Pheochromocytoma in rats with multiple endocrine neoplasia (MENX) shares gene expression patterns with human pheochromocytoma

Pheochromocytomas are rare neoplasias of neural crest origin arising from chromaffin cells of the adrenal medulla and sympathetic ganglia (extra-adrenal pheochromocytoma). Pheochromocytoma that develop in rats homozygous for a loss-of-function mutation in p27Kip1 (MENX syndrome) show a clear progression from hyperplasia to tumor, offering the possibility to gain insight into tumor pathobiology. We compared the gene-expression signatures of both adrenomedullary hyperplasia and pheochromocytoma with normal rat adrenal medulla. Hyperplasia and tumor show very similar transcriptome profiles, indicating early determination of the tumorigenic signature. Overrepresentation of developmentally regulated neural genes was a feature of the rat lesions. Quantitative RT-PCR validated the up-regulation of 11 genes, including some involved in neural development: Cdkn2a, Cdkn2c, Neurod1, Gal, Bmp7, and Phox2a. Overexpression of these genes precedes histological changes in affected adrenal glands. Their presence at early stages of tumorigenesis indicates they are not acquired during progression and may be a result of the lack of functional p27Kip1. Adrenal and extra-adrenal pheochromocytoma development clearly follows diverged molecular pathways in MENX rats. To correlate these findings to human pheochromocytoma, we studied nine genes overexpressed in the rat lesions in 46 sporadic and familial human pheochromocytomas. The expression of GAL, DGKH, BMP7, PHOX2A, L1CAM, TCTE1, EBF3, SOX4, and HASH1 was up-regulated, although with different frequencies. Immunohistochemical staining detected high L1CAM expression selectively in 27 human pheochromocytomas but not in 140 nonchromaffin neuroendocrine tumors. These studies reveal clues to the molecular pathways involved in rat and human pheochromocytoma and identify previously unexplored biomarkers for clinical use.

The contribution of surface residues to membrane binding and ligand transfer by the -tocopherol transfer protein ( -TTP)

Previous work has shown that the -tocopherol transfer protein ( -TTP) can bind to vesicular or immobilized phospholipid membranes. Revealing the molecular mechanisms by which -TTP associates with membranes is thought to be critical to understanding its function and role in the secretion of tocopherol from hepatocytes into the circulation. Calculations presented in the Orientations of Proteins in Membranes database have provided a testable model for the spatial arrangement of -TTP and other CRAL-TRIO family proteins with respect to the lipid bilayer. These calculations predicted that a hydrophobic surface mediates the interaction of -TTP with lipid membranes. To test the validity of these predictions, we used site-directed mutagenesis and examined the substituted mutants with regard to intermembrane ligand transfer, association with lipid layers and biological activity in cultured hepatocytes. Substitution of residues in helices A8 (F165A and F169A) and A10 (I202A, V206A and M209A) decreased the rate of intermembrane ligand transfer as well as protein adsorption to phospholipid bilayers. The largest impairment was observed upon mutation of residues that are predicted to be fully immersed in the lipid bilayer in both apo (open) and holo (closed) conformations such as Phe165 and Phe169. Mutation F169A, and especially F169D, significantly impaired -TTP-assisted secretion of -tocopherol outside cultured hepatocytes. Mutation of selected basic residues (R192H, K211A, and K217A) had little effect on transfer rates, indicating no significant involvement of nonspecific electrostatic interactions with membranes.

Ventricular-arterial coupling in a rat model of reduced arterial compliance provoked by hypervitaminosis D and nicotine

The vitamin D(3) and nicotine (VDN) model is one of isolated systolic hypertension (ISH) in which arterial calcification raises arterial stiffness and vascular impedance. The effects of VDN treatment on arterial and cardiac hemodynamics have been investigated; however, a complete analysis of ventricular-arterial interaction is lacking. Wistar rats were treated with VDN (VDN group, n = 9), and a control group (n = 10) was included without the VDN. At week 8, invasive indexes of cardiac function were obtained using a conductance catheter. Simultaneously, aortic pressure and flow were measured to derive vascular impedance and characterize ventricular-vascular interaction. VDN caused significant increases in systolic (138 +/- 6 vs. 116 +/- 13 mmHg, P < 0.01) and pulse (42 +/- 10 vs. 26 +/- 4 mmHg, P < 0.01) pressures with respect to control. Total arterial compliance decreased (0.12 +/- 0.08 vs. 0.21 +/- 0.04 ml/mmHg in control, P < 0.05), and pulse wave velocity increased significantly (8.8 +/- 2.5 vs. 5.1 +/- 2.0 m/s in control, P < 0.05). The arterial elastance and end-systolic elastance rose significantly in the VDN group (P < 0.05). Wave reflection was augmented in the VDN group, as reflected by the increase in the wave reflection coefficient (0.63 +/- 0.06 vs. 0.52 +/- 0.05 in control, P < 0.05) and the amplitude of the reflected pressure wave (13.3 +/- 3.1 vs. 8.4 +/- 1.0 mmHg in control, P < 0.05). We studied ventricular-arterial coupling in a VDN-induced rat model of reduced arterial compliance. The VDN treatment led to development of ISH and provoked alterations in cardiac function, arterial impedance, arterial function, and ventricular-arterial interaction, which in many aspects are similar to effects of an aged and stiffened arterial tree.

Effects of glenoid component version on humeral head displacement and joint reaction forces: an experimental study

The purpose of this study was to determine whether changes in glenoid version are associated with humeral head displacement and changes in the joint reaction forces, as these might contribute to instability or loosening in total shoulder replacement. A total shoulder prosthesis was implanted in neutral version in 6 cadaveric shoulders. Glenoid version was then changed in steps of 4 degrees toward more anteversion and retroversion. An increase in anteversion resulted in anterior translation of the humeral head and in eccentric loading of the anterior part of the glenoid. Retroversion was associated with posterior displacement and posterior loading of the glenoid. A change in rotation of the humeral component did not compensate for altered version of the glenoid component. These results suggest that both instability and glenoid component loosening may be related to the version of the glenoid component. Therefore, assessment of loosening and instability justifies precise assessment of glenoid component version.

Effects of an aging vascular model on healthy and diseased hearts

The vitamin D(3) and nicotine (VDN) model is a model of isolated systolic hypertension (ISH) due to arterial calcification raising arterial stiffness and vascular impedance similar to an aged and stiffened arterial tree. We therefore analyzed the impact of this aging model on normal and diseased hearts with myocardial infarction (MI). Wistar rats were treated with VDN (n = 9), subjected to MI by coronary ligation (n = 10), or subjected to a combination of both MI and VDN treatment (VDN/MI, n = 14). A sham-treated group served as control (Ctrl, n = 10). Transthoracic echocardiography was performed every 2 wk, whereas invasive indexes were obtained at week 8 before death. Calcium, collagen, and protein contents were measured in the heart and the aorta. Systolic blood pressure, pulse pressure, thoracic aortic calcium, and end-systolic elastance as an index of myocardial contractility were highest in the aging model group compared with MI and Ctrl groups (P(VDN) < 0.05, 2-way ANOVA). Left ventricular wall stress and brain natriuretic peptide (P(VDNxMI) = not significant) were highest, while ejection fraction, stroke volume, and cardiac output were lowest in the combined group versus all other groups (P(VDNxMI) < 0.05). The combination of ISH due to this aging model and MI demonstrates significant alterations in cardiac function. This model mimics several clinical phenomena of cardiovascular aging and may thus serve to further study novel therapies.

CD39 is incorporated into plasma microparticles where it maintains functional properties and impacts endothelial activation

Plasma microparticles (MPs, <1.5 mum) originate from platelet and cell membrane lipid rafts and possibly regulate inflammatory responses and thrombogenesis. These actions are mediated through their phospholipid-rich surfaces and associated cell-derived surface molecules. The ectonucleotidase CD39/ecto-nucleoside triphosphate diphosphohydrolase1 (E-NTPDase1) modulates purinergic signalling through pericellular ATP and ADP phosphohydrolysis and is localized within lipid rafts in the membranes of endothelial- and immune cells. This study aimed to determine whether CD39 associates with circulating MPs and might further impact phenotype and function. Plasma MPs were found to express CD39 and exhibited classic E-NTPDase ecto-enzymatic activity. Entpd1 (Cd39) deletion in mice produced a pro-inflammatory phenotype associated with quantitative and qualitative differences in the MP populations, as determined by two dimensional-gel electrophoresis, western blot and flow cytometry. Entpd1-null MPs were also more abundant, had significantly higher proportions of platelet- and endothelial-derived elements and decreased levels of interleukin-10, tumour necrosis factor receptor 1 and matrix metalloproteinase 2. Consequently, Cd39-null MP augment endothelial activation, as determined by inflammatory cytokine release and upregulation of adhesion molecules in vitro. In conclusion, CD39 associates with circulating MP and may directly or indirectly confer functional properties. Our data also suggest a modulatory role for CD39 within MP in the exchange of regulatory signals between leucocytes and vascular cells.

Lifestyle factors and colorectal cancer risk (1): systematic review and meta-analysis of associations with body mass index

OBJECTIVE: Excess body weight, defined by body mass index (BMI), may increase the risk of colorectal cancer. As a prerequisite to the determination of lifestyle attributable risks, we undertook a systematic review and meta-analysis of prospective observational studies to quantify colorectal cancer risk associated with increased BMI and explore for differences by gender, sub-site and study characteristics. METHOD: We searched MEDLINE and EMBASE (to December 2007), and other sources, selecting reports based on strict inclusion criteria. Random-effects meta-analyses and meta-regressions of study-specific incremental estimates were performed to determine the risk ratio (RR) and 95% confidence intervals (CIs) associated with a 5 kg/m(2) increase in BMI. RESULTS: We analysed 29 datasets from 28 articles, including 67,361 incident cases. Higher BMI was associated with colon (RR 1.24, 95% CIs: 1.20-1.28) and rectal (1.09, 1.05-1.14) cancers in men, and with colon cancer (1.09, 1.04-1.12) in women. Associations were stronger in men than in women for colon (P < 0.001) and rectal (P = 0.005) cancers. Associations were generally consistent across geographic populations. Study characteristics and adjustments accounted for only moderate variations of associations. CONCLUSION: Increasing BMI is associated with a modest increased risk of developing colon and rectal cancers, but this modest risk may translate to large attributable proportions in high-prevalence obese populations. Inter-gender differences point to potentially important mechanistic differences, which merit further research.

Estimating and quantifying uncertainties on level sets using the Vorob'ev expectation and deviation with Gaussian process models

Several methods based on Kriging have recently been proposed for calculating a probability of failure involving costly-to-evaluate functions. A closely related problem is to estimate the set of inputs leading to a response exceeding a given threshold. Now, estimating such a level set—and not solely its volume—and quantifying uncertainties on it are not straightforward. Here we use notions from random set theory to obtain an estimate of the level set, together with a quantification of estimation uncertainty. We give explicit formulae in the Gaussian process set-up and provide a consistency result. We then illustrate how space-filling versus adaptive design strategies may sequentially reduce level set estimation uncertainty.

Kernels and Designs for Modelling Invariant Functions: From Group Invariance to Additivity

We focus on kernels incorporating different kinds of prior knowledge on functions to be approximated by Kriging. A recent result on random fields with paths invariant under a group action is generalised to combinations of composition operators, and a characterisation of kernels leading to random fields with additive paths is obtained as a corollary. A discussion follows on some implications on design of experiments, and it is shown in the case of additive kernels that the so-called class of “axis designs” outperforms Latin hypercubes in terms of the IMSE criterion.

The implicit achievement motive and general life stress affect time spent on competitive matches in racquet sports

The match time spent on court in racquet sports can be perceived as dependent on the effort an athlete is willing to exert in a competition. Achievement motivation is defined as the effort a person spends on a difficult task with the completion of which she wants to meet a personal standard of excellence, wants to improve herself, or outperform others (McClelland, Atkinson, Clark, & Lowell, 1953). Fifty-two professionals of three racquet sports (tennis, table tennis, and badminton) filled in a questionnaire on their explicit achievement motive, a scale on general life stress, and a measure of the implicit achievement motive. Results indicate that the implicit but not the explicit achievement motive was able to predict the athletes' time spent on court (effort). Additionally the general life stress scale was negatively related to time spent on court. Findings are in line with theoretical assumptions that actual behavior is linked to the implicit achievement motive and that higher levels of general life stress lead to impaired performance in sports.

Scientific rationale for Saturn׳s in situ exploration

Remote sensing observations meet some limitations when used to study the bulk atmospheric composition of the giant planets of our solar system. A remarkable example of the superiority of in situ probe measurements is illustrated by the exploration of Jupiter, where key measurements such as the determination of the noble gases׳ abundances and the precise measurement of the helium mixing ratio have only been made available through in situ measurements by the Galileo probe. This paper describes the main scientific goals to be addressed by the future in situ exploration of Saturn placing the Galileo probe exploration of Jupiter in a broader context and before the future probe exploration of the more remote ice giants. In situ exploration of Saturn׳s atmosphere addresses two broad themes that are discussed throughout this paper: first, the formation history of our solar system and second, the processes at play in planetary atmospheres. In this context, we detail the reasons why measurements of Saturn׳s bulk elemental and isotopic composition would place important constraints on the volatile reservoirs in the protosolar nebula. We also show that the in situ measurement of CO (or any other disequilibrium species that is depleted by reaction with water) in Saturn׳s upper troposphere may help constraining its bulk O/H ratio. We compare predictions of Jupiter and Saturn׳s bulk compositions from different formation scenarios, and highlight the key measurements required to distinguish competing theories to shed light on giant planet formation as a common process in planetary systems with potential applications to most extrasolar systems. In situ measurements of Saturn׳s stratospheric and tropospheric dynamics, chemistry and cloud-forming processes will provide access to phenomena unreachable to remote sensing studies. Different mission architectures are envisaged, which would benefit from strong international collaborations, all based on an entry probe that would descend through Saturn׳s stratosphere and troposphere under parachute down to a minimum of 10 bar of atmospheric pressure. We finally discuss the science payload required on a Saturn probe to match the measurement requirements.