underlying mechanisms of neuronal death after stroke that could be possibly translated into new therapies is lacking. One exception is the hypothesis that cellular death is mediated by oxidative stress. Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources. Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS. Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4. Here we discuss the state-of-the-art of this target with respect to stroke and open questions that need to be addressed on the path towards clinical translation. KW - NADPH oxidases (NOX) KW - stroke therapy KW - oxidative stress Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124197 VL - 4 IS - 11 ER - TY - JOUR A1 - Langhauser, Friederike L. A1 - Heiler, Patrick M. A1 - Grudzenski, Saskia A1 - Lemke, Andreas A1 - Alonso, Angelika A1 - Schad, Lothar R. A1 - Hennerici, Michael G. A1 - Meairs, Stephen A1 - Fata, Marc T1 - Thromboembolic stroke in C57BL/6 mice monitored by 9.4 T MRI using a 1H cryo probe JF - Experimental and Translational Stroke Medicine N2 - Background A new thromboembolic animal model showed beneficial effects of t-PA with an infarct volume reduction of 36.8% in swiss mice. Because knock-out animal experiments for stroke frequently used C57BL76 mice we evaluated t-PA effects in this mouse strain and measured infarct volume and vascular recanalisation in-vivo by using high-field 9.4 T MRI and a 1H surface cryo coil. Methods Clot formation was triggered by microinjection of murine thrombin into the right middle cerebral artery (MCA). Animals (n = 28) were treated with 10 mg/kg, 5 mg/kg or no tissue plasminogen activator (t-PA) 40 min after MCA occlusion. For MR-imaging a Bruker 9.4 T animal system with a 1H surface cryo probe was used and a T2-weighted RARE sequence, a diffusion weighted multishot EPI sequence and a 3D flow-compensated gradient echo TOF angiography were performed. Results The infarct volume in animals treated with t-PA was significantly reduced (0.67 ± 1.38 mm3 for 10 mg/kg and 10.9 ± 8.79 mm3 for 5 mg/kg vs. 19.76 ± 2.72 mm3 ; p < 0.001) compared to untreated mice. An additional group was reperfused with t-PA inside the MRI. Already ten minutes after beginning of t-PA treatment, reperfusion flow was re-established in the right MCA. However, signal intensity was lower than in the contralateral MCA. This reduction in cerebral blood flow was attenuated during the first 60 minutes after reperfusion. 24 h after MCA occlusion and reperfusion, no difference in signal intensity of the contralateral and ipsilateral MCAs was observed. Conclusions We confirm a t-Pa effect using this stroke model in the C57BL76 mouse strain and demonstrate a chronological sequence MRI imaging after t-PA using a 1H surface cryo coil in a 9.4 T MRI. This setting will allow testing of new thrombolytic strategies for stroke treatment in-vivo in C57BL76 knock-out mice. KW - animal models KW - MRI KW - experimental KW - embolic stroke KW - T-PA Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124218 VL - 4 IS - 18 ER - TY - JOUR A1 - Wild, J. M. A1 - Marshall, H. A1 - Bock, M. A1 - Schad, L. R. A1 - Jakob, P. M. A1 - Puderbach, M. A1 - Molinari, F. A1 - Van Beek, E. J. R. A1 - Biederer, J. T1 - MRI of the lung (1/3): methods JF - Insights into Imaging N2 - Proton magnetic resonance imaging (MRI) has recently emerged as a clinical tool to image the lungs. This paper outlines the current technical aspects of MRI pulse sequences, radiofrequency (RF) coils and MRI system requirements needed for imaging the pulmonary parenchyma and vasculature. Lung MRI techniques are presented as a “technical toolkit”, from which MR protocols will be composed in the subsequent papers for comprehensive imaging of lung disease and function (parts 2 and 3). This paper is pitched at MR scientists, technicians and radiologists who are interested in understanding and establishing lung MRI methods. Images from a 1.5 T scanner are used for illustration of the sequences and methods that are highlighted. Main Messages • Outline of the hardware and pulse sequence requirements for proton lung MRI • Overview of pulse sequences for lung parenchyma, vascular and functional imaging with protons • Demonstration of the pulse-sequence building blocks for clinical lung MRI protocols KW - MRI KW - lung KW - proton Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124238 VL - 3 IS - 4 ER - TY - JOUR A1 - Biederer, J. A1 - Beer, M. A1 - Hirsch, W. A1 - Wild, J. A1 - Fabel, M. A1 - Puderbach, M. A1 - Van Beek, E. J. R. T1 - MRI of the lung (2/3). Why … when … how? JF - Insights into Imaging N2 - Background Among the modalities for lung imaging, proton magnetic resonance imaging (MRI) has been the latest to be introduced into clinical practice. Its value to replace X-ray and computed tomography (CT) when radiation exposure or iodinated contrast material is contra-indicated is well acknowledged: i.e. for paediatric patients and pregnant women or for scientific use. One of the reasons why MRI of the lung is still rarely used, except in a few centres, is the lack of consistent protocols customised to clinical needs. Methods This article makes non-vendor-specific protocol suggestions for general use with state-of-the-art MRI scanners, based on the available literature and a consensus discussion within a panel of experts experienced in lung MRI. Results Various sequences have been successfully tested within scientific or clinical environments. MRI of the lung with appropriate combinations of these sequences comprises morphological and functional imaging aspects in a single examination. It serves in difficult clinical problems encountered in daily routine, such as assessment of the mediastinum and chest wall, and even might challenge molecular imaging techniques in the near future. Conclusion This article helps new users to implement appropriate protocols on their own MRI platforms. Main Messages • MRI of the lung can be readily performed on state-of-the-art 1.5-T MRI scanners. • Protocol suggestions based on the available literature facilitate its use for routine • MRI offers solutions for complicated thoracic masses with atelectasis and chest wall invasion. • MRI is an option for paediatrics and science when CT is contra-indicated KW - magnetic resonance imaging KW - lung KW - sequence imaging protocol Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124268 VL - 3 IS - 4 ER - TY - JOUR A1 - Biederer, Jürgen A1 - Mirsadraee, S. A1 - Beer, M. A1 - Molinari, F. A1 - Hintze, C. A1 - Bauman, G. A1 - Both, M. A1 - Van Beek, E. J. R. A1 - Wild, J. A1 - Puderbach, M. T1 - MRI of the lung (3/3)—current applications and future perspectives JF - Insights into Imaging N2 - Background MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. Methods Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. Results In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a “buffet” of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. Conclusion New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations. KW - functional imaging KW - magnetic resonance imaging KW - cystic fibrosis KW - pulmonary embolism KW - tumor KW - infiltrate Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124348 VL - 3 IS - 4 ER - TY - JOUR A1 - Durrenberger, Pascal F. A1 - Grünblatt, Edna A1 - Fernando, Francesca S. A1 - Monoranu, Camelia Maria A1 - Evans, Jordan A1 - Riederer, Peter A1 - Reynolds, Richard A1 - Dexter, David T. T1 - Inflammatory Pathways in Parkinson’s Disease; A BNE Microarray Study JF - Parkinson's Disease N2 - The aetiology of Parkinson's disease (PD) is yet to be fully understood but it is becoming more and more evident that neuronal cell death may be multifactorial in essence. The main focus of PD research is to better understand substantia nigra homeostasis disruption, particularly in relation to the wide-spread deposition of the aberrant protein α-synuclein. Microarray technology contributed towards PD research with several studies to date and one gene, ALDH1A1 (Aldehyde dehydrogenase 1 family, member A1), consistently reappeared across studies including the present study, highlighting dopamine (DA) metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Neuronal cell death leads to increased inflammation through the activation of astrocytes and microglia. Using our dataset, we aimed to isolate some of these pathways so to offer potential novel neuroprotective therapeutic avenues. To that effect our study has focused on the upregulation of P2X7 (purinergic receptor P2X, ligand-gated ion channel, 7) receptor pathway (microglial activation) and on the NOS3 (nitric oxide synthase 3) pathway (angiogenesis). In summary, although the exact initiator of striatal DA neuronal cell death remains to be determined, based on our analysis, this event does not remain without consequence. Extracellular ATP and reactive astrocytes appear to be responsible for the activation of microglia which in turn release proinflammatory cytokines contributing further to the parkinsonian condition. In addition to tackling oxidative stress pathways we also suggest to reduce microglial and endothelial activation to support neuronal outgrowth. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124380 VL - 2012 IS - 214714 ER - TY - JOUR A1 - Rall, Susanne A1 - Grimm, Tiemo T1 - Survival in Duchenne muscular dystrophy JF - Acta Myologica N2 - Objective: To determine the survival in a population of German patients with Duchenne muscular dystrophy. Patients and methods: Information about 94 patients born between 1970 and 1980 was obtained by telephone interviews and questionnaires. In addition to age of death or actual age during the investigation, data concerning clinical course and medical interventions were collected. Results: 67 patients with molecularly confirmed diagnoses had a median survival of 24.0 years. Patients without molecular confirmation (clinical diagnosis only) had a chance of 67 % to reach that age. Grouping of our patient cohort according to the year of death (before and after 2000), ventilation was recognized as main intervention affecting survival with ventilated reaching a median survival of 27.0 years. For those without ventilation it was 19.0 years. Conclusion and clinical relevance: our study provides survival data for a cohort of DMD patients in Germany stratified by year of death. Median survival was 24.0 years in patients confirmed by molecular testing. Ventilated patients had a median survival of 27 years. We consider this piece of information helpful in the medical care of DMD patients. KW - survival KW - duchenne muscular dystrophy KW - ventilation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124404 VL - 31 IS - 2 ER - TY - JOUR A1 - Steppuhn, Henriette A1 - Langen, Ute A1 - Scheidt-Nave, Christa A1 - Keil, Thomas T1 - Major comorbid conditions in asthma and association with asthma-related hospitalizations and emergency department admissions in adults: results from the German national health telephone interview survey (GEDA) 2010 JF - BMC Pulmonary Medicine N2 - Background: It remains unclear to what extent asthma in adults is linked to allergic rhinitis (AR), gastroesophageal reflux disease (GERD), and acetylsalicylic acid exacerbated respiratory disease (AERD), and how these comorbidities may affect asthma outcomes in the general population. We therefore aimed to assess the prevalence of these major comorbidities among adults with asthma and examine their impact on asthma exacerbations requiring hospital care. Methods: A total of 22,050 adults 18 years and older were surveyed in the German National Health Telephone Interview Survey (GEDA) 2010 using a highly standardized computer-assisted interview technique. The study population comprised participants with self-reported physician-diagnosed asthma, among which the current (last 12 months) prevalence of AR and GERD-like symptoms (GERS), and life-time prevalence of AERD was estimated. Weighted bivariate analyses and logistic regression models were applied to assess the association of each comorbid condition with the asthma outcome (any self-reported asthma-related hospitalization and/or emergency department (ED) admission in the past year). Results: Out of 1,136 adults with asthma, 49.6% had GERS and 42.3% had AR within the past 12 months; 14.0% met the criteria of AERD, and 75.7% had at least one out of the three conditions. Overall, the prevalence of at least one exacerbation requiring emergency room or hospital admission within the past year was 9.0%. Exacerbation prevalence was higher among participants with comorbidities than among those without (9.8% vs. 8.2% for GERS; 11.2% vs. 7.6% for AR, and 22.2% vs. 7.0% for AERD), but only differences in association with AERD were statistically significant. A strong association between asthma exacerbation and AERD persisted in multivariable logistic regression analyses adjusting for sex, age group, level of body mass index, smoking status, educational attainment, and duration of asthma: odds ratio (OR) = 4.5, 95% confidence interval (CI) = 2.5-8.2. Conclusions: Data from this large nation-wide study provide evidence that GERS, AR and AERD are all common comorbidities among adults with asthma. Our data underline the public health and clinical impact of asthma with complicating AERD, contributing considerably to disease-specific hospitalization and/or ED admission in a defined asthma population, and emphasize the importance of its recognition in asthma care. KW - management KW - update KW - impact KW - risk KW - severity KW - prevalence KW - clinical-practice KW - aspirin sensitivity KW - allergic rhinitis KW - exacebrated respiratory-disease KW - gastroesophageal reflux disease KW - gastroesophageal reflux KW - hospitalization KW - national health survey KW - acetylsalicylic acid exacerbated respiratory disease KW - adult KW - aspirin-induced asthma KW - asthma Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122121 VL - 13 IS - 46 ER - TY - JOUR A1 - Kunath, Frank A1 - Krause, Steffen F. A1 - Wullich, Bernd A1 - Goebell, Peter J. A1 - Engehausen, Dirk G. A1 - Burger, Maximilian A1 - Meerpohl, Joerg J. A1 - Keck, Bastian T1 - Bladder cancer - the neglected tumor: a descriptive analysis of publications referenced in MEDLINE and data from the register clinicaltrials.gov JF - BMC Urology N2 - Background: Uro-oncological neoplasms have both a high incidence and mortality rate and are therefore a major public health problem. The aim of this study was to evaluate research activity in uro-oncology over the last decade. Methods: We searched MEDLINE and ClinicalTrials.gov systematically for studies on prostatic, urinary bladder, kidney, and testicular neoplasms. The increase in newly published reports per year was analyzed using linear regression. The results are presented with 95% confidence intervals, and a p value <0.05 was considered statistically significant. Results: The number of new publications per year increased significantly for prostatic, kidney and urinary bladder neoplasms (all <0.0001). We identified 1,885 randomized controlled trials (RCTs); also for RCTs, the number of newly published reports increased significantly for prostatic (p = 0.001) and kidney cancer (p = 0.005), but not for bladder (p = 0.09) or testicular (p = 0.44) neoplasms. We identified 3,114 registered uro-oncological studies in ClinicalTrials.gov. However, 85% of these studies are focusing on prostatic (45%) and kidney neoplasms (40%), whereas only 11% were registered for bladder cancers. Conclusions: While the number of publications on uro-oncologic research rises yearly for prostatic and kidney neoplasms, urothelial carcinomas of the bladder seem to be neglected despite their important clinical role. Clinical research on neoplasms of the urothelial bladder must be explicitly addressed and supported. KW - update KW - kidney neoplasms KW - prostatic neoplasms KW - randomized controlled trial KW - testicular neoplasms KW - surgery KW - journals KW - EAU guidelines KW - radical cystectomy KW - urinary bladder neoplasms KW - controlled clinical-trials Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122133 VL - 13 IS - 56 ER - TY - JOUR A1 - Timofeev, Oleg A1 - Schlereth, Katharina A1 - Wanzel, Michael A1 - Braun, Attila A1 - Nieswandt, Bernhard A1 - Pagenstecher, Axel A1 - Rosenwald, Andreas A1 - Elsässer, Hans-Peter A1 - Stiewe, Thorsten T1 - p53 DNA Binding Cooperativity Is Essential for Apoptosis and Tumor Suppression In Vivo JF - Cell Reports N2 - Four molecules of the tumor suppressor p53 assemble to cooperatively bind proapoptotic target genes. The structural basis for cooperativity consists of interactions between adjacent DNA binding domains. Mutations at the interaction interface that compromise cooperativity were identified in cancer patients, suggesting a requirement of cooperativity for tumor suppression. We report on an analysis of cooperativity mutant p53(E177R) mice. Apoptotic functions of p53 triggered by DNA damage and oncogenes were abolished in these mice, whereas functions in cell-cycle control, senescence, metabolism, and antioxidant defense were retained and were sufficient to suppress development of spontaneous T cell lymphoma. Cooperativity mutant mice are nevertheless highly cancer prone and susceptible to different oncogene-induced tumors. Our data underscore the relevance of DNA binding cooperativity for p53-dependent apoptosis and tumor suppression and highlight cooperativity mutations as a class of p53 mutations that result in a selective loss of apoptotic functions due to an altered quaternary structure of the p53 tetramer. KW - mutant p53 KW - senescence KW - mice KW - tumorigenesis KW - restoration KW - damage responses KW - antioxidant function KW - p53-inducible regulator KW - p53-dependent apoptosis KW - cell-cycle arrest Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122168 VL - 3 ER - TY - JOUR A1 - Jain, M. A1 - Vélez, J. I. A1 - Acosta, M. T. A1 - Palacio, L. G. A1 - Balog, J. A1 - Roessler, E. A1 - Pineda, D. A1 - Londoño, A. C. A1 - Palacio, J. D. A1 - Arbelaez, A. A1 - Lopera, F. A1 - Elia, J. A1 - Hakonarson, H. A1 - Seitz, C. A1 - Freitag, C. M. A1 - Palmason, H. A1 - Meyer, J. A1 - Romanos, M. A1 - Walitza, S. A1 - Hemminger, U. A1 - Warnke, A. A1 - Romanos, J. A1 - Renner, T. A1 - Jacob, C. A1 - Lesch, K.-P. A1 - Swanson, J. A1 - Castellanos, F. X. A1 - Bailey-Wilson, J. E. A1 - Arcos-Burgos, M. A1 - Muenke, M. T1 - A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD JF - Molecular Psychiatry N2 - In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10−8) and 11q and 17p (P<1 × 10−6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q–11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome. KW - ADHD KW - genetic interaction KW - LPHN3 KW - NCAM1 KW - DRD2 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125128 VL - 17 ER - TY - JOUR A1 - Gerlach, Manfred A1 - Maetzler, Walter A1 - Broich, Karl A1 - Hampel, Harald A1 - Rems, Lucas A1 - Reum, Torsten A1 - Riederer, Peter A1 - Stäffler, Albrecht A1 - Streffer, Johannes A1 - Berg, Daniela T1 - Biomarker candidates of neurodegeneration in Parkinson's disease for the evaluation of disease-modifying therapeutics JF - Journal of Neural Transmission N2 - Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies. KW - disease progression KW - biomarkers KW - neuroprotection KW - disease-modifying therapies KW - Parkinson’s disease KW - surrogate endpoints KW - drug development Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125375 VL - 119 IS - 1 ER - TY - JOUR A1 - Galetzka, Danuta A1 - Hansmann, Tamara A1 - El Hajj, Nady A1 - Weis, Eva A1 - Irmscher, Benjamin A1 - Ludwig, Marco A1 - Schneider-Rätzke, Brigitte A1 - Kohlschmidt, Nicolai A1 - Beyer, Vera A1 - Bartsch, Oliver A1 - Zechner, Ulrich A1 - Spix, Claudia A1 - Haaf, Thomas T1 - Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer JF - Epigenetics N2 - We describe monozygotic twins discordant for childhood leukemia and secondary thyroid carcinoma. We used bisulfite pyrosequencing to compare the constitutive promoter methylation of BRCA1 and several other tumor suppressor genes in primary fibroblasts. The affected twin displayed an increased BRCA1 methylation (12%), compared with her sister (3%). Subsequent bisulfite plasmid sequencing demonstrated that 13% (6 of 47) BRCA1 alleles were fully methylated in the affected twin, whereas her sister displayed only single CpG errors without functional implications. This between-twin methylation difference was also found in irradiated fibroblasts and untreated saliva cells. The BRCA1 epimutation may have originated by an early somatic event in the affected twin: approximately 25% of her body cells derived from different embryonic cell lineages carry one epigenetically inactivated BRCA1 allele. This epimutation was associated with reduced basal protein levels and a higher induction of BRCA1 after DNA damage. In addition, we performed a genome-wide microarray analysis of both sisters and found several copy number variations, i.e., heterozygous deletion and reduced expression of the RSPO3 gene in the affected twin. This monozygotic twin pair represents an impressive example of epigenetic somatic mosaicism, suggesting a role for constitutive epimutations, maybe along with de novo genetic alterations in recurrent tumor development. KW - BRCA1 KW - childhood cancer KW - DNA Methylation KW - epimutation KW - monozygotic twins KW - secondary cancer KW - somatic mosaicism Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125386 VL - 7 IS - 1 ER - TY - JOUR A1 - Horn, Michael A1 - Baumann, Reto A1 - Pereira, Jorge A. A1 - Sidiropoulos, Páris N. M. A1 - Somandin, Christian A1 - Welzl, Hans A1 - Stendel, Claudia A1 - Lühmann, Tessa A1 - Wessig, Carsten A1 - Toyka, Klaus V. A1 - Relvas, João B. A1 - Senderek, Jan A1 - Suter, Ueli T1 - Myelin is dependent on the Charcot–Marie–Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells JF - Brain N2 - Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot–Marie–Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4–Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4–Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies. KW - Frabin/Fgd4 KW - myelination KW - hereditary motor and sensory neuropathy KW - Charcot–Marie–Tooth disease KW - Rho-GTPase Cdc42 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125390 VL - 135 ER -