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 -