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1.  Does Chronic Idiopathic Dizziness Reflect an Impairment of Sensory Predictions of Self-Motion? 
Most patients suffering from chronic idiopathic dizziness do not present signs of vestibular dysfunction or organic failures of other kinds. Hence, this kind of dizziness is commonly seen as psychogenic in nature, sharing commonalities with specific phobias, panic disorder, and generalized anxiety. A more specific concept put forward by Brandt and Dieterich (1) states that these patients suffer from dizziness because of an inadequate compensation of self-induced sensory stimulation. According to this hypothesis self-motion-induced reafferent visual stimulation is interpreted as motion in the world since a predictive signal reflecting the consequences of self-motion, needed to compensate the reafferent stimulus, is inadequate. While conceptually intriguing, experimental evidence supporting the idea of an inadequate prediction of the sensory consequences of own movements has as yet been lacking. Here we tested this hypothesis by applying it to the perception of background motion induced by smooth pursuit eye movements. As a matter of fact, we found the same mildly undercompensating prediction, responsible for the perception of slight illusory world motion (“Filehne illusion”) in the 15 patients tested and their age-matched controls. Likewise, the ability to adapt this prediction to the needs of the visual context was not deteriorated in patients. Finally, we could not find any correlation between measures of the individual severity of dizziness and the ability to predict. In sum, our results do not support the concept of a deviant prediction of self-induced sensory stimulation as cause of chronic idiopathic dizziness.
doi:10.3389/fneur.2013.00181
PMCID: PMC3820974  PMID: 24265626
dizziness; vertigo; chronic idiopathic dizziness; phobic postural vertigo; efference copy; smooth pursuit; self-motion perception; Filehne illusion
2.  Sensitive Detection of Viral Transcripts in Human Tumor Transcriptomes 
PLoS Computational Biology  2013;9(10):e1003228.
In excess of % of human cancer incidents have a viral cofactor. Epidemiological studies of idiopathic human cancers indicate that additional tumor viruses remain to be discovered. Recent advances in sequencing technology have enabled systematic screenings of human tumor transcriptomes for viral transcripts. However, technical problems such as low abundances of viral transcripts in large volumes of sequencing data, viral sequence divergence, and homology between viral and human factors significantly confound identification of tumor viruses. We have developed a novel computational approach for detecting viral transcripts in human cancers that takes the aforementioned confounding factors into account and is applicable to a wide variety of viruses and tumors. We apply the approach to conducting the first systematic search for viruses in neuroblastoma, the most common cancer in infancy. The diverse clinical progression of this disease as well as related epidemiological and virological findings are highly suggestive of a pathogenic cofactor. However, a viral etiology of neuroblastoma is currently contested. We mapped transcriptomes of neuroblastoma as well as positive and negative controls to the human and all known viral genomes in order to detect both known and unknown viruses. Analysis of controls, comparisons with related methods, and statistical estimates demonstrate the high sensitivity of our approach. Detailed investigation of putative viral transcripts within neuroblastoma samples did not provide evidence for the existence of any known human viruses. Likewise, de-novo assembly and analysis of chimeric transcripts did not result in expression signatures associated with novel human pathogens. While confounding factors such as sample dilution or viral clearance in progressed tumors may mask viral cofactors in the data, in principle, this is rendered less likely by the high sensitivity of our approach and the number of biological replicates analyzed. Therefore, our results suggest that frequent viral cofactors of metastatic neuroblastoma are unlikely.
Author Summary
Many human cancers are caused by infections with tumor viruses and identification of these pathogens is considered a critical contribution to cancer prevention. Deep sequencing enables us to systematically investigate viral nucleotide signatures in order to either verify or exclude the existence of viruses in idiopathic human cancers. We have developed Virana, a novel computational approach for identifying tumor viruses in human cancers that is applicable to a wide variety of tumors and viruses. Virana firstly addresses several important biological confounding factors that may hinder successful detection of these pathogens. We applied our approach in the first systematic search for cancer-causing viruses in metastatic neuroblastoma, the most common form of cancer in infancy. Although the heterogeneous clinical progression of this disease as well as epidemiological and virological findings are suggestive of a pathogenic cofactor, the viral etiology of neuroblastoma is currently contested. We conducted an analysis of experimental controls, comparisons with related approaches, as well as statistical analyses in order to validate our method. In spite of the high sensitivity of our approach, analyses of neuroblastoma transcriptomes did not provide evidence for the existence of any known or unknown human viruses. Our results therefore suggest that frequent viral cofactors of metastatic neuroblastoma are unlikely.
doi:10.1371/journal.pcbi.1003228
PMCID: PMC3789765  PMID: 24098097
3.  Clinical Significance of Tumor-Associated Inflammatory Cells in Metastatic Neuroblastoma 
Journal of Clinical Oncology  2012;30(28):3525-3532.
Purpose
Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature.
Methods
Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age-dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts.
Results
Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age ≥ 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age ≥ 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively.
Conclusion
These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets.
doi:10.1200/JCO.2011.40.9169
PMCID: PMC3675667  PMID: 22927533
4.  Novel candidate genes influencing natural variation in potato tuber cold sweetening identified by comparative proteomics and association mapping 
BMC Plant Biology  2013;13:113.
Background
Higher plants evolved various strategies to adapt to chilling conditions. Among other transcriptional and metabolic responses to cold temperatures plants accumulate a range of solutes including sugars. The accumulation of the reducing sugars glucose and fructose in mature potato tubers during exposure to cold temperatures is referred to as cold induced sweetening (CIS). The molecular basis of CIS in potato tubers is of interest not only in basic research on plant adaptation to environmental stress but also in applied research, since high amounts of reducing sugars affect negatively the quality of processed food products such as potato chips. CIS-tolerance varies considerably among potato cultivars. Our objective was to identify by an unbiased approach genes and cellular processes influencing natural variation of tuber sugar content before and during cold storage in potato cultivars used in breeding programs. We compared by two-dimensional polyacrylamide gel electrophoresis the tuber proteomes of cultivars highly diverse for CIS. DNA polymorphisms in genomic sequences encoding differentially expressed proteins were tested for association with tuber starch content, starch yield and processing quality.
Results
Pronounced natural variation of CIS was detected in tubers of a population of 40 tetraploid potato cultivars. Significant differences in protein expression were detected between CIS-tolerant and CIS-sensitive cultivars before the onset as well as during cold storage. Identifiable differential proteins corresponded to protease inhibitors, patatins, heat shock proteins, lipoxygenase, phospholipase A1 and leucine aminopeptidase (Lap). Association mapping based on single nucleotide polymorphisms supported a role of Lap in the natural variation of the quantitative traits tuber starch and sugar content.
Conclusions
The combination of comparative proteomics and association genetics led to the discovery of novel candidate genes for influencing the natural variation of quantitative traits in potato tubers. One such gene was a leucine aminopeptidase not considered so far to play a role in starch sugar interconversion. Novel SNP’s diagnostic for increased tuber starch content, starch yield and chip quality were identified, which are useful for selecting improved potato processing cultivars.
doi:10.1186/1471-2229-13-113
PMCID: PMC3750364  PMID: 23919263
5.  MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma 
Nucleic Acids Research  2013;41(12):6018-6033.
MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function.
doi:10.1093/nar/gkt346
PMCID: PMC3695529  PMID: 23625969
6.  Choice of hospital after out-of-hospital cardiac arrest - a decision with far-reaching consequences: a study in a large German city 
Critical Care  2012;16(5):R164.
Introduction
Between 1 and 31% of patients suffering out-of-hospital cardiac arrest (OHCA) survive to discharge from hospital. International studies have shown that the level of care provided by the admitting hospital determines survival for patients suffering from OHCA. These data may only be partially transferable to the German medical system where responders are in-field emergency medical physicians. The present study determines the influence of the emergency physician's choice of admitting hospital on patient outcome after OHCA in a large urban setting.
Methods
All data for patients collected in the German Resuscitation Registry for the city of Dortmund during 2007 and 2008 were analyzed. Patients under 18 years of age, with traumatic mechanism, and with incomplete charts were excluded. Admitting hospitals were divided into two groups: those without the capability for percutaneous coronary intervention (PCI), and those with PCI capability. Data were analyzed by multivariate statistics, taking into account the effects of mild therapeutic hypothermia treatment and PCI capability of the admitting hospital with respect to the neurological status upon hospital discharge.
Results
Between 2007 and 2008 a total of 1,109 cardiopulmonary resuscitation attempts were registered for the city of Dortmund, of which 889 could be included in our study. Return of spontaneous circulation was achieved in 360 of 889 patients (40.5%). In total, 282 of 889 patients displayed return of spontaneous circulation during transport to the hospital (31.7%); 152 were transported with ongoing cardiopulmonary resuscitation (17.1%). Of the total 434 patients admitted to hospital, 264 were admitted to hospitals without PCI capability and 170 to hospitals with PCI capability. Multivariate analysis demonstrated a significant influence on patient discharge with good neurological status for those admitted to PCI hospitals (odds ratio 3.14 (95% confidence interval 1.51 to 6.56)), independent of receiving mild therapeutic hypothermia and/or PCI. Compared with patients admitted to hospitals without PCI capability, significantly more patients in PCI hospitals were discharged alive (41% vs. 13%, P < 0.001) and remained alive 1 year after the event (28% vs. 6%, P < 0.001).
Conclusions
The choice of admitting hospital for patients suffering OHCA significantly influences treatment and outcome. This influence is independent of PCI performance and of mild therapeutic hypothermia. Further analysis is required to determine the possible parameters determining patient outcome.
doi:10.1186/cc11516
PMCID: PMC3682259  PMID: 22971320
7.  The impact of response time reliability on CPR incidence and resuscitation success: a benchmark study from the German Resuscitation Registry 
Critical Care  2011;15(6):R282.
Introduction
Sudden cardiac arrest is one of the most frequent causes of death in the world. In highly qualified emergency medical service (EMS) systems, including well-trained emergency physicians, spontaneous circulation may be restored in up to 53% of patients at least until admission to hospital. Compared with these highly qualified EMS systems, markedly lower success rates are observed in other systems. These data clearly show that there are considerable differences between EMS systems concerning treatment success following cardiac arrest and resuscitation, although in all systems international guidelines for resuscitation are used. In this study, we investigated the impact of response time reliability (RTR) on cardiopulmonary resuscitation (CPR) incidence and resuscitation success by using the return of spontaneous circulation (ROSC) after cardiac arrest (RACA) scores and data from seven German EMS systems participating in the German Resuscitation Registry.
Methods
Anonymised patient data after out-of-hospital cardiac arrest gathered from seven EMS systems in Germany from 2006 to 2009 were analysed with regard to socioeconomic factors (population, area and EMS unit-hours), process quality (RTR, CPR incidence, special CPR measures and prehospital cooling), patient factors (age, gender, cause of cardiac arrest and bystander CPR). End points were defined as ROSC, admission to hospital, 24-hour survival and hospital discharge rate. χ2 tests, odds ratios and the Bonferroni correction were used for statistical analyses.
Results
Our present study comprised 2,330 prehospital CPR patients at seven centres. The incidence of sudden cardiac arrest ranged from 36.0 to 65.1/100,000 inhabitants/year. We identified two EMS systems (RTR < 70%) that reached patients within 8 minutes of the call to the dispatch centre 62.0% and 65.6% of the time, respectively. The other five EMS systems (RTR > 70%) reached patients within 8 minutes of the call to the dispatch centre 70.4% up to 95.5% of the time. EMS systems arriving relatively later at the patients side (RTR < 70%) initiate CPR less frequently and admit fewer patients alive to hospital (calculated per 100,000 inhabitants/year) (CPR incidence (1/100,000 inhabitants/year) RTR > 70% = 57.2 vs RTR < 70% = 36.1, OR = 1.586 (99% CI = 1.383 to 1.819); P < 0.01) (admitted to hospital with ROSC (1/100,000 inhabitants/year) RTR > 70% = 24.4 vs RTR < 70% = 15.6, OR = 1.57 (99% CI = 1.274 to 1.935); P < 0.01). Using ROSC rate and the multivariate RACA score to predict outcomes, we found that the two groups did not differ, but ROSC rates were higher than predicted in both groups (ROSC RTR > 70% = 46.6% vs RTR < 70% = 47.3%, OR = 0.971 (95% CI = 0.787 to 1.196); P = n.s.) (ROSC RACA RTR > 70% = 42.4% vs RTR < 70% = 39.5%, OR = 1.127 (95% CI = 0.911 to 1.395); P = n.s.)
Conclusion
This study demonstrates that, on the level of EMS systems, faster ones more often initiate CPR and increase the number of patients admitted to hospital alive. Furthermore, we show that, with very different approaches, all centres that adhere to and are intensely trained according to the 2005 European Resuscitation Council guidelines are superior and, on the basis of international comparisons, achieve excellent success rates following CPR.
doi:10.1186/cc10566
PMCID: PMC3388696  PMID: 22112746
8.  Cardiopulmonary resuscitation traumatic cardiac arrest - there are survivors. An analysis of two national emergency registries 
Critical Care  2011;15(6):R276.
Introduction
Cardiac arrest following trauma occurs infrequently compared with cardiac aetiology. Within the German Resuscitation Registry a traumatic cause is documented in about 3% of cardiac arrest patients. Regarding the national Trauma Registry, only a few of these trauma patients with cardiac arrest survive. The aim of the present study was to analyze the outcome of cardiopulmonary resuscitation (CPR) after traumatic cardiac arrest by combining data from two different large national registries in Germany.
Methods
This study includes 368 trauma patients (2.8%) out of 13,329 cardiac arrest patients registered within the Resuscitation Registry, whereby 3,673 patients with a cardiac cause and successful CPR served as a cardiac control group. We further analyzed a second group of 1,535 trauma patients with cardiac arrest and early CPR registered within the Trauma Registry, whereby a total of 25,366 trauma patients without any CPR attempts served as a trauma control group. The relative frequencies from each database were used to calculate relative percentages for patients with traumatic cardiac arrest in whom resuscitation was attempted.
Results
Within the Resuscitation Registry, cardiac arrest was present in 331 patients (89.9%) when the EMS personal arrived at the scene and in 37 patients (10.1%) when cardiac arrest occurred after arrival. Spontaneous circulation could be achieved in 107 patients (29.1%). A total of 101 (27.4%) were transferred to hospital, 95 of whom (25.8%) had return of spontaneous circulation (ROSC) on admission. According to the Trauma Registry, the overall hospital mortality rate for cardiac arrest patients following trauma was 73% (n = 593 of 814). About half of the patients who were admitted alive to hospital died within 24 hours, resulting in 13% survivors within 24 hours. 7% of the patients survived until hospital discharge, and only 2% of the patients had good neurological outcome.
Conclusions
Our present study encourages CPR attempts in cardiac arrest patients following severe trauma. When a manageable number of patients is present, the decision on whether to start CPR or not should be done liberally, using comparable criteria as in patients with cardiac etiology. In this respect, trauma management programs that restrict CPR attempts should not be encouraged.
doi:10.1186/cc10558
PMCID: PMC3388703  PMID: 22108048
9.  The role of complex genomic alterations in neuroblastoma risk estimation 
Genome Medicine  2010;2(5):31.
Specific genomic alterations, such as loss of the chromosomal region 11q or amplification of the oncogene MYCN, are well established markers of poor outcome in neuroblastoma. The advent of microarray-based comparative genomic hybridization (array-CGH) has enabled the analysis of pangenomic alteration profiles in the cancer genome, offering the possibility of identifying new prognostic markers from complex aberration patterns. Results from recent studies examining large primary neuroblastoma cohorts by array-CGH show that global genomic profiles may add significant prognostic information. Here, we discuss potential implications for risk estimation of neuroblastoma patients in clinical practice as well as for the understanding of neuroblastoma pathogenesis.
doi:10.1186/gm152
PMCID: PMC2887075  PMID: 20497596
10.  Outcome Prediction of Children with Neuroblastoma using a Multigene Expression Signature, a Retrospective SIOPEN/COG/GPOH Study 
The lancet oncology  2009;10(7):663-671.
BACKGROUND
More accurate prognostic assessment of patients with neuroblastoma is required to improve the choice of risk-related therapy. The aim of this study is to develop and validate a gene expression signature for improved outcome prediction.
METHODS
Fifty-nine genes were carefully selected based on an innovative data-mining strategy and profiled in the largest neuroblastoma patient series (n=579) to date using RT-qPCR starting from only 20 ng of RNA. A multigene expression signature was built using 30 training samples, tested on 313 test samples and subsequently validated in a blind study on an independent set of 236 additional tumours.
FINDINGS
The signature accurately classifies patients with respect to overall and progression-free survival (p<0·0001). The signature has a performance, sensitivity, and specificity of 85·4% (95%CI: 77·7–93·2), 84·4% (95%CI: 66·5–94·1), and 86·5% (95%CI: 81·1–90·6), respectively to predict patient outcome. Multivariate analysis indicates that the signature is a significant independent predictor after controlling for currently used riskfactors. Patients with high molecular risk have a higher risk to die from disease and for relapse/progression than patients with low molecular risk (odds ratio of 19·32 (95%CI: 6·50–57·43) and 3·96 (95%CI: 1·97–7·97) for OS and PFS, respectively). Patients with increased risk for adverse outcome can also be identified within the current treatment groups demonstrating the potential of this signature for improved clinical management. These results were confirmed in the validation study in which the signature was also independently statistically significant in a model adjusted for MYCN status, age, INSS stage, ploidy, INPC grade of differentiation, and MKI. The high patient/gene ratio (579/59) underlies the observed statistical power and robustness.
INTERPRETATION
A 59-gene expression signature predicts outcome of neuroblastoma patients with high accuracy. The signature is an independent risk predictor, identifying patients with increased risk in the current clinical risk groups. The applied method and signature is suitable for routine lab testing and ready for evaluation in prospective studies.
FUNDING
The Belgian Foundation Against Cancer, found of public interest (project SCIE2006-25), the Children Cancer Fund Ghent, the Belgian Society of Paediatric Haematology and Oncology, the Belgian Kid’s Fund and the Fondation Nuovo-Soldati (JV), the Fund for Scientific Research Flanders (KDP, JH), the Fund for Scientific Research Flanders (grant number: G•0198•08), the Institute for the Promotion of Innovation by Science and Technology in Flanders, Strategisch basisonderzoek (IWT-SBO 60848), the Fondation Fournier Majoie pour l’Innovation, the Instituto Carlos III,RD 06/0020/0102 Spain, the Italian Neuroblastoma Foundation, the European Community under the FP6 (project: STREP: EET-pipeline, number: 037260), and the Belgian program of Interuniversity Poles of Attraction, initiated by the Belgian State, Prime Minister's Office, Science Policy Programming.
doi:10.1016/S1470-2045(09)70154-8
PMCID: PMC3045079  PMID: 19515614
11.  Postresuscitation care with mild therapeutic hypothermia and coronary intervention after out-of-hospital cardiopulmonary resuscitation: a prospective registry analysis 
Critical Care  2011;15(1):R61.
Introduction
Mild therapeutic hypothermia (MTH) has been shown to result in better neurological outcome after cardiopulmonary resuscitation. Percutaneous coronary intervention (PCI) may also be beneficial in patients after out-of-hospital cardiac arrest (OHCA).
Methods
A selected cohort study of 2,973 prospectively documented adult OHCA patients within the German Resuscitation Registry between 2004 and 2010. Data were analyzed by backwards stepwise binary logistic regression to identify the impact of MTH and PCI on both 24-hour survival and neurological outcome that was based on cerebral performance category (CPC) at hospital discharge. Odds ratios (95% confidence intervals) were calculated adjusted for the following confounding factors: age, location of cardiac arrest, presumed etiology, bystander cardiopulmonary resuscitation, witnessing, first electrocardiogram rhythm, and thrombolysis.
Results
The Preclinical care dataset included 2,973 OHCA patients with 44% initial return of spontaneous circulation (n = 1,302) and 35% hospital admissions (n = 1,040). Seven hundred and eleven out of these 1,040 OHCA patients (68%) were also registered within the Postresuscitation care dataset. Checking for completeness of datasets required the exclusion of 127 Postresuscitation care cases, leaving 584 patients with complete data for final analysis. In patients without PCI (n = 430), MTH was associated with increased 24-hour survival (8.24 (4.24 to 16.0), P < 0.001) and the proportion of patients with CPC 1 or CPC 2 at hospital discharge (2.13 (1.17 to 3.90), P < 0.05) as an independent factor. In normothermic patients (n = 405), PCI was independently associated with increased 24-hour survival (4.46 (2.26 to 8.81), P < 0.001) and CPC 1 or CPC 2 (10.81 (5.86 to 19.93), P < 0.001). Additional analysis of all patients (n = 584) revealed that 24-hour survival was increased by MTH (7.50 (4.12 to 13.65), P < 0.001) and PCI (3.88 (2.11 to 7.13), P < 0.001), while the proportion of patients with CPC 1 or CPC 2 was significantly increased by PCI (5.66 (3.54 to 9.03), P < 0.001) but not by MTH (1.27 (0.79 to 2.03), P = 0.33), although an unadjusted Fisher exact test suggested a significant effect of MTH (unadjusted odds ratio 1.83 (1.23 to 2.74), P < 0.05).
Conclusions
PCI may be an independent predictor for good neurological outcome (CPC 1 or CPC 2) at hospital discharge. MTH was associated with better neurological outcome, although subsequent logistic regression analysis did not show statistical significance for MTH as an independent predictor for good neurological outcome. Thus, postresuscitation care on the basis of standardized protocols including coronary intervention and hypothermia may be beneficial after successful resuscitation. One of the main limitations may be a selection bias for patients subjected to PCI and MTH.
doi:10.1186/cc10035
PMCID: PMC3221994  PMID: 21320342
12.  Co-regulated expression of HAND2 and DEIN by a bidirectional promoter with asymmetrical activity in neuroblastoma 
BMC Molecular Biology  2009;10:28.
Background
HAND2, a key regulator for the development of the sympathetic nervous system, is located on chromosome 4q33 in a head-to-head orientation with DEIN, a recently identified novel gene with stage specific expression in primary neuroblastoma (NB). Both genes are expressed in primary NB as well as most NB cell lines and are separated by a genomic sequence of 228 bp. The similar expression profile of both genes suggests a common transcriptional regulation mediated by a bidirectional promoter.
Results
Northern Blot analysis of DEIN and HAND2 in 20 primary NBs indicated concurrent expression levels of the two genes, which was confirmed by microarray analysis of 236 primary NBs (Pearson's correlation coefficient r = 0.65). While DEIN expression in the latter cohort was associated with stage 4S (p = 0.02), HAND2 expression was not associated with tumor stage. In contrast, both HAND2 and DEIN transcript levels were highly associated with age at diagnosis <12 months (p = 0.001). The intergenic region shows substantial homology in different species (89%, 72% and 53% identity between human and mouse, chicken and zebrafish, respectively) and contains many highly conserved putative transcription factor binding sites. Using luciferase reporter gene constructs, asymmetrical bidirectional promoter activity was found in four NB cell lines: In DEIN orientation, an average 3.4 fold increase in activity was observed as compared to the promoterless vector, whereas an average 15.4 fold activation was detected in HAND2 orientation. The presence of two highly conserved putative regulatory elements, one of which was shown to enhance HAND2 expression in branchial arches previously, displayed weak repressor activity for both genes.
Conclusion
HAND2 and DEIN represent a gene pair that is tightly linked by a bidirectional promoter in an evolutionary highly conserved manner. Expression of both genes in NB is co-regulated by asymmetrical activity of this promoter and modulated by the activity of two cis-regulatory elements acting as weak repressors. The concurrent quantitative and tissue specific expression of HAND2 and DEIN suggests a functional link between both genes.
doi:10.1186/1471-2199-10-28
PMCID: PMC2670301  PMID: 19348682
13.  Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas 
Genome Biology  2008;9(10):R150.
Differences in MYCN/c-MYC target gene expression are associated with distinct neuroblastoma subtypes and clinical outcome.
Background
Amplified MYCN oncogene resulting in deregulated MYCN transcriptional activity is observed in 20% of neuroblastomas and identifies a highly aggressive subtype. In MYCN single-copy neuroblastomas, elevated MYCN mRNA and protein levels are paradoxically associated with a more favorable clinical phenotype, including disseminated tumors that subsequently regress spontaneously (stage 4s-non-amplified). In this study, we asked whether distinct transcriptional MYCN or c-MYC activities are associated with specific neuroblastoma phenotypes.
Results
We defined a core set of direct MYCN/c-MYC target genes by applying gene expression profiling and chromatin immunoprecipitation (ChIP, ChIP-chip) in neuroblastoma cells that allow conditional regulation of MYCN and c-MYC. Their transcript levels were analyzed in 251 primary neuroblastomas. Compared to localized-non-amplified neuroblastomas, MYCN/c-MYC target gene expression gradually increases from stage 4s-non-amplified through stage 4-non-amplified to MYCN amplified tumors. This was associated with MYCN activation in stage 4s-non-amplified and predominantly c-MYC activation in stage 4-non-amplified tumors. A defined set of MYCN/c-MYC target genes was induced in stage 4-non-amplified but not in stage 4s-non-amplified neuroblastomas. In line with this, high expression of a subset of MYCN/c-MYC target genes identifies a patient subtype with poor overall survival independent of the established risk markers amplified MYCN, disease stage, and age at diagnosis.
Conclusions
High MYCN/c-MYC target gene expression is a hallmark of malignant neuroblastoma progression, which is predominantly driven by c-MYC in stage 4-non-amplified tumors. In contrast, moderate MYCN function gain in stage 4s-non-amplified tumors induces only a restricted set of target genes that is still compatible with spontaneous regression.
doi:10.1186/gb-2008-9-10-r150
PMCID: PMC2760877  PMID: 18851746
14.  Cross-study analysis of gene expression data for intermediate neuroblastoma identifies two biological subtypes 
BMC Cancer  2007;7:89.
Background
Neuroblastoma patients show heterogeneous clinical courses ranging from life-threatening progression to spontaneous regression. Recently, gene expression profiles of neuroblastoma tumours were associated with clinically different phenotypes. However, such data is still rare for important patient subgroups, such as patients with MYCN non-amplified advanced stage disease. Prediction of the individual course of disease and optimal therapy selection in this cohort is challenging. Additional research effort is needed to describe the patterns of gene expression in this cohort and to identify reliable prognostic markers for this subset of patients.
Methods
We combined gene expression data from two studies in a meta-analysis in order to investigate differences in gene expression of advanced stage (3 or 4) tumours without MYCN amplification that show contrasting outcomes (alive or dead) at five years after initial diagnosis. In addition, a predictive model for outcome was generated. Gene expression profiles from 66 patients were included from two studies using different microarray platforms.
Results
In the combined data set, 72 genes were identified as differentially expressed by meta-analysis at a false discovery rate (FDR) of 8.33%. Meta-analysis detected 34 differentially expressed genes that were not found as significant in either single study. Outcome prediction based on data of both studies resulted in a predictive accuracy of 77%. Moreover, the genes that were differentially expressed in subgroups of advanced stage patients without MYCN amplification accurately separated MYCN amplified tumours from low stage tumours without MYCN amplification.
Conclusion
Our findings support the hypothesis that neuroblastoma consists of two biologically distinct subgroups that differ by characteristic gene expression patterns, which are associated with divergent clinical outcome.
doi:10.1186/1471-2407-7-89
PMCID: PMC1904223  PMID: 17531100
15.  Practice of sedation and analgesia in German intensive care units: results of a national survey 
Critical Care  2005;9(2):R117-R123.
Introduction
Sedation and analgesia are provided by using different agents and techniques in different countries. The goal is to achieve early spontaneous breathing and to obtain an awake and cooperative pain-free patient. It was the aim of this study to conduct a survey of the agents and techniques used for analgesia and sedation in intensive care units in Germany.
Methods
A survey was sent by mail to 261 hospitals in Germany. The anesthesiologists running the intensive care unit were asked to fill in the structured questionnaire about their use of sedation and analgesia.
Results
A total of 220 (84%) questionnaires were completed and returned. The RAMSAY sedation scale was used in 8% of the hospitals. A written policy was available in 21% of hospitals. For short-term sedation in most hospitals, propofol was used in combination with sufentanil or fentanyl. For long-term sedation, midazolam/fentanyl was preferred. Clonidine was a common part of up to two-thirds of the regimens. Epidural analgesia was used in up to 68%. Neuromuscular blocking agents were no longer used.
Conclusion
In contrast to the US 'Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult', our survey showed that in Germany different agents, and frequently neuroaxial techniques, were used.
doi:10.1186/cc3035
PMCID: PMC1175921  PMID: 15774043

Results 1-15 (15)