Radiosensibilité individuelle : les tests vont changer nos pratiques [Intrinsic radiosensitivity: predictive assays that will change the daily practice].

The impact of curative radiotherapy depends mainly on the total dose delivered homogenously in the targeted volume. Nevertheless, the dose delivered to the surrounding healthy tissues may reduce the therapeutic ratio of many radiation treatments. In a same population treated in one center with the same technique, it appears that individual radiosensitivity clearly exists, namely in terms of late side effects that are in principle non-reversible. This review details the different radiobiological approaches that have been developed to better understand the mechanisms of radiation-induced late effects. We also present the possibilities of clinical use of predictive assays in the close future.

The attractiveness of nations in global competition : an empirical assessment of the effects of country attractiveness on the success of strategy for hosting international sports events, 1990-2012

This dissertation aims to investigate empirical evidence on the importance and influence of attractiveness of nations in global competition. The notion of country attractiveness, which has been widely developed in the research areas of international business, tourism and migration, is a multi-dimensional construct to measure a country's characteristics with regard to its market or destination that attract international investors, tourists and migrants. This analytical concept provides an account of the mechanism as to how potential stakeholders evaluate more attractive countries based on certain criteria. Thus, in the field of international sport-event bidding, do international sport event owners also have specific country attractiveness for their sport event hosts? The dissertation attempts to address this research question by statistically assessing the effects of country attractiveness on the success of strategy for hosting international sports events. Based on theories of signaling and soft power, country attractiveness is defined and measured as the three dimensions of sustainable development: economic, social, and environmental attractiveness. This thesis proceeds to examine the concept of sport-event-hosting strategy and explore multi-level factors affecting the success in international sport-event bidding. By exploring past history of the Olympic Movement from theoretical perspectives, the thesis proposes and tests the hypotheses that economic, social and environmental attractiveness of a country may be correlated with its bid wins or the success of sport-event-hosting strategy. Quantitative analytical methods with various robustness checks are employed with using collected data on bidding results of major events in Olympic sports during the period from 1990 to 2012. The analysis results reveal that event owners of international Olympic sports are likely to prefer countries that have higher economic, social, and environmental attractiveness. The empirical assessment of this thesis suggests that high country attractiveness can be an essential element of prerequisites for a city/country to secure in order to bid with an increased chance of success.

Plutonium from above-ground nuclear tests in milk teeth: investigation of placental transfer in children born between 1951 and 1995 in Switzerland.

BACKGROUND: Occupational risks, the present nuclear threat, and the potential danger associated with nuclear power have raised concerns regarding the metabolism of plutonium in pregnant women. OBJECTIVE: We measured plutonium levels in the milk teeth of children born between 1951 and 1995 to assess the potential risk that plutonium incorporated by pregnant women might pose to the radiosensitive tissues of the fetus through placenta transfer. METHODS: We used milk teeth, whose enamel is formed during pregnancy, to investigate the transfer of plutonium from the mother's blood plasma to the fetus. We measured plutonium using sensitive sector field inductively coupled plasma mass spectrometry techniques. We compared our results with those of a previous study on strontium-90 ((90)Sr) released into the atmosphere after nuclear bomb tests. RESULTS: Results show that plutonium activity peaks in the milk teeth of children born about 10 years before the highest recorded levels of plutonium fallout. By contrast, (90)Sr, which is known to cross the placenta barrier, manifests differently in milk teeth, in accordance with (90)Sr fallout deposition as a function of time. CONCLUSIONS: These findings demonstrate that plutonium found in milk teeth is caused by fallout that was inhaled around the time the milk teeth were shed and not from any accumulation during pregnancy through placenta transfer. Thus, plutonium may not represent a radiologic risk for the radiosensitive tissues of the fetus.

Anchoring of an immunogenic Plasmodium falciparum circumsporozoite protein on the surface of Dictyostelium discoideum.

The circumsporozoite protein (CSP), a major antigen of Plasmodium falciparum, was expressed in the slime mold Dictyostelium discoideum. Fusion of the parasite protein to a leader peptide derived from Dictyostelium contact site A was essential for expression. The natural parasite surface antigen, however, was not detected at the slime mold cell surface as expected but retained intracellularly. Removal of the last 23 amino acids resulted in secretion of CSP, suggesting that the C-terminal segment of the CSP, rather than an ectoplasmic domain, was responsible for retention. Cell surface expression was obtained when the CSP C-terminal segment was replaced by the D. discoideum contact site A glycosyl phosphatidylinositol anchor signal sequence. Mice were immunized with Dictyostelium cells harboring CSP at their surface. The raised antibodies recognized two different regions of the CSP. Anti-sporozoite titers of these sera were equivalent to anti-peptide titers detected by enzyme-linked immunosorbent assay. Thus, cell surface targeting of antigens can be obtained in Dictyostelium, generating sporozoite-like cells having potentials for vaccination, diagnostic tests, or basic studies involving parasite cell surface proteins.

Effect of low-level pathogenic helminth infection on energy metabolism in Gambian children.

The aim of the present study was to determine whether an increase in resting energy expenditure (REE) contributes to the impaired nutritional status of Gambian children infected by a low level of infection with pathogenic helminths. The REE of 24 children infected with hookworm, Ascaris, Strongyloides, or Trichuris (mean +/- SEM age = 11.9 +/- 0.1 years) and eight controls without infection (mean +/- SEM age = 11.8 +/- 0.1 years) were measured by indirect calorimetry with a hood system (test A). This measurement was repeated after treatment with 400 mg of albendazole (patients) or a placebo (controls) (test B). When normalized for fat free mass, REE in test A was not different in the patients (177 +/- 2 kJ/kg x day) and in the controls (164 +/- 7 kJ/kg x day); furthermore, REE did not change significantly after treatment in the patients (173 +/- 3 kJ/kg x day) or in the controls (160 +/- 8 kJ/kg x day). There was no significant difference in the respiratory quotient between patients and controls, nor between tests A and B. It is concluded that a low level of helminth infection does not affect significantly the energy metabolism of Gambian children.

The impact of social relationships on the maintenance of independence in advanced old age: findings of a Swiss Longitudinal Study .

The impact of social relationships on the maintenance of independence over periods of 12-18 months in a group of 306 octogenarians is assessed in this study. The study is based on the results of the Swilsoo (Swiss Interdisciplinary Longitudinal Study on the Oldest Old). Participants (80-84 years old at baseline) were interviewed five times between 1994 and 1999. Independence was defined as the capacity to perform without assistance eight activities of daily living. We distinguished in our analyses kinship and friendship networks and evaluated social relationships with the help of a series of variables serving as indicators of network composition and contact frequency. Logistic regression models were used to identify the short-term effects of social relationships on independence, after controlling for sociodemographic and health-related variables; independence at a given wave of interviews was interpreted in the light of social factors measured at the previous wave. Our analyses indicate that the existence of a close friend has a significant impact on the maintenance of independence (OR=1.58, p<0.05), which is not the case with the other variables concerning network composition. Kinship contacts were also observed to have a positive impact on independence (OR=1.12, p<0.01).

Detection of human growth hormone doping in urine: out of competition tests are necessary.

The misuse of human growth hormone (hGH) in sport is deemed to be unethical and dangerous because of various adverse effects. Thus, it has been added to the International Olympic Committee list of banned substances. Until now, the very low concentration of hGH in the urine made its measurement difficult using classical methodology. Indeed, for routine diagnosis, only plasma measurements were available. However, unlike blood samples, urine is generally provided in abundant quantities and is, at present, the only body fluid allowed to be analysed in sport doping controls. A recently developed enzyme-linked immunosorbent assay (Norditest) makes it now possible, without any extraction, to measure urinary hGH (u-hGH) in a dynamic range of 2-50 ng hGH/l. In our protocol, untreated and treated non-athlete volunteers were followed. Some of them received therapeutical doses of recombinant hGH (Norditropin) for one week either intramuscularly (three increasing doses) or subcutaneously (12 i.u. every day). The u-hGH excretion after treatment showed dramatic increases of 50-100 times the basal values and returned to almost the mean normal level after 24 h. u-hGH was also measured in samples provided by the anti-doping controls at major and minor competitions. Depending on the type of efforts made during the competition, the hGH concentration in urine was dramatically increased. Insulin-like growth factor binding proteins and beta 2-microglobulins in urine and/or in blood could be necessary for the correct investigation of any hGH doping test procedure.

Endoglycan mediates malignant leukocyte rolling on e-selectin and signals through SYK and the MAPK pathway

Selectins play a key role regulating leukocyte migration into tissues by mediating leukocyte tethering (capture) and rolling on inflamed endothelium and/or on adherent leukocytes or platelets. During leukocyte rolling, endothelial E- or P-selectin bind to glycoprotein ligands carrying sialyl Lewis χ (sLex) determinant. P-selectin glycoprotein ligand-1 (PSGL-1) is a common ligand for L-, P- and E-selectin, which sequentially cooperates with CD44 and E- selectin ligand-1 (ESL-1) to roll on E-selectin. During rolling on endothelial selectins, PSGL-1 and CD44 signal through Src family kinases and Syk, leading to αι_β2 integrin partial activation and slow rolling on intercellular adhesion molecule-1 (ICAM-1). Leukocyte exposure to chemokines then leads to firm adhesion. Little information is available on ligands that mediate malignant leukocyte rolling on E- selectin. We defined these ligands on U937 monoblasts by immunoadsorbtion and immunoblotting using mAb raised against CD43, CD44, PSGL-1, sLex/CLA determinants and E-selectin/IgM chimera. Immunoblotting and blot rolling assays demonstrated that PSGL-1, CD43, CD44 and a -125 kDa sLex/CLA positive ligand contribute to support E-seiectin- dependent rolling. This -125 kDa ligand is endoglycan, a member of the CD34 family of sialomucins. Endoglycan was frequently detected by flow cytometry on primary leukemia, lymphoma and multiple myeloma ceils (in -50% of cases). Endoglycan, immunopurified from U937 cells, as well as endoglycan/IgG chimera efficiently supported E-selectin dependent rolling. Membrane fractionation on sucrose gradient demonstrated that endoglycan is expressed in lipid rafts. We tested the hypothesis that it signals, like PSGL-1 and CD44, through Src kinases and the MAPK pathway. Indeed, endoglycan engagement induced Syk and ERK phosphorylation in a iipid raft-dependent manner. Syk activation was dependent on Src kinase activity. Downstream of Syk, endoglycan activated PI3K and Akt as well as Bruton's tyrosine kinase and p38 MAPK. Thus, endoglycan is a ligand for endothelial selectins which may contribute to regulate leukemia, lymphoma and multiple myeloma cell trafficking and interactions with bone marrow microenvironment. - Les sélectines contrôlent la migration tissulaire des leucocytes en assurant leur capture et leur roulement sur l'endothélium vasculaire enflammé et/ou sur des plaquettes ou des leucocytes adhérant à la paroi vasculaire. Lors du roulement leucocytaire, les sélectines endothéliales (E- et P-sélectine) se lient à des ligands porteurs du saccharide sialyl Lewis χ (sLex). PSGL-1 est un ligand commun des sélectines qui coopère avec CD44 et ESL-1 pour permettre la capture et le roulement des neutrophiles. Lorsque PSGL-1 et CD44 se lient aux sélectines endothéliales, elles induisent la phosphorylation des kinases Src et de Syk conduisant à l'activation partielle de l'intégrine aLp2 et au ralentissement des leucocytes sur les sélectines et ICAM-1. Les chimiokines induisent ensuite l'adhésion ferme des leucocytes. Les ligands des sélectines qui assurent le roulement, sur la E-sélectine, des cellules issues d'hémopathies malignes sont peu connus. Nous avons caractérisé ces ligands en les purifiant avec des anticorps dirigés contre CD43, CD44, PSGL-1, sLex/CLA et en utilisant la chimère E-sélectine/IgM. Des tests d'adhésion ont montré que PSGL-1, CD43, CD44 et une glycoprotéine de ~125 kDa soutiennent les interactions cellulaires dépendant de la E- sélectine. Le ligand de -125 kDa a été identifié comme étant l'endoglycan. Il a été détecté, par cytométrie de flux, sur les cellules leucémiques, les cellules de lymphomes ou de myélome multiple, dans ~50% des cas analysés. Sa forme membranaire, immunopurifiée, ou recombinante (endoglycan/lgG) soutient les interactions cellulaires dépendant de la E- sélectine. Nous avons montré qu'il réside dans les rafts lipidiques membranaires puis avons testé l'hypothèse que l'endoglycan, comme PSGL-1 et CD44, induit une signalisation via les kinases de type Src et la voie des MAPK. Nous avons pu observer que son engagement induit la phosphorylation de Syk et de ERK pour autant que la structure des rafts soit préservée. En aval de Syk, l'endoglycan active la PI3K, Akt, Btk et la MAPK p38. Ces résultats montrent que l'endoglycan est un ligand des sélectines endothéliales qui pourrait participer au contrôle du trafic et des interactions des cellules leucémiques, de lymphomes ou de myélomes multiples avec leur microenvironnement. - Le sang est un élément clé du fonctionnement de notre corps. La circulation sanguine permet la communication et le transfert de molécules et cellules entre divers organes. Lors d'une inflammation aiguë due à une réaction allergique, une infection ou une blessure, on observe un oedème local accompagné de rougeur, de chaleur et souvent de douleurs. Au sein des tissus enflammés, on observe des globules blancs (leucocytes) et diverses molécules inflammatoires qui attirent les leucocytes dans les tissus lésés (chimiokines). Le sang est composé de globules rouges, de plaquettes et de leucocytes spécialisés dans les défenses immunes. Pour atteindre le site d'inflammation, les leucocytes doivent quitter la circulation sanguine. Ils utilisent pour cela des molécules d'adhésion présentes à leur surface qui se lient à d'autres molécules d'adhésion de la paroi sanguine. Leurs interactions permettent aux leucocytes de rouler à la surface du vaisseau sanguin. Lorsqu'ils roulent au voisinage d'un site d'inflammation, les leucocytes sont exposés à des chimiokines qui induisent leur arrêt et les dirigent dans les tissus enflammés. Ce processus physiologique est aussi impliqué dans des pathologies telles que l'infarctus, l'artériosclérose ou la thrombose. Il peut être détourné à des fins moins louables par des cellules cancéreuses pour permettre leur dissémination (métastatisation). Dans ce travail de thèse, nous avons caractérisé une molécule d'adhésion qui soutient l'adhésion des leucocytes aux sélectines endothéliales: l'endoglycan. Nous avons observé que cette molécule d'adhésion est fréquemment exprimée par les cellules malignes de nombreuses maladies du sang comme les leucémies, les lymphomes et le myélome multiple. Nous avons également pu montrer que l'endoglycan envoie des signaux à l'intérieur des cellules malignes lorsqu'elles se lient aux sélectines endothéliales. Ces signaux pourraient jouer un rôle déterminant dans la régulation des interactions des cellules malignes avec leur microenvironnement. Elles pourraient peut-être aussi favoriser leur survie et leur prolifération.

Effect of inspiratory threshold loading on ventilatory kinetics during constant-load exercise.

Humoral factors play an important role in the control of exercise hyperpnea. The role of neuromechanical ventilatory factors, however, is still being investigated. We tested the hypothesis that the afferents of the thoracopulmonary system, and consequently of the neuromechanical ventilatory loop, have an influence on the kinetics of oxygen consumption (VO2), carbon dioxide output (VCO2), and ventilation (VE) during moderate intensity exercise. We did this by comparing the ventilatory time constants (tau) of exercise with and without an inspiratory load. Fourteen healthy, trained men (age 22.6 +/- 3.2 yr) performed a continuous incremental cycle exercise test to determine maximal oxygen uptake (VO2max = 55.2 +/- 5.8 ml x min(-1) x kg(-1)). On another day, after unloaded warm-up they performed randomized constant-load tests at 40% of their VO2max for 8 min, one with and the other without an inspiratory threshold load of 15 cmH2O. Ventilatory variables were obtained breath by breath. Phase 2 ventilatory kinetics (VO2, VCO2, and VE) could be described in all cases by a monoexponential function. The bootstrap method revealed small coefficients of variation for the model parameters, indicating an accurate determination for all parameters. Paired Student's t-tests showed that the addition of the inspiratory resistance significantly increased the tau during phase 2 of VO2 (43.1 +/- 8.6 vs. 60.9 +/- 14.1 s; P < 0.001), VCO2 (60.3 +/- 17.6 vs. 84.5 +/- 18.1 s; P < 0.001) and VE (59.4 +/- 16.1 vs. 85.9 +/- 17.1 s; P < 0.001). The average rise in tau was 41.3% for VO2, 40.1% for VCO2, and 44.6% for VE. The tau changes indicated that neuromechanical ventilatory factors play a role in the ventilatory response to moderate exercise.

Predicting outcome after acute basilar artery occlusion based on admission characteristics.

OBJECTIVE: To develop a simple prognostic model to predict outcome at 1 month after acute basilar artery occlusion (BAO) with readily available predictors. METHODS: The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational, international registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO. We considered predictors available at hospital admission in multivariable logistic regression models to predict poor outcome (modified Rankin Scale [mRS] score 4-5 or death) at 1 month. We used receiver operator characteristic curves to assess the discriminatory performance of the models. RESULTS: Of the 619 patients, 429 (69%) had a poor outcome at 1 month: 74 (12%) had a mRS score of 4, 115 (19%) had a mRS score of 5, and 240 (39%) had died. The main predictors of poor outcome were older age, absence of hyperlipidemia, presence of prodromal minor stroke, higher NIH Stroke Scale (NIHSS) score, and longer time to treatment. A prognostic model that combined demographic data and stroke risk factors had an area under the receiver operating characteristic curve (AUC) of 0.64. This performance improved by including findings from the neurologic examination (AUC 0.79) and CT imaging (AUC 0.80). A risk chart showed predictions of poor outcome at 1 month varying from 25 to 96%. CONCLUSION: Poor outcome after BAO can be reliably predicted by a simple model that includes older age, absence of hyperlipidemia, presence of prodromal minor stroke, higher NIHSS score, and longer time to treatment.

Disparate activation of the coronary sinus and inferior left atrium during atrial tachycardia after persistent atrial fibrillation ablation: prevalence, pitfalls, and impact on mapping.

INTRODUCTION: Persistent atrial fibrillation (AF) ablation may lead to partial disconnection of the coronary sinus (CS). As a result, disparate activation sequences of the local CS versus contiguous left atrium (LA) may be observed during atrial tachycardia (AT). We aimed to evaluate the prevalence of this phenomenon and its impact on activation mapping. METHODS: AT occurring after persistent AF ablation were investigated in 74 consecutive patients. Partial CS disconnection during AT was suspected when double potentials with disparate activation sequences were observed on the CS catheter. Endocardial mapping facing CS bipoles was performed to differentiate LA far-field from local CS potentials. RESULTS: A total of 149 ATs were observed. Disparate LA-CS activations were apparent in 20 ATs after magnifying the recording scale (13%). The most common pattern (90%) was distal to proximal endocardial LA activation against proximal to distal CS activation, the latter involving the whole CS or its distal part. Perimitral macroreentry was more common when disparate LA-CS activations were observed (67% vs 29%; P = 0.002). Partial CS disconnection also resulted in "pseudo" mitral isthmus (MI) block during LA appendage pacing in 20% of patients as local CS activation was proximal to distal despite distal to proximal activation of the contiguous LA. CONCLUSION: Careful analysis of CS recordings during AT following persistent AF ablation often reveals disparate patterns of activation. Recognizing when endocardial LA activation occurs in the opposite direction to the more obvious local CS signals is critical to avoid misleading interpretations during mapping of AT and evaluation of MI block.

Could a satellite-based navigation system (GPS) be used to assess the physical activity of individuals on earth?

OBJECTIVES: To test whether the Global Positioning System (GPS) could be potentially useful to assess the velocity of walking and running in humans. SUBJECT: A young man was equipped with a GPS receptor while walking running and cycling at various velocity on an athletic track. The speed of displacement assessed by GPS, was compared to that directly measured by chronometry (76 tests). RESULTS: In walking and running conditions (from 2-20 km/h) as well as cycling conditions (from 20-40 km/h), there was a significant relationship between the speed assessed by GPS and that actually measured (r = 0.99, P < 0.0001) with little bias in the prediction of velocity. The overall error of prediction (s.d. of difference) averaged +/-0.8 km/h. CONCLUSION: The GPS technique appears very promising for speed assessment although the relative accuracy at walking speed is still insufficient for research purposes. It may be improved by using differential GPS measurement.

Tests for sex-biased dispersal using bi-parentally inherited genetic markers.

Understanding why dispersal is sex-biased in many taxa is still a major concern in evolutionary ecology. Dispersal tends to be male-biased in mammals and female-biased in birds, but counter-examples exist and little is known about sex bias in other taxa. Obtaining accurate measures of dispersal in the field remains a problem. Here we describe and compare several methods for detecting sex-biased dispersal using bi-parentally inherited, codominant genetic markers. If gene flow is restricted among populations, then the genotype of an individual tells something about its origin. Provided that dispersal occurs at the juvenile stage and that sampling is carried out on adults, genotypes sampled from the dispersing sex should on average be less likely (compared to genotypes from the philopatric sex) in the population in which they were sampled. The dispersing sex should be less genetically structured and should present a larger heterozygote deficit. In this study we use computer simulations and a permutation test on four statistics to investigate the conditions under which sex-biased dispersal can be detected. Two tests emerge as fairly powerful. We present results concerning the optimal sampling strategy (varying number of samples, individuals, loci per individual and level of polymorphism) under different amounts of dispersal for each sex. These tests for biases in dispersal are also appropriate for any attribute (e.g. size, colour, status) suspected to influence the probability of dispersal. A windows program carrying out these tests can be freely downloaded from http://www.unil.ch/izea/softwares/fstat.html

Use of active personal dosemeters in interventional radiology and cardiology: Tests in hospitals - ORAMED project

Although active personal dosemeters (APDs) are not used quite often in hospital environments, the possibility to assess the dose and/or dose rate in real time is particularly interesting in interventional radiology and cardiology (IR/IC) since operators can receive relatively high doses while standing close to the primary radiation field.A study concerning the optimization of the use of APDs in IR/IC was performed in the framework of the ORAMED project, a Collaborative Project (2008-2011) supported by the European Commission within its 7th Framework Program. This paper reports on tests performed with APDs on phantoms using an X-ray facility in a hospital environment and APDs worn by interventionalists during routine practice in different European hospitals.The behaviour of the APDs is more satisfactory in hospitals than in laboratories with respect to the influence of the tube peak high voltage and pulse width, because the APDs are tested in scattered fields with dose equivalent rates generally lower than 1 Sv.h(-1).

Effect of roscovitine on intracellular calcium dynamics: differential enantioselective responses.

Cyclin-dependent kinases (CDKs) inhibitors have emerged as interesting therapeutic candidates. Of these, (S)-roscovitine has been proposed as potential neuroprotective molecule for stroke while (R)-roscovitine is currently entering phase II clinical trials against cancers and phase I clinical tests against glomerulonephritis. In addition, (R)-roscovitine has been suggested as potential antihypertensive and anti-inflammatory drug. Dysfunction of intracellular calcium balance is a common denominator of these diseases, and the two roscovitine enantiomers (S and R) are known to modulate calcium voltage channel activity differentially. Here, we provide a detailed description of short- and long-term responses of roscovitine on intracellular calcium handling in renal epithelial cells. Short-term exposure to (S)-roscovitine induced a cytosolic calcium peak, which was abolished after stores depletion with cyclopiazonic acid (CPA). Instead, (R)-roscovitine caused a calcium peak followed by a small calcium plateau. Cytosolic calcium response was prevented after stores depletion. Bafilomycin, a selective vacuolar H(+)-ATPase inhibitor, abolished the small calcium plateau. Long-term exposure to (R)-roscovitine significantly reduced the basal calcium level compared to control and (S)-roscovitine treated cells. However, both enantiomers increased calcium accumulation in the endoplasmic reticulum (ER). Consistently, cells treated with (R)-roscovitine showed a significant increase in SERCA activity, whereas (S)-roscovitine incubation resulted in a reduced PMCA expression. We also found a tonic decreased ability to release calcium from the ER, likely via IP3 signaling, under treatment with (S)- or (R)-roscovitine. Together our data revealed that (S)-roscovitine and (R)-roscovitine exert distinct enantiospecific effects on intracellular calcium signaling in renal epithelial cells. This distinct pharmacological profile can be relevant for roscovitine clinical use.