Showing papers by "Humboldt University of Berlin published in 2008"

Dynamics of fat cell turnover in humans

Abstract: Obesity is increasing in an epidemic manner in most countries and constitutes a public health problem by enhancing the risk for cardiovascular disease and metabolic disorders such as type 2 diabetes. Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history. The factors determining fat mass in adult humans are not fully understood, but increased lipid storage in already developed fat cells (adipocytes) is thought to be most important. Here we show that adipocyte number is a major determinant for the fat mass in adults. However, the number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss, indicating that the number of adipocytes is set during childhood and adolescence. To establish the dynamics within the stable population of adipocytes in adults, we have measured adipocyte turnover by analysing the integration of 14C derived from nuclear bomb tests in genomic DNA. Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index. Neither adipocyte death nor generation rate is altered in early onset obesity, suggesting a tight regulation of fat cell number in this condition during adulthood. The high turnover of adipocytes establishes a new therapeutic target for pharmacological intervention in obesity.

Diagnostic Performance of Coronary Angiography by 64-Row CT

Abstract: Methods We conducted a multicenter study to examine the accuracy of 64-row, 0.5-mm multidetector CT angiography as compared with conventional coronary angiography in patients with suspected coronary artery disease. Nine centers enrolled patients who underwent calcium scoring and multidetector CT angiography before conventional coronary angiography. In 291 patients with calcium scores of 600 or less, segments 1.5 mm or more in diameter were analyzed by means of CT and conventional angiography at independent core laboratories. Stenoses of 50% or more were considered obstructive. The area under the receiver-operating-characteristic curve (AUC) was used to evaluate diagnostic accuracy relative to that of conventional angiography and subsequent revascularization status, whereas disease severity was assessed with the use of the modified Duke Coronary Artery Disease Index. Results A total of 56% of patients had obstructive coronary artery disease. The patient-based diagnostic accuracy of quantitative CT angiography for detecting or ruling out stenoses of 50% or more according to conventional angiography revealed an AUC of 0.93 (95% confidence interval [CI], 0.90 to 0.96), with a sensitivity of 85% (95% CI, 79 to 90), a specificity of 90% (95% CI, 83 to 94), a positive predictive value of 91% (95% CI, 86 to 95), and a negative predictive value of 83% (95% CI, 75 to 89). CT angiography was similar to conventional angiography in its ability to identify patients who subsequently underwent revascularization: the AUC was 0.84 (95% CI, 0.79 to 0.88) for multidetector CT angiography and 0.82 (95% CI, 0.77 to 0.86) for conventional angiography. A per-vessel analysis of 866 vessels yielded an AUC of 0.91 (95% CI, 0.88 to 0.93). Disease severity ascertained by CT and conventional angiography was well correlated (r = 0.81; 95% CI, 0.76 to 0.84). Two patients had important reactions to contrast medium after CT angiography. Conclusions Multidetector CT angiography accurately identifies the presence and severity of obstructive coronary artery disease and subsequent revascularization in symptomatic patients. The negative and positive predictive values indicate that multidetector CT angiography cannot replace conventional coronary angiography at present. (ClinicalTrials.gov number, NCT00738218.)

Improved Cosmological Constraints from New, Old, and Combined Supernova Data Sets

Abstract: We present a new compilation of Type Ia supernovae (SNe Ia), a new data set of low-redshift nearby-Hubble-flow SNe, and new analysis procedures to work with these heterogeneous compilations This "Union" compilation of 414 SNe Ia, which reduces to 307 SNe after selection cuts, includes the recent large samples of SNe Ia from the Supernova Legacy Survey and ESSENCE Survey, the older data sets, as well as the recently extended data set of distant supernovae observed with the Hubble Space Telescope (HST) A single, consistent, and blind analysis procedure is used for all the various SN Ia subsamples, and a new procedure is implemented that consistently weights the heterogeneous data sets and rejects outliers We present the latest results from this Union compilation and discuss the cosmological constraints from this new compilation and its combination with other cosmological measurements (CMB and BAO) The constraint we obtain from supernovae on the dark energy density is ΩΛ = 0713+ 0027−0029(stat)+ 0036−0039(sys) , for a flat, ΛCDM universe Assuming a constant equation of state parameter, w, the combined constraints from SNe, BAO, and CMB give w = − 0969+ 0059−0063(stat)+ 0063−0066(sys) While our results are consistent with a cosmological constant, we obtain only relatively weak constraints on a w that varies with redshift In particular, the current SN data do not yet significantly constrain w at z > 1 With the addition of our new nearby Hubble-flow SNe Ia, these resulting cosmological constraints are currently the tightest available

How many species are infected with Wolbachia?--A statistical analysis of current data.

Abstract: Wolbachia are intracellular bacteria found in many species of arthropods and nematodes They manipulate the reproduction of their arthropod hosts in various ways, may play a role in host speciation and have potential applications in biological pest control Estimates suggest that at least 20% of all insect species are infected with Wolbachia These estimates result from several Wolbachia screenings in which numerous species were tested for infection; however, tests were mostly performed on only one to two individuals per species The actual percent of species infected will depend on the distribution of infection frequencies among species We present a meta-analysis that estimates percentage of infected species based on data on the distribution of infection levels among species We used a beta-binomial model that describes the distribution of infection frequencies of Wolbachia, shedding light on the overall infection rate as well as on the infection frequency within species Our main findings are that (1) the proportion of Wolbachia-infected species is estimated to be 66%, and that (2) within species the infection frequency follows a ‘most-or-few’ infection pattern in a sense that the Wolbachia infection frequency within one species is typically either very high (>90%) or very low (<10%)

Crystal structure of opsin in its G-protein-interacting conformation

Abstract: Opsin, the ligand-free form of the G-protein-coupled receptor rhodopsin, at low pH adopts a conformationally distinct, active G-protein-binding state known as Ops*. A synthetic peptide derived from the main binding site of the heterotrimeric G protein-the carboxy terminus of the alpha-subunit (GalphaCT)-stabilizes Ops*. Here we present the 3.2 A crystal structure of the bovine Ops*-GalphaCT peptide complex. GalphaCT binds to a site in opsin that is opened by an outward tilt of transmembrane helix (TM) 6, a pairing of TM5 and TM6, and a restructured TM7-helix 8 kink. Contacts along the inner surface of TM5 and TM6 induce an alpha-helical conformation in GalphaCT with a C-terminal reverse turn. Main-chain carbonyl groups in the reverse turn constitute the centre of a hydrogen-bonded network, which links the two receptor regions containing the conserved E(D)RY and NPxxY(x)(5,6)F motifs. On the basis of the Ops*-GalphaCT structure and known conformational changes in Galpha, we discuss signal transfer from the receptor to the G protein nucleotide-binding site.

Crystal structure of the ligand-free G-protein-coupled receptor opsin

Abstract: In the G-protein-coupled receptor (GPCR) rhodopsin, the inactivating ligand 11-cis-retinal is bound in the seven-transmembrane helix (TM) bundle and is cis/trans isomerized by light to form active metarhodopsin II. With metarhodopsin II decay, all-trans-retinal is released, and opsin is reloaded with new 11-cis-retinal. Here we present the crystal structure of ligand-free native opsin from bovine retinal rod cells at 2.9 angstrom (A) resolution. Compared to rhodopsin, opsin shows prominent structural changes in the conserved E(D)RY and NPxxY(x)(5,6)F regions and in TM5-TM7. At the cytoplasmic side, TM6 is tilted outwards by 6-7 A, whereas the helix structure of TM5 is more elongated and close to TM6. These structural changes, some of which were attributed to an active GPCR state, reorganize the empty retinal-binding pocket to disclose two openings that may serve the entry and exit of retinal. The opsin structure sheds new light on ligand binding to GPCRs and on GPCR activation.

Basic notions of information structure

Abstract: This article takes stock of the basic notions of Information Structure (IS). It first provides a general characterization of IS—following Chafe (1976)—within a communicative model of Common Ground (CG), which distinguishes between CG content and CG management. IS is concerned with those features of language that affect the local CG. Second, this paper defines and discusses the notions of Focus (as indicating alternatives) and its various uses, Givenness (as indicating that a denotation is already present in the CG), and Topic (as specifying what a statement is about). It also proposes a new notion, Delimitation, which comprises contrastive topics and frame setters, and indicates that the current conversational move does not entirely satisfy the local communicative needs. It also points out that rhetorical structuring partly belongs to IS.

Beyond global sociosexual orientations: A more differentiated look at sociosexuality and its effects on courtship and romantic relationships.

Abstract: Sociosexuality is usually assessed as the overall orientation toward uncommitted sex, although this global approach may mask unique contributions of different components. In a large online study (N = 2,708) and a detailed behavioral assessment of 283 young adults (both singles and couples) with a 1-year follow-up, the authors established 3 theoretically meaningful components of sociosexuality: past behavioral experiences, the attitude toward uncommitted sex, and sociosexual desire (all measured by a revised version of the Sociosexual Orientation Inventory). Discriminant validity was shown with regard to (a) their factorial structure, (b) sex differences, (c) many established correlates of sociosexuality, and (d) the prediction of observed flirting behavior when meeting an attractive opposite-sex stranger, even down to the level of objectively coded behaviors, as well as (e) the self-reported number of sexual partners and (f) changes in romantic relationship status over the following year. Within couples, the 3 components also showed distinct degrees of assortative mating and distinct effects on the romantic partner. Implications for the evolutionary psychology of mating tactics are discussed.

Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine.

Abstract: Objective:To develop consensus statements for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients.Participants:A multidisciplinary, multispecialty task force of experts in critical care medicine was convened from the membership of the Society of Critical Car

Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) - Update 2008

Abstract: EFSUMB study group M. Claudon1, D. Cosgrove2, T. Albrecht3, L. Bolondi4, M. Bosio5, F. Calliada6, J.-M. Correas7, K. Darge8, C. Dietrich9, M. D'On ofrio10, D. H. Evans11, C. Filice12, L. Greiner13, K. Jäger14, N. de. Jong15, E. Leen16, R. Lencioni17, D. Lindsell18, A. Martegani19, S. Meairs20, C. Nolsøe21, F. Piscaglia22, P. Ricci23, G. Seidel24, B. Skjoldbye25, L. Solbiati26, L. Thorelius27, F. Tranquart28, H. P. Weskott29, T. Whittingham30

Energy Spectrum of Cosmic-Ray Electrons at TeV Energies

Abstract: The very large collection area of ground-based gamma-ray telescopes gives them a substantial advantage over balloon/satellite based instruments in the detection of very-high-energy (>600 GeV) cosmic-ray electrons. Here we present the electron spectrum derived from data taken with the H.E.S.S. system of imaging atmospheric Cherenkov telescopes. In this measurement, the first of this type, we are able to extend the measurement of the electron spectrum beyond the range accessible to direct measurements. We find evidence for a substantial steepening in the energy spectrum above 600 GeV compared to lower energies.

Phanerozoic trends in the global diversity of marine invertebrates.

Abstract: It has previously been thought that there was a steep Cretaceous and Cenozoic radiation of marine invertebrates. This pattern can be replicated with a new data set of fossil occurrences representing 3.5 million specimens, but only when older analytical protocols are used. Moreover, analyses that employ sampling standardization and more robust counting methods show a modest rise in diversity with no clear trend after the mid-Cretaceous. Globally, locally, and at both high and low latitudes, diversity was less than twice as high in the Neogene as in the mid-Paleozoic. The ratio of global to local richness has changed little, and a latitudinal diversity gradient was present in the early Paleozoic.

The Multilevel Latent Covariate Model: A New, More Reliable Approach to Group-Level Effects in Contextual Studies.

Abstract: In multilevel modeling (MLM), group-level (L2) characteristics are often measured by aggregating individual-level (L1) characteristics within each group so as to assess contextual effects (e.g., group-average effects of socioeconomic status, achievement, climate). Most previous applications have used a multilevel manifest covariate (MMC) approach, in which the observed (manifest) group mean is assumed to be perfectly reliable. This article demonstrates mathematically and with simulation results that this MMC approach can result in substantially biased estimates of contextual effects and can substantially underestimate the associated standard errors, depending on the number of L1 individuals per group, the number of groups, the intraclass correlation, the sampling ratio (the percentage of cases within each group sampled), and the nature of the data. To address this pervasive problem, the authors introduce a new multilevel latent covariate (MLC) approach that corrects for unreliability at L2 and results in unbiased estimates of L2 constructs under appropriate conditions. However, under some circumstances when the sampling ratio approaches 100%, the MMC approach provides more accurate estimates. Based on 3 simulations and 2 real-data applications, the authors evaluate the MMC and MLC approaches and suggest when researchers should most appropriately use one, the other, or a combination of both approaches.

Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson's disease: a randomised, multicentre study

Abstract: Summary Background Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces motor symptoms in patients with Parkinson's disease (PD) and improves their quality of life; however, the effect of DBS on cognitive functions and its psychiatric side-effects are still controversial. To assess the neuropsychiatric consequences of DBS in patients with PD we did an ancillary protocol as part of a randomised study that compared DBS with the best medical treatment. Methods 156 patients with advanced Parkinson's disease and motor fluctuations were randomly assigned to have DBS of the STN or the best medical treatment for PD according to the German Society of Neurology guidelines. 123 patients had neuropsychological and psychiatric examinations to assess the changes between baseline and after 6 months. The primary outcome was the comparison of the effect of DBS with the best medical treatment on overall cognitive functioning (Mattis dementia rating scale). Secondary outcomes were the effects on executive function, depression, anxiety, psychiatric status, manic symptoms, and quality of life. Analysis was per protocol. The study is registered at ClinicalTrials.gov, number NCT00196911. Findings 60 patients were randomly assigned to receive STN-DBS and 63 patients to have best medical treatment. After 6 months, impairments were seen in executive function (difference of changes [DBS–best medical treatment] in verbal fluency [semantic] −4·50 points, 95% CI −8·07 to −0·93, Cohen's d =−;0·4; verbal fluency [phonemic] −3·06 points, −5·50 to −0·62, −0·5; Stroop 2 naming colour error rate −0·37 points, −0·73 to 0·00, −0·4; Stroop 3 word reading time −5·17 s, −8·82 to −1·52, −0·5; Stroop 4 colour naming time −13·00 s, −25·12 to −0·89, −0·4), irrespective of the improvement in quality of life (difference of changes in PDQ-39 10·16 points, 5·45 to 14·87, 0·6; SF-36 physical 16·55 points, 10·89 to 22·21, 0·9; SF-36 psychological 9·74 points, 2·18 to 17·29, 0·5). Anxiety was reduced in the DBS group compared with the medication group (difference of changes in Beck anxiety inventory 10·43 points, 6·08 to 14·78, 0·8). Ten patients in the DBS group and eight patients in the best medical treatment group had severe psychiatric adverse events. Interpretation DBS of the STN does not reduce overall cognition or affectivity, although there is a selective decrease in frontal cognitive functions and an improvement in anxiety in patients after the treatment. These changes do not affect improvements in quality of life. DBS of the STN is safe with respect to neuropsychological and psychiatric effects in carefully selected patients during a 6-month follow-up period. Funding German Federal Ministry of Education and Research (01GI0201).

Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri

Abstract: The introduction of two microbial opsin-based tools, channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), to neuroscience has generated interest in fast, multimodal, cell type-specific neural circuit control. Here we describe a cation-conducting channelrhodopsin (VChR1) from Volvox carteri that can drive spiking at 589 nm, with excitation maximum red-shifted approximately 70 nm compared with ChR2. These results demonstrate fast photostimulation with yellow light, thereby defining a functionally distinct third category of microbial rhodopsin proteins.

Orientation-dependent ionization energies and interface dipoles in ordered molecular assemblies

Abstract: Although an isolated individual molecule clearly has only one ionization potential, multiple values are found for molecules in ordered assemblies. Photoelectron spectroscopy of archetypical pi-conjugated organic compounds on metal substrates combined with first-principles calculations and electrostatic modelling reveal the existence of a surface dipole built into molecular layers. Conceptually different from the surface dipole at metal surfaces, its origin lies in details of the molecular electronic structure and its magnitude depends on the orientation of molecules relative to the surface of an ordered assembly. Suitable pre-patterning of substrates to induce specific molecular orientations in subsequently grown films thus permits adjusting the ionization potential of one molecular species over up to 0.6 eV via control over monolayer morphology. In addition to providing in-depth understanding of this phenomenon, our study offers design guidelines for improved organic-organic heterojunctions, hole- or electron-blocking layers and reduced barriers for charge-carrier injection in organic electronic devices.

Querying distributed RDF data sources with SPARQL

Abstract: Integrated access to multiple distributed and autonomous RDF data sources is a key challenge for many semantic web applications. As a reaction to this challenge, SPARQL, the W3C Recommendation for an RDF query language, supports querying of multiple RDF graphs. However, the current standard does not provide transparent query federation, which makes query formulation hard and lengthy. Furthermore, current implementations of SPARQL load all RDF graphs mentioned in a query to the local machine. This usually incurs a large overhead in network traffic, and sometimes is simply impossible for technical or legal reasons. To overcome these problems we present DARQ, an engine for federated SPARQL queries. DARQ provides transparent query access to multiple SPARQL services, i.e., it gives the user the impression to query one single RDF graph despite the real data being distributed on the web. A service description language enables the query engine to decompose a query into sub-queries, each of which can be answered by an individual service. DARQ also uses query rewriting and cost-based query optimization to speed-up query execution. Experiments show that these optimizations significantly improve query performance even when only a very limited amount of statistical information is available. DARQ is available under GPL License at http://darq.sf.net/.

The cost of interrupted work: more speed and stress

Abstract: We performed an empirical study to investigate whether the context of interruptions makes a difference. We found that context does not make a difference but surprisingly, people completed interrupted tasks in less time with no difference in quality. Our data suggests that people compensate for interruptions by working faster, but this comes at a price: experiencing more stress, higher frustration, time pressure and effort. Individual differences exist in the management of interruptions: personality measures of openness to experience and need for personal structure predict disruption costs of interruptions. We discuss implications for how system design can support interrupted work.

Tight regulation of unstructured proteins: from transcript synthesis to protein degradation.

Abstract: Altered abundance of several intrinsically unstructured proteins (IUPs) has been associated with perturbed cellular signaling that may lead to pathological conditions such as cancer. Therefore, it is important to understand how cells precisely regulate the availability of IUPs. We observed that regulation of transcript clearance, proteolytic degradation, and translational rate contribute to controlling the abundance of IUPs, some of which are present in low amounts and for short periods of time. Abundant phosphorylation and low stochasticity in transcription and translation indicate that the availability of IUPs can be finely tuned. Fidelity in signaling may require that most IUPs be available in appropriate amounts and not present longer than needed.

Behavioural report of single neuron stimulation in somatosensory cortex

Abstract: Understanding how neural activity in sensory cortices relates to perception is a central theme of neuroscience. Action potentials of sensory cortical neurons can be strongly correlated to properties of sensory stimuli and reflect the subjective judgements of an individual about stimuli. Microstimulation experiments have established a direct link from sensory activity to behaviour, suggesting that small neuronal populations can influence sensory decisions. However, microstimulation does not allow identification and quantification of the stimulated cellular elements. The sensory impact of individual cortical neurons therefore remains unknown. Here we show that stimulation of single neurons in somatosensory cortex affects behavioural responses in a detection task. We trained rats to respond to microstimulation of barrel cortex at low current intensities. We then initiated short trains of action potentials in single neurons by juxtacellular stimulation. Animals responded significantly more often in single-cell stimulation trials than in catch trials without stimulation. Stimulation effects varied greatly between cells, and on average in 5% of trials a response was induced. Whereas stimulation of putative excitatory neurons led to weak biases towards responding, stimulation of putative inhibitory neurons led to more variable and stronger sensory effects. Reaction times for single-cell stimulation were long and variable. Our results demonstrate that single neuron activity can cause a change in the animal's detection behaviour, suggesting a much sparser cortical code for sensations than previously anticipated.

Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction

Abstract: BACKGROUND: Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction. METHODS AND RESULTS: Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding beta-myosin heavy chain (MYH7), alpha-cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated familial disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in beta-myosin heavy chain were located mainly within the ATP binding site. CONCLUSIONS: We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.

G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth.

Abstract: Hypotrichosis simplex is a group of nonsyndromic human alopecias. We mapped an autosomal recessive form of this disorder to chromosome 13q14.11-13q21.33, and identified homozygous truncating mutations in P2RY5, which encodes an orphan G protein-coupled receptor. Furthermore, we identified oleoyl-L-alpha-lysophosphatidic acid (LPA), a bioactive lipid, as a ligand for P2Y5 in reporter gene and radioligand binding experiments. Homology and studies of signaling transduction pathways suggest that P2Y5 is a member of a subgroup of LPA receptors, which also includes LPA4 and LPA5. Our study is the first to implicate a G protein-coupled receptor as essential for and specific to the maintenance of human hair growth. This finding may provide opportunities for new therapeutic approaches to the treatment of hair loss in humans.

Fungi and inflammatory bowel diseases: Alterations of composition and diversity

Abstract: Objective. Altered bacterial diversity of the intestinal mucosa-associated microbiota may reflect the net influence of lifestyle factors associated with the development of chronic inflammatory bowel diseases (IBD). While a reduced bacterial diversity has been reported in IBD, little is known about the fungal microbiota. The aim of this study was to carry out a systematic analysis of intestinal fungal microbiota in IBD. Material and methods. The mucosa-associated fungal microbiota of 104 colonic biopsy tissues from 47 controls and 57 IBD patients was investigated using metagenomic 18S rDNA-based denaturing gradient gel electrophoresis (DGGE), clone libraries, sequencing, and in situ hybridization techniques. Results. Fungi-specific 18S rDNA signatures could be detected in all 104 patients, accounting for only a small proportion of the intestinal microbiota (0.02% of the mucosal and 0.03% of the fecal microbiota). An overall fungal biodiversity of 43 different operational taxonomic units (OTUs) was found in...

Prognostic Relevance of a Novel TNM Classification System for Upper Gastroenteropancreatic Neuroendocrine Tumors

Abstract: BACKGROUND. Neuroendocrine tumors (NETs) of the gastroenteropancreatic (GEP) system comprise a rare but challenging group of malignant neoplasms and occur at virtually any site of the GEP system. In 2006, a new TNM classification system was proposed for the staging and grading of upper GEP NETs. METHODS. The prognostic relevance of the TNM classification system was analyzed retrospectively in 202 patients from a referral center with histologically proven foregut NET. Patients were classified according to previous classification systems and the TNM classification. Survival data were acquired and statistical analyses were performed by using log-rank and Cox regression testing. RESULTS. Primary tumors were gastric (n = 48), duodenal (n = 23), and pancreatic (n = 131). During the observation period, 21% of patients died. The overall 5- and 10-year survival rates were 75% and 64%, respectively. Previous classification systems discriminated between low-grade and high-grade malignant NETs but did not allow further prognostic differentiation. In contrast, the proposed TNM classification was able to differentiate significantly between different tumor stages (stages I-III vs stage IV; P < .01) and cellular proliferation rates according to Ki-67 labeling (grade 1 vs grade 2, P = .04; grade 1 vs grade 3 and grade 2 vs grade 3, P < .01). Cox regression analysis confirmed an increased risk of reduced survival for patients with stage III or IV NET and grade 2 or 3 NET. CONCLUSIONS. The current results demonstrated the prognostic relevance of the newly proposed TNM classification system for foregut NETs with statistical significance for the subgroups of both the staging classification and the grading system. Thus, the new classification system provides a valid and powerful tool for prognostic stratification of GEP NETs in clinical practice and research. Cancer 2008. © 2008 American Cancer Society.