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1.  Non-invasive assessment of atherosclerotic coronary lesion length using multidetector computed tomography angiography: comparison to quantitative coronary angiography 
Multidetector computed tomography angiography (CTA) provides information on plaque extent and stenosis in the coronary wall. More accurate lesion assessment may be feasible with CTA as compared to invasive coronary angiography (ICA). Accordingly, lesion length assessment was compared between ICA and CTA in patients referred for CTA who underwent subsequent percutaneous coronary intervention (PCI). 89 patients clinically referred for CTA were subsequently referred for ICA and PCI. On CTA, lesion length was measured from the proximal to the distal shoulder of the plaque. Quantitative coronary angiography (QCA) was performed to analyze lesion length. Stent length was recorded for each lesion. In total, 119 lesions were retrospectively identified. Mean lesion length on CTA was 21.4 ± 8.4 mm and on QCA 12.6 ± 6.1 mm. Mean stent length deployed was 17.4 ± 5.3 mm. Lesion length on CTA was significantly longer than on QCA (difference 8.8 ± 6.7 mm, P < 0.001). Moreover, lesion length visualized on CTA was also significantly longer than mean stent length (CTA lesion length-stent length was 4.2 ± 8.7 mm, P < 0.001). Lesion length assessed by CTA is longer than that assessed by ICA. Possibly, CTA provides more accurate lesion length assessment than ICA and may facilitate improved guidance of percutaneous treatment of coronary lesions.
doi:10.1007/s10554-012-0015-7
PMCID: PMC3485532  PMID: 22271073
Coronary artery disease; Multidetector computed tomography; Quantitative coronary angiography
2.  Comprehensive assessment of spotty calcifications on computed tomography angiography: Comparison to plaque characteristics on intravascular ultrasound with radiofrequency backscatter analysis 
Journal of Nuclear Cardiology  2011;18(5):893-903.
Background
The purpose of the study was to systematically compare calcification patterns in plaques on computed tomography angiography (CTA) with plaque characteristics on intravascular ultrasound with radiofrequency backscatter analysis (IVUS-VH).
Methods and Results
In total, 108 patients underwent CTA and IVUS-VH. On CTA, calcification patterns in plaques were classified as non-calcified, spotty or dense calcifications. Plaques with spotty calcifications were differentiated into small spotty (<1 mm), intermediate spotty (1-3 mm) and large spotty calcifications (≥3 mm). Plaque characteristics deemed more high-risk on IVUS-VH were defined by % necrotic core (NC) and presence of thin cap fibroatheroma (TCFA). Overall, 300 plaques were identified both on CTA and IVUS-VH. % NC core was significantly higher in plaques with small spotty calcifications as compared to non-calcified plaques (20% vs 13%, P = .006). In addition, there was a trend for a higher % NC in plaques with small spotty calcifications than in plaques with intermediate spotty calcifications (20% vs 14%, P = .053). Plaques with small spotty calcifications had the highest % TCFA as compared to large spotty and dense calcifications (31% vs 9% and 31% vs 6%, P < .05).
Conclusion
Plaques with small spotty calcifications on CTA were related to plaque characteristics deemed more high-risk on IVUS-VH. Therefore, CTA may be valuable in the assessment of the vulnerable plaque.
doi:10.1007/s12350-011-9428-2
PMCID: PMC3175045  PMID: 21769702
Atherosclerosis; computed tomography (CT); vulnerable atherosclerotic plaque
3.  Quantitative T2 measurement of a single voxel with arbitrary shape using pinwheel excitation and CPMG acquisition 
Magma (New York, N.Y.)  2007;20(5-6):233-240.
Objective
The aim of this study is to present a new approach for making quantitative single-voxel T2 measurements from an arbitrarily shaped region of interest (ROI), where the advantage of the signal-to-noise ratio (SNR) per unit time of the single-voxel approach over conventional imaging approach can be achieved.
Materials and methods
Two-dimensional (2D) spatially selective radiofrequency (RF) pulses are proposed in this work for T2 measurements based on using interleaved spiral trajectories in excitation k-space (pinwheel excitation pulses), combined with a summed Carr—Purcell Meiboom—Gill (CPMG) echo acquisition. The technique is described and compared to standard multi-echo imaging methods, on a two-compartment water phantom and an excised brain tissue.
Results
The studies show good agreement between imaging and our method. The measured improvement factors of SNR per unit time of our single-voxel approach over imaging approach are close to the predicted values.
Conclusion
Measuring T2 relaxation times from a selected ROI of arbitrary shape using a single-voxel rather than an imaging approach can increase the SNR per unit time, which is critical for dynamic T2 or multi-component T2 measurements.
doi:10.1007/s10334-007-0088-9
PMCID: PMC2634838  PMID: 17999101
T2 measurement; Arbitrary shape localization; Interleaved spiral trajectory in k-space; CPMG
4.  ANS Responses and Facial Expressions Differentiate between the Taste of Commercial Breakfast Drinks 
PLoS ONE  2014;9(4):e93823.
The high failure rate of new market introductions, despite initial successful testing with traditional sensory and consumer tests, necessitates the development of other tests. This study explored the ability of selected physiological and behavioral measures of the autonomic nervous system (ANS) to distinguish between repeated exposures to foods from a single category (breakfast drinks) and with similar liking ratings. In this within-subject study 19 healthy young adults sipped from five breakfast drinks, each presented five times, while ANS responses (heart rate, skin conductance response and skin temperature), facial expressions, liking, and intensities were recorded. The results showed that liking was associated with increased heart rate and skin temperature, and more neutral facial expressions. Intensity was associated with reduced heart rate and skin temperature, more neutral expressions and more negative expressions of sadness, anger and surprise. Strongest associations with liking were found after 1 second of tasting, whereas strongest associations with intensity were found after 2 seconds of tasting. Future studies should verify the contribution of the additional information to the prediction of market success.
doi:10.1371/journal.pone.0093823
PMCID: PMC3979707  PMID: 24714107
5.  Slow Food: Sustained Impact of Harder Foods on the Reduction in Energy Intake over the Course of the Day 
PLoS ONE  2014;9(4):e93370.
Background
Previous research has shown that oral processing characteristics like bite size and oral residence duration are related to the satiating efficiency of foods. Oral processing characteristics are influenced by food texture. Very little research has been done on the effect of food texture within solid foods on energy intake.
Objectives
The first objective was to investigate the effect of hardness of food on energy intake at lunch, and to link this effect to differences in food oral processing characteristics. The second objective was to investigate whether the reduction in energy intake at lunch will be compensated for in the subsequent dinner.
Design
Fifty subjects (11 male, BMI: 21±2 kg/m2, age: 24±2 y) participated in a cross-over study in which they consumed ad libitum from a lunch with soft foods or hard foods on two separate days. Oral processing characteristics at lunch were assessed by coding video records. Later on the same days, subjects consumed dinner ad libitum.
Results
Hard foods led to a ∼13% lower energy intake at lunch compared to soft foods (P<0.001). Hard foods were consumed with smaller bites, longer oral duration per gram food, and more chewing per gram food compared to the soft foods (P<0.05). Energy intake at dinner did not differ after both lunches (P = 0.16).
Conclusions
Hard foods led to reduced energy intake compared to soft foods, and this reduction in energy intake was sustained over the next meal. We argue that the differences in oral processing characteristics produced by the hardness of the foods explain the effect on intake. The sustained reduction in energy intake suggests that changes in food texture can be a helpful tool in reducing the overall daily energy intake.
doi:10.1371/journal.pone.0093370
PMCID: PMC3973680  PMID: 24695412
6.  Disorder-specific cognitive profiles in major depressive disorder and generalized anxiety disorder 
BMC Psychiatry  2014;14:96.
Background
This investigation examines differences in cognitive profiles in subjects with major depressive disorder (MDD) and generalized anxiety disorder (GAD).
Methods
Data were used from subjects with current MDD (n = 655), GAD (n = 107) and comorbid MDD/GAD (n = 266) diagnosis from the Netherlands Study of Depression and Anxiety (NESDA). The Composite Interview Diagnostic Instrument was used to diagnose MDD and GAD. Cognitive profiles were measured using the Leiden Index of Depression Sensitivity, the Anxiety Sensitivity Index, and the Penn State Worry Questionnaire.
Results
Results showed that differences in cognitive profiles between single MDD and single GAD subjects were present: scores on hopelessness/suicidality and rumination were significantly higher in MDD than GAD, whereas anxiety sensitivity for physical concerns and pathological worry were higher in GAD than MDD. The cognitive profile of comorbid MDD/GAD showed more extreme depression cognitions compared to single disorders, and a similar anxiety profile compared to single GAD subjects.
Conclusions
Despite the commonalities in cognitive profiles in MDD and GAD, there are differences suggesting that MDD and GAD have disorder-specific cognitive profiles. Findings of this investigation give support for models like the cognitive content-specificity model and the tripartite model and could provide useful handles for treatment focus.
doi:10.1186/1471-244X-14-96
PMCID: PMC3975137  PMID: 24690413
Major depressive disorder; Generalized anxiety disorder; Cognitive profiles; Treatment; Classification
8.  Lipoprotein Metabolism Indicators Improve Cardiovascular Risk Prediction 
PLoS ONE  2014;9(3):e92840.
Background
Cardiovascular disease risk increases when lipoprotein metabolism is dysfunctional. We have developed a computational model able to derive indicators of lipoprotein production, lipolysis, and uptake processes from a single lipoprotein profile measurement. This is the first study to investigate whether lipoprotein metabolism indicators can improve cardiovascular risk prediction and therapy management.
Methods and Results
We calculated lipoprotein metabolism indicators for 1981 subjects (145 cases, 1836 controls) from the Framingham Heart Study offspring cohort in which NMR lipoprotein profiles were measured. We applied a statistical learning algorithm using a support vector machine to select conventional risk factors and lipoprotein metabolism indicators that contributed to predicting risk for general cardiovascular disease. Risk prediction was quantified by the change in the Area-Under-the-ROC-Curve (ΔAUC) and by risk reclassification (Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI)). Two VLDL lipoprotein metabolism indicators (VLDLE and VLDLH) improved cardiovascular risk prediction. We added these indicators to a multivariate model with the best performing conventional risk markers. Our method significantly improved both CVD prediction and risk reclassification.
Conclusions
Two calculated VLDL metabolism indicators significantly improved cardiovascular risk prediction. These indicators may help to reduce prescription of unnecessary cholesterol-lowering medication, reducing costs and possible side-effects. For clinical application, further validation is required.
doi:10.1371/journal.pone.0092840
PMCID: PMC3965475  PMID: 24667559
9.  Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure 
Journal of medicinal chemistry  2013;56(5):2087-2096.
Trypanosoma brucei cyclic nucleotide phosphodiesterase B1 (TbrPDEB1) and TbrPDEB2 have recently been validated as new therapeutic targets for human African Trypanosomiasis by both genetic and pharmacological means. In this study we report the crystal structure of the catalytic domain of the unliganded TbrPDEB1 and its use for the in silico screening for new TbrPDEB1 inhibitors with novel scaffolds. The TbrPDEB1 crystal structure shows the characteristic folds of human PDE enzymes, but also contains the parasite-specific P-pocket found in the structures of Leishmania major PDEB1 and Trypanosoma cruzi PDEC. The unliganded TbrPDEB1 X-ray structure was subjected to a structure-based in silico screening approach that combines molecular docking simulations with a protein-ligand interaction fingerprint (IFP) scoring method. This approach identified, six novel TbrPDEB1 inhibitors with IC50 values of 10–80 μM, which may be further optimized as potential selective TbrPDEB inhibitors.
doi:10.1021/jm3017877
PMCID: PMC3635145  PMID: 23409953
10.  The Sum of Its Parts—Effects of Gastric Distention, Nutrient Content and Sensory Stimulation on Brain Activation 
PLoS ONE  2014;9(3):e90872.
During food consumption the brain integrates multiple interrelated neural and hormonal signals involved in the regulation of food intake. Factors influencing the decision to stop eating include the foods' sensory properties, macronutrient content, and volume, which in turn affect gastric distention and appetite hormone responses. So far, the contributions of gastric distention and oral stimulation by food on brain activation have not been studied. The primary objective of this study was to assess the effect of gastric distention with an intra-gastric load and the additional effect of oral stimulation on brain activity after food administration. Our secondary objective was to study the correlations between hormone responses and appetite-related ratings and brain activation. Fourteen men completed three functional magnetic resonance imaging sessions during which they either received a naso-gastric infusion of water (stomach distention), naso-gastric infusion of chocolate milk (stomach distention + nutrients), or ingested chocolate-milk (stomach distention + nutrients + oral exposure). Appetite ratings and blood parameters were measured at several time points. During gastric infusion, brain activation was observed in the midbrain, amygdala, hypothalamus, and hippocampus for both chocolate milk and water, i.e., irrespective of nutrient content. The thalamus, amygdala, putamen and precuneus were activated more after ingestion than after gastric infusion of chocolate milk, whereas infusion evoked greater activation in the hippocampus and anterior cingulate. Moreover, areas involved in gustation and reward were activated more after oral stimulation. Only insulin responses following naso-gastric infusion of chocolate milk correlated with brain activation, namely in the putamen and insula. In conclusion, we show that normal (oral) food ingestion evokes greater activation than gastric infusion in stomach distention and food intake-related brain areas. This provides neural evidence for the importance of sensory stimulation in the process of satiation.
Trial Registration
ClinicalTrials.gov NCT01644539.
doi:10.1371/journal.pone.0090872
PMCID: PMC3948722  PMID: 24614074
11.  Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia 
Neurology  2013;80(9):814-823.
Objective:
We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubule-associated protein tau and progranulin mutations.
Methods:
In this case-control study, 75 healthy individuals (aged 20–70 years) with 50% risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex.
Results:
Although carriers (n = 37) and noncarriers (n = 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found.
Conclusions:
This study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.
doi:10.1212/WNL.0b013e31828407bc
PMCID: PMC3598452  PMID: 23390180
12.  Effect of Bodily Fluids from Honey Bee (Apis mellifera) Larvae on Growth and Genome-Wide Transcriptional Response of the Causal Agent of American Foulbrood Disease (Paenibacillus larvae) 
PLoS ONE  2014;9(2):e89175.
Paenibacillus larvae, the causal agent of American Foulbrood disease (AFB), affects honey bee health worldwide. The present study investigates the effect of bodily fluids from honey bee larvae on growth velocity and transcription for this Gram-positive, endospore-forming bacterium. It was observed that larval fluids accelerate the growth and lead to higher bacterial densities during stationary phase. The genome-wide transcriptional response of in vitro cultures of P. larvae to larval fluids was studied by microarray technology. Early responses of P. larvae to larval fluids are characterized by a general down-regulation of oligopeptide and sugar transporter genes, as well as by amino acid and carbohydrate metabolic genes, among others. Late responses are dominated by general down-regulation of sporulation genes and up-regulation of phage-related genes. A theoretical mechanism of carbon catabolite repression is discussed.
doi:10.1371/journal.pone.0089175
PMCID: PMC3930689  PMID: 24586572
13.  Dynamics of autonomic nervous system responses and facial expressions to odors 
Why we like or dislike certain products may be better captured by physiological and behavioral measures of the autonomic nervous system (ANS) than by conscious or classical sensory tests. Responses to pleasant and unpleasant food odors presented in varying concentrations were assessed continuously using facial expressions and responses of the ANS. Results of 26 young and healthy female participants showed that the unpleasant fish odor triggered higher heart rates and skin conductance responses, lower skin temperature, fewer neutral facial expressions and more disgusted and angry expressions (p < 0.05). Neutral facial expressions differentiated between odors within 100 ms, after the start of the odor presentation followed by expressions of disgust (180 ms), anger (500 ms), surprised (580 ms), sadness (820 ms), scared (1020 ms), and happy (1780 ms) (all p-values < 0.05). Heart rate differentiated between odors after 400 ms, whereas skin conductance responses differentiated between odors after 3920 ms. At shorter intervals (between 520 and 1000 ms and between 2690 and 3880 ms) skin temperature for fish was higher than that for orange, but became considerable lower after 5440 ms. This temporal unfolding of emotions in reactions to odors, as seen in facial expressions and physiological measurements supports sequential appraisal theories.
doi:10.3389/fpsyg.2014.00110
PMCID: PMC3923144  PMID: 24592246
skin conductance; skin temperature; heart rate; ANS responses; odor; valence; concentration; facial expressions
14.  NPHP4 Variants are Associated with Pleiotropic Heart Malformations 
Circulation research  2012;110(12):1564-1574.
Rationale
Congenital heart malformations are a major cause of morbidity and mortality especially in young children. Failure to establish normal left-right (L-R) asymmetry often results in cardiovascular malformations and other laterality defects of visceral organs.
Objective
To identify genetic mutations causing cardiac laterality defects.
Methods and Results
We performed a genome-wide linkage analysis in patients with cardiac laterality defects from a consanguineous family. The patients had combinations of defects that included dextrocardia, transposition of great arteries, double outlet right ventricle, atrio-ventricular septal defects and caval vein abnormalities. Sequencing of positional candidate genes identified mutations in NPHP4. We performed mutation analysis of NPHP4 in 146 unrelated patients with similar cardiac laterality defects. Forty-one percent of these patients also had laterality defects of the abdominal organs. We identified eight additional missense variants that were absent or very rare in controls. To study the role of nphp4 in establishing L-R asymmetry, we used antisense morpholinos to knockdown nphp4 expression in zebrafish. Depletion of nphp4 disrupted L-R patterning as well as cardiac and gut laterality. Cardiac laterality defects were partially rescued by human NPHP4 mRNA, whereas mutant NPHP4 containing genetic variants found in patients failed to rescue. We show that nphp4 is involved in the formation of motile cilia in Kupffer’s vesicle (KV), which generate asymmetric fluid flow necessary for normal L-R asymmetry.
Conclusions
NPHP4 mutations are associated with cardiac laterality defects and heterotaxy. In zebrafish, nphp4 is essential for the development and function of KV cilia and is required for global L-R patterning.
doi:10.1161/CIRCRESAHA.112.269795
PMCID: PMC3916111  PMID: 22550138
Congenital heart malfortmations; heterotaxy; nphp4; cilia; zebrafish
15.  Evaluation of the Compliance, Acceptance, and Usability of a Web-Based eHealth Intervention for Parents of Children With Infantile Hemangiomas: Usability Study 
JMIR Research Protocols  2013;2(2):e54.
Background
Infantile hemangiomas (IH) are common benign vascular tumors in children. Recognition and timely referral of high risk IH to specialized centers is important. This might be achieved by involving parents in the care for IH by means of an eHealth intervention.
Objective
The objective of our study was to evaluate parent compliance, acceptance, and usability of an open access, Web-based eHealth intervention (including e-learning and e-consult) designed to increase parents’ knowledge and (risk) evaluation of IH.
Methods
A cross-sectional study of parents who completed the eHealth intervention between October 2010 and November 2012 was carried out. All parents were sent a study questionnaire. Questions to evaluate compliance (to the advice given by a dermatologist during e-consultation) were asked. Acceptance and usability were evaluated by using the modified Technology Acceptance Model.
Results
A total of 224 parents completed the eHealth intervention and received the questionnaire, 135/224 parents responded (response rate was 60.3%). There were 128/135 questionnaires that were completed and included. A total of 110/128 (85.9%) parents were compliant to the advice of the dermatologist. There were 116.8/128 (91.3%) that perceived the eHealth intervention as useful and almost all parents (98.4%, 126/128) found the information in the e-learning clear. There were 29/128 (22.7%) that experienced technical problems. The majority of the parents (94.5%, 121/128) found the eHealth intervention reliable and most of them (98.4%, 126/128) would recommend the eHealth intervention to other parents. Noncompliant parents judged the eHealth intervention significantly less reliable compared to compliant parents (71%, 10/14 versus 97.3%, 107/110; P=.003).
Conclusions
Parents of children with an IH showed a high compliance (85.9%, 110/128) to the advice of the dermatologist given via our Web-based eHealth intervention. This high compliance might be positively influenced by the good acceptance and usability of the eHealth intervention and might result in timely presentation and treatment of children with high risk IH in specialized centers.
doi:10.2196/resprot.2897
PMCID: PMC3875905  PMID: 24345450
eHealth; e-learning; Internet; compliance; acceptance; usability; dermatology; optimizing care; infantile hemangioma; child
16.  Genetic Variability of the Neogregarine Apicystis bombi, an Etiological Agent of an Emergent Bumblebee Disease 
PLoS ONE  2013;8(12):e81475.
The worldwide spread of diseases is considered a major threat to biodiversity and a possible driver of the decline of pollinator populations, particularly when novel species or strains of parasites emerge. Previous studies have suggested that populations of introduced European honeybee (Apis mellifera) and bumblebee species (Bombus terrestris and Bombus ruderatus) in Argentina share the neogregarine parasite Apicystis bombi with the native bumblebee (Bombus dahlbomii). In this study we investigated whether A. bombi is acting as an emergent parasite in the non-native populations. Specifically, we asked whether A. bombi, recently identified in Argentina, was introduced by European, non-native bees. Using ITS1 and ITS2 to assess the parasite’s intraspecific genetic variation in bees from Argentina and Europe, we found a largely unstructured parasite population, with only 15% of the genetic variation being explained by geographic location. The most abundant haplotype in Argentina (found in all 9 specimens of non-native species) was identical to the most abundant haplotype in Europe (found in 6 out of 8 specimens). Similarly, there was no evidence of structuring by host species, with this factor explaining only 17% of the genetic variation. Interestingly, parasites in native Bombus ephippiatus from Mexico were genetically distant from the Argentine and European samples, suggesting that sufficient variability does exist in the ITS region to identify continent-level genetic structure in the parasite. Thus, the data suggest that A. bombi from Argentina and Europe share a common, relatively recent origin. Although our data did not provide information on the direction of transfer, the absence of genetic structure across space and host species suggests that A. bombi may be acting as an emergent infectious disease across bee taxa and continents.
doi:10.1371/journal.pone.0081475
PMCID: PMC3855659  PMID: 24324696
17.  Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model 
EMBO Molecular Medicine  2013;5(12):1804-1820.
The t(8;21) chromosomal translocation activates aberrant expression of the AML1-ETO (AE) fusion protein and is commonly associated with core binding factor acute myeloid leukaemia (CBF AML). Combining a conditional mouse model that closely resembles the slow evolution and the mosaic AE expression pattern of human t(8;21) CBF AML with global transcriptome sequencing, we find that disease progression was characterized by two principal pathogenic mechanisms. Initially, AE expression modified the lineage potential of haematopoietic stem cells (HSCs), resulting in the selective expansion of the myeloid compartment at the expense of normal erythro- and lymphopoiesis. This lineage skewing was followed by a second substantial rewiring of transcriptional networks occurring in the trajectory to manifest leukaemia. We also find that both HSC and lineage-restricted granulocyte macrophage progenitors (GMPs) acquired leukaemic stem cell (LSC) potential being capable of initiating and maintaining the disease. Finally, our data demonstrate that long-term expression of AE induces an indolent myeloproliferative disease (MPD)-like myeloid leukaemia phenotype with complete penetrance and that acute inactivation of AE function is a potential novel therapeutic option.
doi:10.1002/emmm.201302661
PMCID: PMC3914523  PMID: 24124051
cancer stem cells; core binding factor acute myeloid leukaemia; preclinical mouse model; therapy target validation; whole transcriptome sequencing
18.  Effect of Replacing Sugar with Non-Caloric Sweeteners in Beverages on the Reward Value after Repeated Exposure 
PLoS ONE  2013;8(11):e81924.
Background
The reward value of food is partly dependent on learned associations. It is not yet known whether replacing sugar with non-caloric sweeteners in food is affecting long-term acceptance.
Objective
To determine the effect of replacing sugar with non-caloric sweeteners in a nutrient-empty drink (soft drink) versus nutrient-rich drink (yoghurt drink) on reward value after repeated exposure.
Design
We used a randomized crossover design whereby forty subjects (15 men, 25 women) with a mean±SD age of 21±2 y and BMI of 21.5±1.7 kg/m2 consumed a fixed portion of a non-caloric sweetened (NS) and sugar sweetened (SS) versions of either a soft drink or a yoghurt drink (counterbalanced) for breakfast which were distinguishable by means of colored labels. Each version of a drink was offered 10 times in semi-random order. Before and after conditioning the reward value of the drinks was assessed using behavioral tasks on wanting, liking, and expected satiety. In a subgroup (n=18) fMRI was performed to assess brain reward responses to the drinks.
Results
Outcomes of both the behavioral tasks and fMRI showed that conditioning did not affect the reward value of the NS and SS versions of the drinks significantly. Overall, subjects preferred the yoghurt drinks to the soft drinks and the ss drinks to the NS drinks. In addition, they expected the yoghurt drinks to be more satiating, they reduced hunger more, and delayed the first eating episode more. Conditioning did not influence these effects.
Conclusion
Our study showed that repeated consumption of a non-caloric sweetened beverage, instead of a sugar sweetened version, appears not to result in changes in the reward value. It cannot be ruled out that learned associations between sensory attributes and food satiating capacity which developed preceding the conditioning period, during lifetime, affected the reward value of the drinks.
doi:10.1371/journal.pone.0081924
PMCID: PMC3842969  PMID: 24312382
19.  Mutational Analysis of ATP8B1 in Patients with Chronic Pancreatitis 
PLoS ONE  2013;8(11):e80553.
Background
Mutations in genes encoding cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (SPINK1) and chymotrypsinogen C (CTRC) are associated with chronic pancreatitis. However, in many patients with a familial chronic pancreatitis pattern suggesting a genetic cause, no mutations in either of these genes can be found, indicating that other, still unknown, associated genes exist. In this respect ATP8B1 is an interesting candidate due to its strong expression in the pancreas, its supposed general function in membrane organization and the higher incidence of pancreatitis in patients with ATP8B1 deficiency.
Methods
We analyzed all 27 ATP8B1 coding exons and adjacent non-coding sequences of 507 chronic pancreatitis patients by direct sequencing. Exons that harbored possible relevant variations were subsequently sequenced in 1,027 healthy controls.
Results
In the exonic regions, 5 novel non-synonymous alterations were detected as well as 14 previously described alterations of which some were associated with ATP8B1 deficiency. However, allele frequencies for any of these variations did not significantly differ between patients and controls. Furthermore, several non-synonymous variants were exclusively detected in control subjects and multiple variants in the non-coding sequence were identified with similar frequencies in both groups.
Conclusions
We did not find an association between heterozygous ATP8B1 variants and chronic pancreatitis in our cohort of patients with hereditary and idiopathic chronic pancreatitis.
doi:10.1371/journal.pone.0080553
PMCID: PMC3834041  PMID: 24260417
20.  Assessing the optimal location for alcohol-based hand rub dispensers in a patient room in an intensive care unit 
BMC Infectious Diseases  2013;13:510.
Background
The introduction of alcohol-based hand rub dispensers has had a positive influence on compliance of healthcare workers with the recommended guidelines for hand hygiene. However, establishing the best location for alcohol-based hand rub dispensers remains a problem, and no method is currently available to optimize the location of these devices. In this paper we describe a method to determine the optimal location for alcohol-based hand rub dispensers in patient rooms.
Methods
We composed a method that consists of a combination of qualitative and quantitative research methods. Firstly, different arrangements of dispensers were determined based on the results of two types of assessment: workflow observations and interviews with nurses and physicians. Each arrangement was then evaluated using two types of assessment: interviews with nurses and physicians and electronic measurements of the user frequency of the dispensers. This procedure was applied in a single-bed patient room on a thoracic surgery intensive care unit.
Results
The workflow observations revealed that the activities of patient care were most often at the entrance and near the computer at the right side of the test room. Healthcare workers stated that the location of the dispenser should meet several requirements. Measurements of the frequency of use showed that the dispenser located near the computer, at the back of the room, was used less frequently than the dispenser located near the sink and the dispenser located at the entrance to the room.
Conclusion
The applied method has potential for determining the optimal location for alcohol-based hand rub dispensers in a patient room. Workflow observations and the expressed preferences of healthcare workers guide the choice for the location of alcohol-based hand rub dispensers. These choices may be optimized based on measurement of the frequency of use of the dispensers.
doi:10.1186/1471-2334-13-510
PMCID: PMC3826999  PMID: 24171702
Patient safety; Hand hygiene; Alcohol-based hand rub dispensers
21.  The Onset of Type 2 Diabetes: Proposal for a Multi-Scale Model 
JMIR Research Protocols  2013;2(2):e44.
Background
Type 2 diabetes mellitus (T2D) is a common age-related disease, and is a major health concern, particularly in developed countries where the population is aging, including Europe. The multi-scale immune system simulator for the onset of type 2 diabetes (MISSION-T2D) is a European Union-funded project that aims to develop and validate an integrated, multilevel, and patient-specific model, incorporating genetic, metabolic, and nutritional data for the simulation and prediction of metabolic and inflammatory processes in the onset and progression of T2D. The project will ultimately provide a tool for diagnosis and clinical decision making that can estimate the risk of developing T2D and predict its progression in response to possible therapies. Recent data showed that T2D and its complications, specifically in the heart, kidney, retina, and feet, should be considered a systemic disease that is sustained by a pervasive, metabolically-driven state of inflammation. Accordingly, there is an urgent need (1) to understand the complex mechanisms underpinning the onset of this disease, and (2) to identify early patient-specific diagnostic parameters and related inflammatory indicators.
Objective
We aim to accomplish this mission by setting up a multi-scale model to study the systemic interactions of the biological mechanisms involved in response to a variety of nutritional and metabolic stimuli and stressors.
Methods
Specifically, we will be studying the biological mechanisms of immunological/inflammatory processes, energy intake/expenditure ratio, and cell cycle rate. The overall architecture of the model will exploit an already established immune system simulator as well as several discrete and continuous mathematical methods for modeling of the processes critically involved in the onset and progression of T2D. We aim to validate the predictions of our models using actual biological and clinical data.
Results
This study was initiated in March 2013 and is expected to be completed by February 2016.
Conclusions
MISSION-T2D aims to pave the way for translating validated multilevel immune-metabolic models into the clinical setting of T2D. This approach will eventually generate predictive biomarkers for this disease from the integration of clinical data with metabolic, nutritional, immune/inflammatory, genetic, and gut microbiota profiles. Eventually, it should prove possible to translate these into cost-effective and mobile-based diagnostic tools.
doi:10.2196/resprot.2854
PMCID: PMC3841357  PMID: 24176906
type 2 diabetes; metaflammation; metabolism; computational biology; simulation; physical activity; multiscale modeling; data integration
23.  Time- and Task-Dependent Non-Neural Effects of Real and Sham TMS 
PLoS ONE  2013;8(9):e73813.
Transcranial magnetic stimulation (TMS) is widely used in experimental brain research to manipulate brain activity in humans. Next to the intended neural effects, every TMS pulse produces a distinct clicking sound and sensation on the head which can also influence task performance. This necessitates careful consideration of control conditions in order to ensure that behavioral effects of interest can be attributed to the neural consequences of TMS and not to non-neural effects of a TMS pulse. Surprisingly, even though these non-neural effects of TMS are largely unknown, they are often assumed to be unspecific, i.e. not dependent on TMS parameters. This assumption is inherent to many control strategies in TMS research but has recently been challenged on empirical grounds. Here, we further develop the empirical basis of control strategies in TMS research. We investigated the time-dependence and task-dependence of the non-neural effects of TMS and compared real and sham TMS over vertex. Critically, we show that non-neural TMS effects depend on a complex interplay of these factors. Although TMS had no direct neural effects, both pre- and post-stimulus TMS time windows modulated task performance on both a sensory detection task and a cognitive angle judgment task. For the most part, these effects were quantitatively similar across tasks but effect sizes were clearly different. Moreover, the effects of real and sham TMS were almost identical with interesting exceptions that shed light on the relative contribution of auditory and somato-sensory aspects of a TMS pulse. Knowledge of such effects is of critical importance for the interpretation of TMS experiments and helps deciding what constitutes an appropriate control condition. Our results broaden the empirical basis of control strategies in TMS research and point at potential pitfalls that should be avoided.
doi:10.1371/journal.pone.0073813
PMCID: PMC3763998  PMID: 24040080
24.  Multi-slice 1H MRSI of the human brain at 7 Tesla using dynamic B0 and B1 shimming 
Proton MR spectroscopic imaging of the human brain at ultra high field (≥7T) is challenging due to increased RF power deposition, increased magnetic field B0 inhomogeneity and increased RF magnetic field inhomogeneity. And, especially for multi-slice sequences, these effects directly inhibit the potential gains of higher magnetic field and can even cause a reduction in data quality. However, recent developments in dynamic B0 magnetic field shimming and dynamic multi-transmit RF control allow for new acquisition strategies. Therefore, in this work slice-by-slice B0 and B1 shimming was developed to optimize both B0 magnetic field homogeneity and nutation angle over a large portion of the brain. Together with a low-power water and lipid suppression sequence and pulse-acquire spectroscopic imaging, a multi-slice MRSI sequence is shown to be feasible at 7T. This now allows for multi-slice metabolic imaging of the human brain with high sensitivity and high chemical shift resolution at ultra high field.
doi:10.1002/mrm.23288
PMCID: PMC3306521  PMID: 22162089
25.  Genetic evolution of the neuraminidase of influenza A (H3N2) viruses from 1968 to 2009 and its correspondence to haemagglutinin evolution 
The Journal of General Virology  2012;93(Pt 9):1996-2007.
Each year, influenza viruses cause epidemics by evading pre-existing humoral immunity through mutations in the major glycoproteins: the haemagglutinin (HA) and the neuraminidase (NA). In 2004, the antigenic evolution of HA of human influenza A (H3N2) viruses was mapped (Smith et al., Science 305, 371–376, 2004) from its introduction in humans in 1968 until 2003. The current study focused on the genetic evolution of NA and compared it with HA using the dataset of Smith and colleagues, updated to the epidemic of the 2009/2010 season. Phylogenetic trees and genetic maps were constructed to visualize the genetic evolution of NA and HA. The results revealed multiple reassortment events over the years. Overall rates of evolutionary change were lower for NA than for HA1 at the nucleotide level. Selection pressures were estimated, revealing an abundance of negatively selected sites and sparse positively selected sites. The differences found between the evolution of NA and HA1 warrant further analysis of the evolution of NA at the phenotypic level, as has been done previously for HA.
doi:10.1099/vir.0.043059-0
PMCID: PMC3542130  PMID: 22718569

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