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The molecular basis of atherosclerosis is not fully understood and mice studies have shown that Ephrins and EPH receptors play a role in the atherosclerotic process. We set out to assess the role for monocytic EPHB2 and its Ephrin ligands in human atherosclerosis and show a role for EPHB2 in monocyte functions independently of its EphrinB ligands. Immunohistochemical staining of human aortic sections at different stages of atherosclerosis showed that EPHB2 and its ligand EphrinB are expressed in atherosclerotic plaques and that expression proportionally increases with plaque severity. Functionally, stimulation with EPHB2 did not affect endothelial barrier function, nor did stimulation with EphrinB1 or EphrinB2 affect monocyte‐endothelial interactions. In contrast, reduced expression of EPHB2 in monocytes resulted in decreased monocyte adhesion to endothelial cells and a decrease in monocyte transmigration, mediated by an altered morphology and a decreased ability to phosphorylate FAK. Our results suggest that EPHB2 expression in monocytes results in monocyte accumulation by virtue of an increase of transendothelial migration, which can subsequently contribute to atherosclerotic plaque progression., Graphical Abstract EPHB2 expression in monocytes promotes monocyte accumulation by increasing monocyte adhesion and transendothelial migration; subsequently, this can contribute to atherosclerotic plaque progression.

Thermal convection is of major importance in various astro- and geophysical systems, exemplary are buoyancy driven flows in the atmosphere or in the stellar interior. It has been studied for decades in an idealized model system - the Rayleigh-Bénard convection (RBC) - which consists of a horizontal fluid layer heated at the bottom and cooled at the top. Within the Oberbeck-Boussinesq approximation this system is controlled by two parameters only. These are the Rayleigh number (Ra), which represents the thermal driving and the Prandtl number (Pr) that relates the momentum and thermal diffusivities of the fluid. Convection flows in geo- and astrophysics are often influenced by Coriolis forces due to the rotation of the planet or the star. In RBC-system, Coriolis forces are introduced by rotating the convection cell around its vertical axis. The rotation is expressed by an additional dimensionless control parameter, i.e., the inverse Rossby number 1/Ro. We study experimentally the influence of rotation on the heat transport and the temperature field at very large Ra in the High Pressure Convection Facility (HPCF) in Göttingen. The facility consists of a cylindrical cell of 1.10m diameter and 2.20m height that is filled with pressurized sulfur hexafluoride (SF6) at up to 19bar. The height of the cell and the large density of SF6 enable us to reach very large Ra (up to 8×1014) at 0.74We find a monotonic decrease of the heat transport with increasing rotation rate. Furthermore, we measure quantities of the flow close to the lateral side walls of the convection cylinder. For large rotation rates we analyze this as part of the recently proposed “Boundary Zonal Flow” (BZF), where the vertical heat transport is enhanced and warm (cold) up (down) flow self-organizes in a periodic manner. In the experiment we observe the BZF most notably in the probability density function of the temperature, which develops a bimodal Gaussian distribution. We also find that the periodic warm-cold structure drifts in anti-cyclonic direction and thus form traveling waves of the temperature field.

In the pathophysiologic setting of acute and chronic kidney injury, the excessive activation and recruitment of blood-borne monocytes prompts their differentiation into inflammatory macrophages, a process that leads to progressive glomerulosclerosis and interstitial fibrosis. Importantly, this differentiation of monocytes into macrophages requires the meticulous coordination of gene expression at both the transcriptional and post-transcriptional level. The transcriptomes of these cells are ultimately determined by RNA-binding proteins such as QUAKING (QKI), that define their pre-mRNA splicing and mRNA transcript patterns. Using two mouse models, namely (1) quaking viable mice (qkv) and (2) the conditional deletion in the myeloid cell lineage using the lysozyme 2-Cre (QKIFL/FL, LysM-Cre mice), we demonstrate that the abrogation of QKI expression in the myeloid cell lineage reduces macrophage infiltration following kidney injury induced by unilateral urethral obstruction (UUO). The qkv and QKIFL/FL, LysM-Cre mice both showed significant diminished interstitial collagen deposition and fibrosis in the UUO-damaged kidney, as compared to wild-type littermates. We show that macrophages isolated from QKIFL/FL, LysM-Cre mice are associated with defects in pre-mRNA splicing. Our findings demonstrate that reduced expression of the alternative splice regulator QKI in the cells of myeloid lineage attenuates renal interstitial fibrosis, suggesting that inhibition of this splice regulator may be of therapeutic value for certain kidney diseases.

For rapidly rotating turbulent Rayleigh--B\'enard convection in a slender cylindrical cell, experiments and direct numerical simulations reveal a boundary zonal flow (BZF) that replaces the classical large-scale circulation. The BZF is located near the vertical side wall and enables enhanced heat transport there. Although the azimuthal velocity of the BZF is cyclonic (in the rotating frame), the temperature is an anticyclonic traveling wave of mode one whose signature is a bimodal temperature distribution near the radial boundary. The BZF width is found to scale like $Ra^{1/4}Ek^{2/3}$ where the Ekman number $Ek$ decreases with increasing rotation rate.

In normal physiology, endothelial cells (ECs) form a vital barrier between the blood and underlying tissue controlling leukocyte diapedesis and vascular inflammation. Emerging data suggest that neuronal guidance cues, typically expressed during development, have roles outside the nervous system in vascular biology and immune responses. In particular, Class III semaphorins have been reported to affect EC migration and angiogenesis. While ECs express high levels of semaphorin 3F (SEMA3F), little is known about its function in mature ECs. Here we show that SEMA3F expression is reduced by inflammatory stimuli and increased by laminar flow. Endothelial cells exposed to laminar flow secrete SEMA3F, which subsequently binds to heparan sulfates on the surface of ECs. However, under pro-inflammatory conditions, reduced levels of SEMA3F make ECs more prone to monocyte diapedesis and display impaired barrier function as measured with an electric cell–substrate impedance sensing system and a microfluidic system. In addition, we demonstrate that SEMA3F can directly inhibit the migration of activated monocytes. Taken together, our data suggest an important homeostatic function for EC-expressed SEMA3F, serving as a mediator of endothelial quiescence.

Objective: Netrin-1 has been shown to play a role in the initiation of atherosclerosis in mice models. However, little is known about the role of Netrin-1 in humans. We set out to study whether Netrin-1 is associated with different stages of atherosclerosis. Approach and Results: Plasma Netrin-1 levels were measured in different patient cohorts: (1) 22 patients with high cardiovascular risk who underwent arterial wall inflammation assessment using positron-emission tomography / computed tomography, (2) 168 patients with a positive family history of premature atherosclerosis in whom coronary artery calcium scores were obtained, and (3) 104 patients with chest pain who underwent coronary computed tomography angiography imaging to evaluate plaque vulnerability and burden. Netrin-1 plasma levels were negatively correlated with arterial wall inflammation (β, −0.01 [95% CI, 0.02 to −0.01] R 2 , 0.61; P P P =0.511). However, Netrin-1 plasma levels were negatively correlated to total plaque volume (β, −0.09 [95% CI, −0.11 to −0.08] R 2 , 0.57, P R 2 , 0.53; P R 2 , 0.41; P ConclusionS: Netrin-1 plasma levels are lower in patients with subclinical atherosclerosis and in patients with arterial wall inflammation. Netrin-1 is not associated with plaque vulnerability; however, it is negatively correlated to plaque burden, suggesting that Netrin-1 is involved in some, but not all, stages of atherosclerosis.

Key Clinical Message Pericarditis is a known complication of mesalazine in the treatment of ulcerative colitis. This case study illustrates that after diagnostic work-up, pericarditis should not always be attributed to the use of mesalazine. It may be the presentation of an extra-intestinal manifestation of ulcerative colitis. Restarting of mesalazine should be considered.

Disruption of circadian rhythm by means of shift work has been associated with cardiovascular disease in humans. However, causality and underlying mechanisms have not yet been established. In this study, we exposed hyperlipidemic APOE*3-Leiden.CETP mice to either regular light-dark cycles, weekly 6 hours phase advances or delays, or weekly alternating light-dark cycles (12 hours shifts), as a well-established model for shift work. We found that mice exposed to 15 weeks of alternating light-dark cycles displayed a striking increase in atherosclerosis, with an approximately twofold increase in lesion size and severity, while mice exposed to phase advances and delays showed a milder circadian disruption and no significant effect on atherosclerosis development. We observed a higher lesion macrophage content in mice exposed to alternating light-dark cycles without obvious changes in plasma lipids, suggesting involvement of the immune system. Moreover, while no changes in the number or activation status of circulating monocytes and other immune cells were observed, we identified increased markers for inflammation, oxidative stress, and chemoattraction in the vessel wall. Altogether, this is the first study to show that circadian disruption by shifting light-dark cycles directly aggravates atherosclerosis development.

A new vertical water tunnel with global temperature control and the possibility for bubble and local heat & mass injection has been designed and constructed. The new facility offers the possibility to accurately study heat and mass transfer in turbulent multiphase flow (gas volume fraction up to $8\%$) with a Reynolds-number range from $1.5 \times 10^4$ to $3 \times 10^5$ in the case of water at room temperature. The tunnel is made of high-grade stainless steel permitting the use of salt solutions in excess of 15$\%$ mass fraction. The tunnel has a volume of 300 liters. The tunnel has three interchangeable measurement sections of $1$ m height but with different cross sections ($0.3 \times 0.04 m^2$, $0.3 \times 0.06 m^2$, $0.3 \times 0.08 m^2$). The glass vertical measurement sections allow for optical access to the flow, enabling techniques such as laser Doppler anemometry, particle image velocimetry, particle tracking velocimetry, and laser-induced fluorescent imaging. Local sensors can be introduced from the top and can be traversed using a built-in traverse system, allowing for e.g. local temperature, hot-wire, or local phase measurements. Combined with simultaneous velocity measurements, the local heat flux in single phase and two phase turbulent flows can thus be studied quantitatvely and precisely.

Netrins form a family of secreted and membrane-associated proteins. Netrins are involved in processes for axonal guidance, morphogenesis, and angiogenesis by regulating cell migration and survival. These processes are of special interest in tumor biology. From the netrin genes various isoforms are translated and regulated by alternative splicing. We review here the diversity of isoforms of the netrin family members and their known and potential roles in cancer.

Chronic kidney disease is associated with progressive renal fibrosis, where perivascular cells give rise to the majority of α-smooth muscle actin (α-SMA) positive myofibroblasts. Here we sought to identify pericytic miRNAs that could serve as a target to decrease myofibroblast formation. Kidney fibrosis was induced in FoxD1-GC;Z/Red-mice by unilateral ureteral obstruction followed by FACS sorting of dsRed-positive FoxD1-derivative cells and miRNA profiling. MiR-132 selectively increased 21-fold during pericyte-to-myofibroblast formation, whereas miR-132 was only 2.5-fold up in total kidney lysates (both in obstructive and ischemia-reperfusion injury). MiR-132 silencing during obstruction decreased collagen deposition (35%) and tubular apoptosis. Immunohistochemistry, Western blot, and qRT-PCR confirmed a similar decrease in interstitial α-SMA + cells. Pathway analysis identified a rate-limiting role for miR-132 in myofibroblast proliferation that was confirmed in vitro . Indeed, antagomir-132–treated mice displayed a reduction in the number of proliferating Ki67 + interstitial myofibroblasts. Interestingly, this was selective for the interstitial compartment and did not impair the reparative proliferation of tubular epithelial cells, as evidenced by an increase in Ki67 + epithelial cells, as well as increased phospho-RB1, Cyclin-A and decreased RASA1, p21 levels in kidney lysates. Additional pathway and gene expression analyses suggest miR-132 coordinately regulates genes involved in TGF-β signaling (Smad2/Smad3), STAT3/ERK pathways, and cell proliferation (Foxo3/p300). Thus, silencing miR-132 counteracts the progression of renal fibrosis by selectively decreasing myofibroblast proliferation and could potentially serve as a novel antifibrotic therapy.

We present results on the global and local characterisation of heat transport in homogeneous bubbly flow. Experimental measurements were performed with and without the injection of $\sim 2.5$ mm diameter bubbles (corresponding to $Re_b \approx 600$) in a rectangular water column heated from one side and cooled from the other. The gas volume fraction $\alpha$ was varied in the range $0\% - 5\%$, and the Rayleigh number $Ra_H$ in the range $4.0 \times 10^9 - 1.2 \times 10^{11}$. We find that the global heat transfer is enhanced up to 20 times due to bubble injection. Interestingly, for bubbly flow, for our lowest concentration $\alpha = 0.5\% $ onwards, the Nusselt number $\overline{Nu}$ is nearly independent of $Ra_H$, and depends solely on the gas volume fraction~$\alpha$. We observe the scaling $\overline{Nu} \propto \alpha^{0.45}$, which is suggestive of a diffusive transport mechanism. Through local temperature measurements, we show that the bubbles induce a huge increase in the strength of liquid temperature fluctuations, e.g. by a factor of 200 for $\alpha = 0.9\%$. Further, we compare the power spectra of the temperature fluctuations for the single- and two-phase cases. In the single-phase cases, most of the spectral power of the temperature fluctuations is concentrated in the large-scale rolls. However, with the injection of bubbles, we observe intense fluctuations over a wide range of scales, extending up to very high frequencies. Thus, while in the single-phase flow the thermal boundary layers control the heat transport, once the bubbles are injected, the bubble-induced liquid agitation governs the process from a very small bubble concentration onwards., Comment: Journal of Fluid Mechanics (accepted)

Introduction: Neuroimmune guidance cues (NGCs), a family of proteins originally known for controlling neuronal migration, have been shown to be involved in atherosclerosis in mice models by regulating adhesion of monocytes to the vascular endothelium. The NGC family consists of multiple receptors and ligands enabling an interplay between inflammatory cells and the vasculature endothelium. We set out to investigate the role of NGCs in atherosclerosis in humans. Methods and results: We sequenced a total of 77 NGC genes in a unique cohort of 89 patients with premature atherosclerotic (PAS), in whom no clear CVD risk factor was present. A total of 178 rare variants were identified and we classified the pathogenicity of these rare (MAF Conclusion: In patients with PAS rare missense variants in NGC genes were identified. Further functional- and expression assays showed an effect of NTN1 and EFNB2 on different aspects of the human atherosclerotic process. The results obtained from these studies substantiate the role of NGCs in human atherosclerotic disease and may further identify NGCs as novel potential therapeutic targets in our strive against cardiovascular disease.

Introduction: Atherosclerosis is a systemic inflammatory disease, characterized by the accumulation of macrophages in the vascular wall. Studies in mice showed that neuroimmune guidance cues (NGCs) are involved in atherosclerosis-related processes. In this study we aimed to determine the NGCs involved in monocyte-endothelium adhesion and transmigration, and subsequent macrophage differentiation. Methods and Results: Combining publically available gene expression data of >600 endothelial, monocytes or macrophage samples we determined the specific NGCs expressed by these cells involved in the onset and progression of atherosclerosis. Next, the mRNA levels of the expressed NGCs were analyzed in primary human endothelial cells and monocytes upon TNFα, IL1β or oxidized LDL stimulation (5 or 24 hours), as wells as in human monocytes differentiated into macrophages. In endothelial cells a significant (P1) downregulation was observed for NTN4, SEMA6C and PLXNA4 while a significant upregulation was observed for EFNA1, EFNB1, UNC5B, ROBO1, SEMA6D and SEMA7A upon stimulation. In monocytes a significant downregulation was detected for SEMA6B, PLXNC1, NRP1, NRP2 and EPHB6 , while SEMA7A and EPHB2 were significantly upregulated upon stimulation. These findings combined resulted in potentially interesting concurrent changes in the NGC ligand-receptor combinations; (1) endothelial PLXNA4 receptor with monocyte SEMA3A and (2) endothelial EFNB1 ligand with monocyte EPHB2 receptor. These changes seen at mRNA were validated at protein level. Remarkably, monocyte to macrophage differentiation induced a major increase and change in NGC expression levels, mainly in the SEMA family of ligands and receptors (including SEMA3G , SEMA7A, NRP1, and NRP2 ), as well as in EPHB2 as seen in monocyte stimulation. Conclusion: In conclusion, in our current study we observed a differential expression of NGC ligands and receptors in endothelial cells, monocytes and macrophages, culprit cell types in atherosclerosis, once subjected to pro-atherogenic stimuli. Our findings confirm a potential role for NGCs in human atherosclerosis. The next step is to further investigate the underlying mechanism of these NGCs and their role in atherosclerosis.

Senescence phenotype of endothelial cells (ECs) has pathophysiological consequences, such as decreased regeneration capacity, pro-atherogenic tendency and dysregulated vessel tune. We find that netrin 4 (NTN4), recognized in neural and vascular development, is highly expressed by mature ECs. Remarkably, little is known about its role in vascular biology after development. NTN4 is deposited in the extracellular matrix. Using human decellularized kidney extracelluar matrix scaffolds, we found that pre-treatment of the scaffolds with NTN4 increased numbers of EC adhesion to the matrix, showing a pro-survival effect of NTN4. Subsequently we explored the regulation of NTN4 expression in ECs. We found a 1.8-fold (±0.3; p In conclusion, our results identified the anti-senescence function of NTN4 and thereby provides novel insights in the role of NTN4 in EC function. In situations like acute inflammation and unfavourable hemodynamic conditions, NTN4 expression decreases, so that there is a possible window for us to improve EC function by normalizing NTN4 expression.

Objective— Accumulating evidence suggests a role of semaphorins in vascular homeostasis. Here, we investigate the role of Sema7A (semaphorin 7A) in atherosclerosis and its underlying mechanism. Approach and Results— Using genetically engineered Sema7A −/− ApoE −/− mice, we showed that deletion of Sema7A attenuates atherosclerotic plaque formation primarily in the aorta of ApoE −/− mice on a high-fat diet. A higher level of Sema7A in the atheroprone lesser curvature suggests a correlation of Sema7A with disturbed flow. This notion is supported by elevated Sema7A expression in human umbilical venous endothelial cells either subjected to oscillatory shear stress or treated with the PKA (protein kinase A)/CREB (cAMP response element-binding protein) inhibitor H89 ( N -[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide·2HCl hydrate). Further studies using the partial carotid artery ligation model showed that disturbed flow in the left carotid artery of Sema7A +/+ ApoE −/− mice promoted the expression of endothelial Sema7A and cell adhesion molecules, leukocyte adhesion, and plaque formation, whereas such changes were attenuated in Sema7A −/− ApoE −/− mice. Further studies showed that blockage of β1 integrin, a known Sema7A receptor, or inhibition of FAK (focal adhesion kinase), MEK1/2 (mitogen-activated protein kinase kinase 1/2), or NF-κB (nuclear factor-κB) significantly reduced the expression of cell adhesion molecules and THP-1 (human acute monocytic leukemia cell line) monocyte adhesion in Sema7A-overexpressing human umbilical venous endothelial cells. Studies using chimeric mice suggest that vascular, most likely endothelial, Sema7A plays a major role in atherogenesis. Conclusions— Our findings indicate a significant role of Sema7A in atherosclerosis by mediating endothelial dysfunction in a β1 integrin–dependent manner.

Pseudoxanthoma elasticum is an ectopic mineralization disease due to biallelic ABCC6 mutations. As no treatment options are currently available, a reliable zebrafish model is invaluable for high throughput compound screening. However, data from previously reported knockdown and mutant zebrafish models for abcc6a, the functional orthologue of ABCC6, showed phenotypic discrepancies. To address this, we developed a complete abcc6a knockout model using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 and compared its phenotype to that of a mutant model (Sa963) and a splice junction morpholino model. Our data showed that abcc6a is not required for embryonic survival, but rather that it has an essential role in controlling mineralization. The three models developed very similar hypermineralization of spine and ribs starting embryonically and progressing in adulthood with development of scoliosis. Our results indicate a direct relation between loss of abcc6a expression and dysregulated osteogenesis. As such, our models recapitulate part of the human phenotype in which ectopic mineralization and pro-osteogenic signaling have been reported. Because of its reproducibility in three models and its ease of quantification, we consider this phenotype to be unequivocally the result of abcc6 deficiency and, as such, an excellent readout for drug screening purposes and multiplex mutagene analysis.

Physical fitness is one of the main therapeutic recommendations for patients with heart disease. Yet, adherence to physical activity regimen in both daily life and rehabilitation programs remains to be low. Elaborating on the analysis of factors associated with physical activity behavior, we noticed that the concept of adherence is complex, and its evaluation depends on a specific behavior and its settings. Evaluation of adherence to exercise in leisure time and exercise in the settings of cardiac rehabilitation program requires an application of different instruments. In this paper, we present a summary of findings from the literature analysis regarding types, settings and evaluation instruments of physical activity adherence in daily life and cardiac rehabilitation settings.

Background: Circulating osteoprotegerin (OPG), a member of the receptor activator of nuclear factor kappa-B (RANK) axis, may influence breast cancer risk via its role as the decoy receptor for both the RANK ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Circulating OPG and breast cancer risk has been examined in only one prior study. Methods: A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 2008 incident invasive breast cancer cases (estrogen receptor (ER)+, n = 1622; ER-, n = 386), matched 1: 1 to controls, were included in the analysis. Women were predominantly postmenopausal at blood collection (77%); postmenopausal women included users and non-users of postmenopausal hormone therapy (HT). Serum OPG was quantified with an electrochemiluminescence assay. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Results: The associations between OPG and ER+ and ER-breast cancer differed significantly. Higher concentrations of OPG were associated with increased risk of ER-breast cancer (top vs. bottom tertile RR = 1.93 [95% CI 1.24-3.02]; p(trend) = 0.03). We observed a suggestive inverse association for ER+ disease overall and among women premenopausal at blood collection. Results for ER-disease did not differ by menopausal status at blood collection (p(het) = 0.97), and we observed no heterogeneity by HT use at blood collection (p(het) >= 0.43) or age at breast cancer diagnosis (p(het) >= 0.30). Conclusions: This study provides the first prospective data on OPG and breast cancer risk by hormone receptor subtype. High circulating OPG may represent a novel risk factor for ER-breast cancer.

Taylor-Couette flow with independently rotating inner (i) and outer (o) cylinders is explored numerically and experimentally to determine the effects of the radius ratio {\eta} on the system response. Numerical simulations reach Reynolds numbers of up to Re_i=9.5 x 10^3 and Re_o=5x10^3, corresponding to Taylor numbers of up to Ta=10^8 for four different radius ratios {\eta}=r_i/r_o between 0.5 and 0.909. The experiments, performed in the Twente Turbulent Taylor-Couette (T^3C) setup, reach Reynolds numbers of up to Re_i=2x10^6$ and Re_o=1.5x10^6, corresponding to Ta=5x10^{12} for {\eta}=0.714-0.909. Effective scaling laws for the torque J^{\omega}(Ta) are found, which for sufficiently large driving Ta are independent of the radius ratio {\eta}. As previously reported for {\eta}=0.714, optimum transport at a non-zero Rossby number Ro=r_i|{\omega}_i-{\omega}_o|/[2(r_o-r_i){\omega}_o] is found in both experiments and numerics. Ro_opt is found to depend on the radius ratio and the driving of the system. At a driving in the range between {Ta\sim3\cdot10^8} and {Ta\sim10^{10}}, Ro_opt saturates to an asymptotic {\eta}-dependent value. Theoretical predictions for the asymptotic value of Ro_{opt} are compared to the experimental results, and found to differ notably. Furthermore, the local angular velocity profiles from experiments and numerics are compared, and a link between a flat bulk profile and optimum transport for all radius ratios is reported., Comment: Submitted to JFM, 28 pages, 17 figures

Background: The diagnosis of Alzheimer's disease (AD) is based on an ever-increasing body of data and knowledge making it a complex task. The PredictAD tool integrates heterogeneous patient data using an interactive user interface to provide decision support. The aim of this project was to investigate the performance of the tool in distinguishing AD from non-AD dementia using a realistic clinical dataset. Methods: We retrieved clinical data from a group of patients diagnosed with AD (n = 72), vascular dementia (VaD, n = 30), frontotemporal dementia (FTD, n = 25) or dementia with Lewy bodies (DLB, n = 14) at the Copenhagen Memory Clinic at Rigshospitalet. Three classification methods were applied to the data in order to differentiate between AD and a group of non-AD dementias. The methods were the PredictAD tool's Disease State Index (DSI), the naïve Bayesian classifier and the random forest. Results: The DSI performed best for this realistic dataset with an accuracy of 76.6% compared to the accuracies for the naïve Bayesian classifier and random forest of 67.4 and 66.7%, respectively. Furthermore, the DSI differentiated between the four diagnostic groups with a p value of Conclusion: In this dataset, the DSI method used by the PredictAD tool showed a superior performance for the differentiation between patients with AD and those with other dementias. However, the methods need to be refined further in order to optimize the differential diagnosis between AD, FTD, VaD and DLB.

A hallmark of inflammatory diseases is the excessive recruitment and influx of monocytes to sites of tissue damage and their ensuing differentiation into macrophages. Numerous stimuli are known to induce transcriptional changes associated with macrophage phenotype, but posttranscriptional control of human macrophage differentiation is less well understood. Here we show that expression levels of the RNA-binding protein Quaking (QKI) are low in monocytes and early human atherosclerotic lesions, but are abundant in macrophages of advanced plaques. Depletion of QKI protein impairs monocyte adhesion, migration, differentiation into macrophages and foam cell formation in vitro and in vivo. RNA-seq and microarray analysis of human monocyte and macrophage transcriptomes, including those of a unique QKI haploinsufficient patient, reveal striking changes in QKI-dependent messenger RNA levels and splicing of RNA transcripts. The biological importance of these transcripts and requirement for QKI during differentiation illustrates a central role for QKI in posttranscriptionally guiding macrophage identity and function., Post-transcriptional control of RNA is important in health and disease. Here, the authors show that the RNA-binding protein Quaking guides pre-mRNA splicing and transcript abundance during monocyte to macrophage differentiation, and that Quaking depletion impairs pro-atherogenic foam cell formation.

Since the generalisability of trial-based economic evaluations may be limited, there is an increasing focus on real-world cost-effectiveness. Real-world studies involve evaluating the effects and costs of treatments in daily clinical practice. This study reports on the real-world resource use and costs of adjuvant treatments of stage III colon cancer in a population-based observational study. Analyses were based on a detailed retrospective medical chart review which was conducted for 206 patients with colon cancer treated in 2005 and 2006 in the Netherlands. Mean total costs per patient were €9681 for 5-FU/LV, €9736 for capecitabine, €32,793 for FOLFOX and €18,361 for CAPOX. Drug costs and the costs related to hospitalisations for chemotherapy administration were the main cost drivers. We identified a potential for substantial cost-savings when the 48 h administration of 5FU/LV in the FOLFOX regimen were to take place in an outpatient setting or be replaced by oral capecitabine as in the CAPOX regimen. This analysis based on detailed real-life data clearly indicates that clinical choices made in oncology based on efficacy of therapy have economic consequences. Considering today's reality of finite healthcare resources, these economic consequences deserve a formal role in clinical decision making, for instance in guideline development.

Objective— The purpose of this study was to investigate the presence and functionality of P-selectin glycoprotein ligand-1 (PSGL-1) on activated endothelial cells (ECs). Methods and Results— We show here that PSGL-1 is expressed at the mRNA and protein levels in umbilical vein and microvascular ECs. Furthermore, this endothelial PSGL-1 (ePSGL-1) is functional and mediates adhesion of monocytes or platelet-monocyte complexes (PMCs) to the activated endothelium in a flow model. ePSGL-1 expression was not affected by treating ECs with inflammatory stimuli (tumor necrosis factor α, interleukin-1β, thrombin, or histamine). However, the functional binding capacity of ePSGL-1 to monocytes or P-selectin/Fc chimera significantly increased by stimulation of the ECs with TNFα. By means of a siRNA approach to specifically knock-down the genes involved in the glycosylation of PSGL-1 we could show that tumor necrosis factor α–induced glycosylation of ePSGL-1 is critical for its binding capacity. Conclusion— Our results show that ECs express functional PSGL-1 which mediates tethering and firm adhesion of monocytes and platelets to inflamed endothelium.

Background Inadequate analgesia during general anaesthesia may present as undesirable haemodynamic responses. No objective measures of the adequacy of analgesia exist. We aimed at developing a simple numerical measure of the level of surgical stress in an anaesthetized patient. Methods Sixty and 12 female patients were included in the development and validation data sets, respectively. All patients had elective surgery with propofol–remifentanil target controlled anaesthesia. Finger photoplethysmography and electrocardiography waveforms were recorded throughout anaesthesia and various waveform parameters were extracted off-line. Total surgical stress (TSS) for a patient was estimated based on stimulus intensity and remifentanil concentration. The surgical stress index (SSI) was developed to correlate with the TSS estimate in the development data set. The performance of SSI was validated within the validation data set during and before surgery, especially at skin incision and during changes of the predicted remifentanil effect-site concentration. Results SSI was computed as a combination of normalized heart beat interval (HBInorm) and plethysmographic pulse wave amplitude (PPGAnorm): SSI=100–(0.7*PPGAnorm+0.3*HBInorm). SSI increased at skin incision and stayed higher during surgery than before surgery; SSI responded to remifentanil concentration changes and was higher at the lower concentrations of remifentanil. Conclusions SSI reacts to surgical nociceptive stimuli and analgesic drug concentration changes during propofol–remifentanil anaesthesia. Further validation studies of SSI are needed to elucidate its usefulness during other anaesthetic and surgical conditions.

Rationale : RNA-binding proteins are critical post-transcriptional regulators of RNA and can influence pre-mRNA splicing, RNA localization, and stability. The RNA-binding protein Quaking (QKI) is essential for embryonic blood vessel development. However, the role of QKI in the adult vasculature, and in particular in vascular smooth muscle cells (VSMCs), is currently unknown. Objective : We sought to determine the role of QKI in regulating adult VSMC function and plasticity. Methods and Results : We identified that QKI is highly expressed by neointimal VSMCs of human coronary restenotic lesions, but not in healthy vessels. In a mouse model of vascular injury, we observed reduced neointima hyperplasia in Quaking viable mice, which have decreased QKI expression. Concordantly, abrogation of QKI attenuated fibroproliferative properties of VSMCs, while potently inducing contractile apparatus protein expression, rendering noncontractile VSMCs with the capacity to contract. We identified that QKI localizes to the spliceosome, where it interacts with the myocardin pre-mRNA and regulates the splicing of alternative exon 2a. This post-transcriptional event impacts the Myocd_v3/Myocd_v1 mRNA balance and can be modulated by mutating the quaking response element in exon 2a of myocardin. Furthermore, we identified that arterial damage triggers myocardin alternative splicing and is tightly coupled with changes in the expression levels of distinct QKI isoforms. Conclusions : We propose that QKI is a central regulator of VSMC phenotypic plasticity and that intervention in QKI activity can ameliorate pathogenic, fibroproliferative responses to vascular injury.

Objective This study examined the short-term and long-term effects of using a screening instrument on psychological distress and health-related quality of life (HRQoL) among cancer patients receiving radiotherapy. In addition, we investigated the effect of early psychosocial treatment on patients' overall health-related outcomes as previous research showed that patients in the screening condition were referred to a psychosocial caregiver at an earlier stage. Methods A cluster randomised controlled trial with a randomisation at the levels of 14 radiotherapists, 568 patients was conducted. Patients were asked to complete questionnaires at 3 and 12 months follow-up. Results Mixed models analyses showed no significant intervention effects on patients' overall extent of psychosocial distress and HRQoL, both on the short and long terms. Post-hoc analyses revealed significant interactions of the intervention with early referral and improved HRQoL and anxiety, suggesting that earlier referral might influence short-term HRQoL and experienced anxiety in patients. Conclusions Our results suggest that the use of a psychosocial screening instrument among patients receiving radiotherapy in itself does not sufficiently improve patients' health-related outcome. The effective delivery of psychosocial care depends upon several components such as identification of distress and successful implementation of screening procedures. One of the challenges is to get insight in the effects of early referral of cancer patients for psychosocial support because early referral might have a favourable effect on some of the patients' health-related outcomes. Copyright © 2013 John Wiley & Sons, Ltd.

When assessing the risks of a research protocol, review boards need to consider not only the possible harms but also the expected discomfort levels caused by the various study procedures. However, data on how children experience various study procedures are scarce. This study assessed perceived discomfort levels in 671 healthy children aged 0–2 years undergoing vaccinations, venipunctures, and nasopharyngeal swab taking. In half of the study participants, venipunctures caused a moderate or high level of discomfort (49%). Corresponding figures for nasopharyngeal swabbing and vaccinations were 28% and 12%, respectively. Within the reported age group, increasing age was related with higher discomfort levels. In a majority of cases for all study procedures, the perceived levels of discomfort met the parents' expectations.

In the present work it will be shown how the curvature of the outer cylinder affects laser Doppler anemometry measurements inside a Taylor?Couette apparatus. The measurement position and the measured velocity are altered by curved surfaces. Conventional methods for curvature correction are not applicable to our setup, and it will be shown how a ray-tracer can be used to solve this complication. By using a ray-tracer the focal position can be calculated, and the velocity can be corrected. The results of the ray-tracer are verified by measuring an a priori known velocity field, and after applying refractive corrections good agreement with theoretical predictions are found. The methods described in this paper are applied to measure the azimuthal velocity profiles in high Reynolds number Taylor?Couette flow for the case of outer cylinder rotation.

Aim: Atherosclerosis is accelerated by excessive monocyte recruitment, influx and differentiation into pro-inflammatory macrophages. While the genome-wide mRNA expression profiles of human monocytes and pro-inflammatory macrophages are well-established, their transcriptomes are ultimately defined by factors, such as RNA-binding proteins, that modulate pre-mRNA splicing patterns and mRNA transcript abundance. This prompted us to investigate the role of the RNA-binding protein Quaking in regulating global changes in pre-mRNA splicing and mature mRNA expression as human monocytes acquire the pro-inflammatory macrophage identity. Methods: We employed RNA-sequencing and splicing-sensitive microarrays to determine genome-wide changes in pre-mRNA splicing and mRNA expression upon conversion of human monocytes into pro-inflammatory macrophages, including those derived from a unique Quaking haploinsufficient patient. Results: Using laser-capture micro-dissection and immunohistochemistry, we discovered that expression levels of Quaking mRNA and protein are low in monocytes of early human atherosclerotic lesions, but abundant in macrophages of advanced plaques. Depletion of Quaking protein using both siRNA and GapmeR technology significantly impaired monocyte adhesion and migration; delayed differentiation into pro-inflammatory macrophages while maintaining the capacity to adopt the anti-inflammatory phenotype; and diminished foam cell formation in vitro and in vivo. RNA-sequencing and microarray analysis of human monocyte and macrophage transcriptomes revealed striking changes in Quaking-dependent pre-mRNA splicing and mRNA transcript levels, with gene ontology analyses identifying an enrichment in transcripts involved in cellular migration and lipid metabolism. Furthermore, these studies uncovered common as well as novel alternatively spliced transcripts with unknown biological functions in monocytes and macrophages. Conclusions: Our studies illustrate a central role for Quaking in post-transcriptionally guiding pro-inflammatory macrophage identity and function.

Proper regulation of endothelial cell-cell contacts is essential for physiological functioning of the endothelium. Interendothelial junctions are actively involved in the control of vascular leakage, leukocyte diapedesis and the initiation and progression of angiogenesis. We found that the RNA-binding protein quaking is highly expressed by endothelial cells and that its expression was augmented by prolonged culture under laminar flow and the transcription factor KLF2 binding to the promoter. Moreover, we demonstrated that quaking directly binds to the mRNA of VE-cadherin and β-catenin and can induce mRNA translation mediated by the 3′UTR of these genes. Reduced quaking levels attenuated VE-cadherin and β-catenin expression and endothelial barrier function in vitro and resulted in increased bradykinin-induced vascular leakage in vivo. Taken together, we report that quaking is essential in maintaining endothelial barrier function. Our results provide novel insight into the importance of post-transcriptional regulation in controlling vascular integrity.

Strongly turbulent Taylor-Couette flow with independently rotating inner and outer cylinders with a radius ratio of \eta = 0.716 is experimentally studied. From global torque measurements, we analyse the dimensionless angular velocity flux Nu_\omega(Ta, a) as a function of the Taylor number Ta and the angular velocity ratio a = -\omega_o/\omega_i in the large-Taylor-number regime 10^{11} \lesssim Ta \lesssim 10^{13}. We analyse the data with the common power-law ansatz for the dimensionless angular velocity transport flux Nu_\omega(Ta, a) = f(a)Ta^\gamma, with an amplitude f(a) and an exponent \gamma. The data are consistent with one effective exponent \gamma = 0.39\pm0.03 for all a. The amplitude of the angular velocity flux f(a) = Nu_\omega(Ta, a)/Ta^0.39 is measured to be maximal at slight counter-rotation, namely at an angular velocity ratio of a_opt = 0.33\pm0.04. This value is theoretically interpreted as the result of a competition between the destabilizing inner cylinder rotation and the stabilizing but shear-enhancing outer cylinder counter-rotation. With the help of laser Doppler anemometry, we provide angular velocity profiles and identify the radial position r_n of the neutral line. While for moderate counter-rotation -0.40 \omega_i \lesssim \omega_o < 0, the neutral line still remains close to the outer cylinder and the probability distribution function (p.d.f.) of the bulk angular velocity is observed to be monomodal. For stronger counter-rotation the neutral line is pushed inwards towards the inner cylinder; in this regime the p.d.f. of the bulk angular velocity becomes bimodal, reflecting intermittent bursts of turbulent structures beyond the neutral line into the outer flow domain, which otherwise is stabilized by the counter-rotating outer cylinder. Finally, a hypothesis is offered allowing a unifying view for all these various results., Comment: 30 pages, 22 figures

Knowledge of the immunological correlates of Staphylococcus aureus and Streptococcus pneumoniae colonization is required for the search for future protein vaccines. We evaluated natural antibody levels against pneumococcal and staphylococcal proteins in relation to previous bacterial colonization with both pathogens. In a randomized controlled trial, nasopharyngeal samples were obtained from children at 1.5, 6, 12, 18, and 24 months and cultured for S. aureus and S. pneumoniae . Approximately 50% of the children were PCV7 vaccinated. Serum IgG against 18 pneumococcal and 40 staphylococcal proteins was semiquantified by Luminex technology from 111 12 month olds and 158 24 month olds. Previous culture-proven S. aureus colonization was associated with higher IgG levels against 6/40 staphylococcal proteins (ClfB, ClfA, Efb, CHIPS, LukD, and LukF [ P ≤ 0.001]) compared to noncarriers. Previous pneumococcal colonization was associated with increased IgG levels against 12/18 pneumococcal proteins compared to noncarriers ( P ≤ 0.003). Increasing age was associated with higher levels of antibodies to most pneumococcal proteins and lower levels of antibodies to over half the staphylococcal proteins, reflecting natural colonization dynamics. Anti- S. pneumoniae and anti- S. aureus protein antibodies at the age of 12 months were not negatively correlated with subsequent colonization with the homologous species in the following year and did not differ between PCV7-vaccinated and nonvaccinated children. Colonization with S. aureus and S. pneumoniae induces serum IgG against many proteins, predominantly proteins with immune-modulating functions, irrespective of PCV7 vaccination. None of them appeared to be protective against new acquisition with both pathogens, possibly due to the polymorphic nature of those proteins in the circulating bacterial population.

Many manufacturers and distributors of LED tubes claim energy savings of 50% and more when replacing T8 fluorescent tubes with linear LED replacement lamps. Several distributors even pretend that the same visual comfort will be maintained after such a replacement. Optical and electrical parameters of twelve commercially available linear LED tubes have been determined and the evolution in time of these parameters has been monitored. Additionally, a case study is presented in which the fluorescent lamps in a small office room were replaced by LED linear replacement lamps in order to compare the illuminance distribution on the work plane, the glare perception and the overall visual appreciation. According to this study, it is clear that a one-to-one replacement of a classical fluorescent tube by a currently available linear LED lamp might have severe consequences on the lighting quality.

PURPOSE The dosimetric impact of gold fiducial markers (FM) implanted prior to external beam radiotherapy of prostate cancer on low dose rate (LDR) brachytherapy seed implants performed in the context of combined therapy was investigated. METHODS A virtual water phantom was designed containing a single FM. Single and multi source scenarios were investigated by performing Monte Carlo dose calculations, along with the influence of varying orientation and distance of the FM with respect to the sources. Three prostate cancer patients treated with LDR brachytherapy for a recurrence following external beam radiotherapy with implanted FM were studied as surrogate cases to combined therapy. FM and brachytherapy seeds were identified on post implant CT scans and Monte Carlo dose calculations were performed with and without FM. The dosimetric impact of the FM was evaluated by quantifying the amplitude of dose shadows and the volume of cold spots. D(90) was reported based on the post implant CT prostate contour. RESULTS Large shadows are observed in the single source-FM scenarios. As expected from geometric considerations, the shadows are dependent on source-FM distance and orientation. Large dose reductions are observed at the distal side of FM, while at the proximal side a dose enhancement is observed. In multisource scenarios, the importance of shadows appears mitigated, although FM at the periphery of the seed distribution caused underdosage (

The sand sequences exposed at the archaeological sites of Arendonk-Korhaan and Lommel-Maatheide offer a unique means to study the possible relation between human occupation patterns and climatic and environmental changes during the Weichselian–Holocene transition in the Campine region (NE Belgium). Of particular importance is that, at these localities, the Final Palaeolithic and Early Mesolithic settlement phases are stratigraphically separated. Optically stimulated luminescence (OSL) dating established a chronology for the evolution of the physical landscape around these sites; such a framework is essential when trying to understand settlement dynamics in response to environmental forcing. Thirty samples in total were dated using quartz SAR-OSL. The luminescence ages range from 16.2 ± 1.4 ka to 10.6 ± 0.7 ka. They indicate that sand deposition at Arendonk and Lommel was already going on during the final phase of the Late Pleniglacial and/or the onset of the Late Glacial. At Arendonk, sediments and soils from the early Late Glacial until the Allerod are missing, whereas a single interruption in the aeolian activity during the Allerod interstadial is reported for Lommel. Landscape stabilisation during the Allerod is also suggested by stratigraphical evidence, i.e. the presence of a bleached horizon both at elevated and low-lying flat areas, and extensive peat growth in wet depressions. The Bolling interstadial, on the other hand, has not been recognised in the lithostratigraphic record; this corroborates earlier suggestions that the climatic amelioration during the Bolling was not accompanied by a general stabilisation of the land surface in the NW European lowlands. The continuation of sand transport and deposition across the Late Pleniglacial/Late Glacial boundary may explain why human societies did not occupy the Campine region until the Allerod. During this interstadial, environmental conditions improved sufficiently to attract Final Palaeolithic Federmessergruppen to settle on higher grounds in the area. The climate deteriorated at the onset of the Late Dryas and, as a consequence, aeolian activity intensified again at Arendonk and Lommel, with at least 0.5–1 m of sand being deposited in a period of ∼1 ka; this may have caused the Federmesser to leave the area. At both localities, no occupation has been attested for the Late Dryas period until the Early Holocene, when Early Mesolithic societies settled in the area. This study illustrates how luminescence dating can contribute to an improved understanding of the environmental context around archaeological sites in the Campine region.

Already in the beginning of the last decade it was noticed that our society is ageing and new kind of partnership will be needed to develop both services and technology. Therefore new concepts must be developed and they must be taken into a use to ensure that people needing services can also reach them. Elderly people are eager to use new services and new technology if it will support their daily living at their own home. In the coming years it is even more important than earlier that private and public sector are in close cooperation and are together responsible for the development work concerning also health care and social welfare applications. Because of the complexity of the topic there is a need to use different kind of methods and so to achieve multidisciplinary information to be used by decision makers. INTRODUCTION Technical Research Centre of Finland (VTT) and Technical University of Tampere, Finland (TUT) started a three years project, ‘Smart Home in a Suitcase, new technologies supporting telemedicine, home care, rehabilitation and safety at home’ in December 2005. This project, called UUTE, will end by the end of 2008. Partners representing public health care and special health care organisations in the project are: Pirkanmaa Hospital District, Tampere University Hospital and Lempaala Health Care Centre. Private companies represent information technology, building development for seniors, technology assisting independent living and home care services. A company providing first aid (ambulance) and safety services and a company interested in balance and walking problems joined the project during spring 2007. AIM OF THE PROJECT The aim of the project is to develop a general technical platform for personally adaptable solutions that will support a person in different living conditions at home. It should support a person to follow-up his or her physical condition during home exercises or at a training centre. One basic objective is that health care personnel can support an outdoor patient at his homecare after hospitalization phase. Because of the challenge to provide good health care services including rehabilitation and safety services for a growing number of elderly people, more co-operation is needed between public, private and so called third sector actors. In Finland, municipalities are responsible for arranging the health care and welfare services, but they can organise the services together with different kind of partners. As one example of the possible network in the future can be seen the co-operation between actors in our project as illustrated in the Fig. 1 (integration into services provided by the participating organisations). METHODS The project has used different kind of research methods from the viewpoints of technical, medical and human sciences. Methods used were: a) Management group meetings, b) interviews, c) scenarios, d) questionnaires, e) Workshops and seminars and f) Testing and piloting the prototype with out patient and elderly people. RESULTS AND DISCUSSION So far the results show that it is beneficial if ICT based applications and services meant for elderly people are developed in co-operation with different kind of actors. The need of services varies a lot among elderly people. Because of the variation it was important to take into account physical, mental and social factors when developing new technical solutions and services based on technical development. It was found out that it is important to discuss with the representatives of health care personnel if you like to carry out a proper research process among patients and personnel. The personnel should be informed on the aim the project because nowadays the staff is working under quite a pressure and the time is limited for extra work. Motivation is a big issue that must be considered. It is also very important to take into account the opinions and expectations of patients and elderly people if the aim is that they are willing to use new services based on technology. Both professionals and elderly people are eager to participate in different kind of development work if they are motivated and interested enough and if they see that in the future there might be new ways to do work or new ways to get and use services at home. UUTE home platform Safety and emergency services Home and housing support Home care and elderly care Exercise and rehabilitation services Health care services Relatives Support groups and self-care Fig.1. Integration into services provided by the participating organisations Gateway provided by companies Gateway provided by research consortium Tel. +358 20 722 3329 Fax +358 20 722 3499 tuula.petakoski-hult@vtt.fi www.vtt.fi Funding: Tekes, the Finnish Funding Agency for Technology and Innovation, VTT Technical Research Centre of Finland, Pikosystems Inc., TietoEnator Inc., YH Lansi Inc., UPM-Kymmene Plc, Turun Orthofysio Inc., Arcticare Technologies Inc., Suomen Ensiapupalvelu Inc. VTT TECHNICAL RESEARCH CENTRE OF FINLAND Visiting address: Tekniikankatu 1, TAMPERE P.O. Box 1300 FIN-02044 VTT, Finland

Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.

Purpose: To describe decisional roles of patients with early-stage prostate cancer in 9 countries and to compare the information they rated important for decision making (DM). Method: A survey of recently treated patients was conducted in Canada, Italy, England, Germany, Poland, Portugal, Netherlands, Spain, and Turkey. Participants indicated their decisional role in their actual decision and the role they would prefer now. Each participant also rated (essential/desired/no opinion/avoid) the importance of obtaining answers, between diagnosis and treatment decision, to each of 92 questions. For each essential/desired question, participants specified all purposes for that information (to help them: understand/ decide/plan/not sure/other). Results: A total of 659 patients participated with country-specific response rates between 58%-77%. Between 83%-96% of each country’s participants recalled actually taking an active decisional role and, in most countries, that increased slightly if they were to make the decision today; there were no significant differences among countries. There was a small reliable difference in the mean number of questions rated essential for DM across countries. More striking, however, was the wide variability within each country: no question was rated essential for DM by even 50% of its participants but almost every question was rated essential by some. Conclusions: Almost all participants from each country want to participate in their treatment decisions. Although there are country-specific differences in the amount of information required, wide variation within each country suggests that information that patients feel is essential or desired for DM should be addressed on an individual basis in all countries. Key words: early-stage prostate cancer, patient information needs, patient education. (Med Decis Making 2011;31:754-766)