Dissertationen zum Thema „Radioactive tracers in physiology“

In recent years tumour hypoxia has been extensively investigated, mainly because it is a source of resistance to the common radio and chemo therapies. In fact, the low levels and heterogeneous distribution of oxygen in hypoxic microenvironment render ionizing radiation ineffective in treating cell proliferation. Furthermore, a low oxygen concentration promotes the activation of HIF-1 transcription factor, which favours the development of a more malignant and resistant cancer cell phenotype often associated with poor prognosis. Positron Emission Tomography (PET) imaging is a valuable diagnostic tool for investigating hypoxia in vivo by means of radiotracers, which incorporates both a radioisotope and a hypoxia-sensitive function. The aim of this multidisciplinary project was to develop small libraries of radiolabelled compounds starting from the biological and chemical features of the two gold standard hypoxia PET tracers [18F]FMISO and [18F]FAZA as well as those of the promising new tracer [18F]HX4. These new radiocompounds display the following peculiar structural characteristics: a 2-nitroimidazole hypoxia-sensitive moiety, different spacers to modulate steric constraint, lipophilicity and metabolic stability and a fluorinated aldopentose sugar as prosthetic group (e.g. [18F]FDR). Two series of compounds were designed and developed based on the conjugation method used to introduce the prosthetic group, namely the oxime bond formation and the thiazolidine ring closure. Six radiotracers belonging to the oxime-derivatives series were tested in vitro on MCF7 breast cancer cell lines in hypoxic conditions and a lead radiocompound incorporating a cyclopropyl group was identified. This new hypoxia tracer showed a better kinetic profile than both [18F]FMISO and [18F]FAZA in MCF7 cancer cell lines and comparable uptake values on a panel of different cancer cell lines, up to 120 min post administration at 1% of O2. These promising results will pave the way for futures in vivo studies.

Mycobacter avium complex serovars 4 and 20 were cultured in the presence of [3H] fucose, [3H]-methionine, and [3H]-mannose to specifically radiolabel the oligosaccharide of the glycopeptidolipid (GPL) antigens. Distribution of radioactivity in lipid was determined by thin-layer chromatographic methods. Examination of acid hydrolysates from radiolabeled antigens revealed that [3H]-methionine incorporated into methylated sugars in polar and apolar GPL components, whereas [3H]-mannose incorporated exclusively into the oligosaccharide of polar GPL antigens. Least incorporation of radiolabel into antigens was observed with [3H]-fucose. Use of radiolabeled serovar 4 antigens in macrophage uptake studies revealed maximum uptake to be slightly above 250 gg/ 3.2 x 105 cells. Timed experiments demonstrated that GPL antigens were relatively inert to degradation by resident peritoneal macrophages.

The purpose of this study is to determine the optimum conditions for obtaining a leukocyte button which most effectively will be subsequently labelled with 111In oxine. As in all radiopharmaceuticals, the highest radiopharmaceutical purity, or the fraction of total radioactivity in the desired radiopharmaceutical form (111In oxine leukocyte), the better the product. Many 111In ocine labelled leukocytes are contaminated by labelled platelets, red cells, and proteins, resulting in a “dirty” product. But with careful leukocyte culturing, sedimentation, centrifugation, and labelling, as demonstrated by this study, a highly desirable, pure radiopharmaceutical can be made. In an attempt to further purify the leukocyte button beyond centrifugation, hypotonic red cell lysing and its effect on leukocyte viability will be studied. The optimum incubation time will be determined by examining the leukocyte and red cell elution profiles at different incubation times. And, 0.9% saline washes of plasma and proteins from the leukocytes will be varied by both volume and number to determine if extra washes will optimize the labelling efficiency.

To investigate the possible changes in pyruvate oxidation during the rapid growth period in an animal model, the oxidation of radioactive labeled pyruvate was measured in mitochondria isolated from the gastrocnemius muscle of Sprague--Dawley rats between 4 and 16 weeks of age. The influence of the fatty acid derivative palmitylcarnitine, as an inhibitor of pyruvate oxidation, was also tested.The gastrocnemius muscle was removed from anesthesized animals at 4, 8 and 16 weeks of age. Isolated mitochondria from the muscle samples were incubated with C1--14C] pyruvate and E1-14C] pyruvate + palmitylcarnitine in a KC1 medium. The decarboxylation of pyruvate was measured by the evolution of radioactive labeled carbon dioxide. Pyruvate oxidation significantly (p .; 0.0001) increased from ages 4 to 16 weeks. The initial low rate of pyruvate oxidation was attributed to the residual metabolic effects of the pre-weaned animal' high-fat diet. The subsequent increase in the capacity of pyruvate oxidation was then explained by the shift in the animaldiet to high-carbohydrate lab chow. These results may also be attributed to the maturation of the hindlimb muscle fibers during this period: the differentiation of predominately red, oxidative fibers to an increase in the percentage of white, glycolytic fibers, common in the adult hindlimb. The fatty acid derivative, palmitylcarnitine, failed to inhibitpyruvate oxidation at the level of decarboxylation. This finding supports the proposal that fatty acids do not inhibit glucose oxidation directly, but instead suppress glycogen breakdown. Thus, the findings indicate an increase in the capacity for- pyruvate oxidation during the rapid growth period without inhibition by the fatty acid derivative, palmitylc_arnitine.
Department of Biology

The purpose of this study was to compare the anabolic response to acute running exercise in two different leg muscles in endurance-trained men using two different stable isotope tracers. 6 male subjects (26±2 yr; V02max 63±2 ml•kg-' •min-') performed a 45 min treadmill run at 77±1 % intensity. Infusions of d3-leucine and d5-phenylalanine were used to measure mixed muscle FSR at rest and 24 hr post-exercise. An additional infusion of 10% amino acid solution was added to the post-exercise infusion to maximize the muscle anabolic response. Muscle biopsies were obtained from the vastus lateralis (VL) and soleus (SOL) at 2 and 6 hr of the infusion for the measurement of isotope incorporation. Additional muscle biopsies were obtained prior to and 4 hr post-exercise for determination of muscle glycogen use. At rest FSR was similar between the VL and SOL using either tracer (p>0.05). At 24 hr post-exercise FSR was elevated in both muscles, independent of the tracer used (p<0.05). Muscle glycogen was decreased to the same extent in both muscles by -31% at 4 hr post-exercise (p<0.05). These data suggest that the VL and SOL muscles are both stimulated similarly during 45 min of level grade running. Additionally, both muscles respond similarly 24 hr post-exercise, independent of the tracer used for the determination of protein synthesis.
School of Physical Education, Sport, and Exercise Science

The current work determined whether there is a constant tissue residue associated with narcotic compounds. In this investigation, the cladoceran, Daphnia magna was exposed to lethal levels (48h LC50) of ten, $ sp{14}$C-labelled, narcotic organic chemicals in a closed system. Exposure times, ambient concentrations, and body sizes were varied to evaluate their effects. The $ sp{14}$C-method developed in current work can detect chemicals in single D. magna in concentrations ranging from 0.02 to 6310 mmol/kg. Moreover, the technique detected phobic and lipophilic chemicals equally well. The technique's sensitivity (nmol/kg) allowed for detection of differences in the internal concentrations of pollutants among the unaffected, immobilized, and dead D. magna. Immobilized D. magna contained between 0.14 mmol/kg and 200 mmol/kg of narcotics. On the average, however, the internal residues were 3.1 mmol/kg (95%CL = 3.1 $ pm$ 2.0). This agreed with literature values. The effects of time of exposure, ambient concentration, and body size on the tissue residues of narcotics varied with the chemical compound.

Thèse (D.R.Min.) -- Université du Québec à Chicoutimi, programme extensionné à l'Université du Québec à Montréal, 2003.
Bibliogr.: f. 203-204. Document électronique également accessible en format PDF. CaQCU

129I is a radioactive isotope (T1/2= 15.7 million years) produced through natural and anthropogenic pathways, but the anthropogenic production is presently dominating the Earth’s surface environments. Sparse data from previous investigations in the Baltic Sea clearly indicated the occurrence of 129I at levels 3-4 orders higher than natural pre-atomic era (before 1940) without comprehensive evaluation of distribution and inventory. In this thesis extensive data on the distribution and inventory of iodine isotopes, 129I and 127I, and their species in waters of the Baltic Sea, Kattegat and Skagerrak are presented and used for estimation of water masses exchange and impact on the environment.  To fulfill these objectives seawater samples were collected in August 2006 and April 2007 in the Baltic Proper, Kattegat and Skagerrak as well as in December 2009 in the Bothnian Sea. After elaborative chemical separation of total iodine and iodine species, the analysis was performed using ICP-MS for 127I and AMS for 129I. The results reveal considerable differences in 129I concentration in terms of spatial and temporal variability and expose relatively high concentrations in the deep waters. Inventory estimates show higher amounts of 129I in August 2006 (24.2 ±15.4 kg) than in April 2007 (14.4± 8.3 kg) within the southern and central Baltic Proper, whereas almost a constant inventory is found in the Kattegat Basin. Relatively high 127I-/127IO3- and 129I-/129IO3- values in water of the Baltic Proper suggest effective reduction of iodate at a maximum rate of  8×10-7 (127IO3-) and 6×10-14 (129IO3-) (g/m3.day). The combination of 129I and 127I as tracers of water circulation in the Baltic Sea suggest that upwelling deep basinal water occurs into the surface along the Gotland deep and intrusion of North Atlantic water into southern Baltic. Furthermore, 129I-based model inventory reveals inflow of 330 km3/y (230-450 km3/y) water from the Kattegat into the Baltic Proper. Water exchange between the Baltic Proper and the Bothnian Sea and vice versa is estimated at 980 km3/y (600-1400 km3/y) and 1180 km3/y (780-1600 km3/y) respectively. Finally, an environmental assessment of radioactivity associated with 129I burden in the Baltic Sea region is discussed.

Thesis (Ph. D.)--Joint Program in Marine Geology and Geophysics (Massachusetts Institute of Technology, Dept. of Earth, Atmospheric, and Planetary Sciences; and the Woods Hole Oceanographic Institution), September 2003.
Includes bibliographical references.
Groundwater discharge into estuaries and the coastal ocean is an important mechanism for the transport of dissolved chemical species to coastal waters. Because many dissolved species are present in groundwater in concentrations that are orders of magnitude higher than typical river concentrations, groundwater-borne nutrients and pollutants can have a substantial impact on the chemistry and biology of estuaries and the coastal ocean. However, direct fluxes of groundwater into the coastal ocean (submarine groundwater discharge, or SGD) can be difficult to quantify. Geochemical tracers of groundwater discharge can reflect the cumulative SGD flux from numerous small, widely dispersed, and perhaps ephemeral sources such as springs, seeps, and diffuse discharge. The natural radiocarbon content (A14C) of dissolved inorganic carbon (DIC) was developed as a tracer of fresh, terrestrially driven fluxes from confined aquifers. This A14C method was tested during five sampling periods from November 1999 to April 2002 in two small estuaries in southeastern North Carolina. In coastal North Carolina, fresh water artesian discharge is characterized by a low A14C signature acquired from the carbonate aquifer rock. Mixing models were used to evaluate the inputs from potential sources of DIC-A'4C to each estuary, including seawater, springs, fresh water stream inputs, and salt marsh respiration DIC additions. These calculations showed that artesian discharge dominated the total fresh water input to these estuaries during nearly all sampling periods.
(cont.) These new A14C-based SGD estimates were compared with groundwater flux estimates derived from radium isotopes and from radon-222. It is clear that these tracers reflect different components of the total SGD. The fluxes of low-A14C and of 222Rn were dominated by artesian discharge. Estuarine 226Ra showed strong artesian influence, but also reflected the salt water SGD processes that controlled the other three radium isotopes. The flux of 228Ra seemed to reflect seepage from the terrestrial surficial aquifer as well as salt water recirculation through estuarine sediments. The fluxes of 224Ra and 223Ra were dominated by salt water recirculation through salt marsh sediments. This multi-tracer approach provides a comprehensive assessment of the various components contributing to the total SGD.
by Carolyn M. Gramling.
Ph.D.

Thesis (Ph. D.)--Joint Program in Chemical Oceanography (Massachusetts Institute of Technology, Dept. of Earth, Atmospheric, and Planetary Sciences; and the Woods Hole Oceanographic Institution), 2007.
Includes bibliographical references (p. 215-225).
The five noble gases (helium, neon, argon, krypton, and xenon) are biologically and chemically inert, making them ideal oceanographic tracers. Additionally, the noble gases have a wide range of solubilities and molecular diffusivities, and thus respond differently to physical forcing. Tritium, an isotope of hydrogen, is useful in tandem with its daughter helium-3 as a tracer for water mass ages. In this thesis, a fourteen month time-series of the five noble gases, helium-3 and tritium was measured at the Bermuda Atlantic Time-series Study (BATS) site. The time-series of five noble gases was used to develop a parameterization of air-sea gas exchange for oligotrophic waters and wind speeds between 0 and 13 m s-1 that explicitly includes bubble processes and that constrains diffusive gas exchange to ± 6% and complete and partial air injection processes to ± 15%. Additionally, the parameterization is based on weeks to seasonal time scales, matching the time scales of many relevant biogeochemical cycles. The time-series of helium isotopes, tritium, argon, and oxygen was used to constrain upper ocean biological production. Specifically, the helium flux gauge technique was used to estimate new production, apparent oxygen utilization rates were used to quantify export production, and euphotic zone seasonal cycles of oxygen and argon were used to determine net community production. The concurrent use of these three methods allows examination of the relationship between the types of production and begins to address a number of apparent inconsistencies in the elemental budgets of carbon, oxygen, and nitrogen.
by Rachel H.R. Stanley.
Ph.D.

Les récepteurs couplés aux protéines G (GPCRs en anglais) représentent la famille de récepteurs intégrales de membrane plus vaste dans la majorité des cellules eucaryotes. Ils jouent un rôle clé dans la transduction de signal, ainsi que la compréhension de leur mécanisme de signalisation représente une des questions principales dans la biologie d'aujourd'hui. Dans la caractérisation du paysage énergétique de ces récepteurs à l'échelle atomique, les structures cristallographiques publiées pendant la décennie dernière par cristallographie aux rayons X représentent la percée scientifique majeure et donnent une contribution fondamentale dans la biologie structurelle de GPCRS. Ces structures représentent un point de départ précieux dans la compréhension du mécanisme de transduction de signal, en plaçant des structures dans l'ensemble conformationnel de ces récepteurs le long du processus d'activation. Pour compléter ce cadre de structures statiques qui correspondent aux états à basse l'énergie et fortement peuplés, une caractérisation de l'ensemble conformationnel et des barrières cinétiques qui sont associées est un point nécessaire et fondamentale. À ce but nous proposons une approche innovant avec la finalité d'observer le paysage conformationnel dynamique des GPCR et étudier la modulation de ces récepteurs par des ligands et des lipides, qui sont connus pour jouer un rôle clé dans la structure et les fonctions des protéines de membrane (e.g.). Un des outilles le plus approprié pour explorer les barrières cinétiques de GPCR c'est la résonance magnétique nucléaire (RMN) en solution. Pour tirer profit au mieux de cette technique, nous avons utilisé des sondes marqués 13CH3 immergées dans un environnement perdeuteré, qui constitue le marquage isotopique le plus approprié en RMN pour examiner les paysages conformationnels des protéines de grosses dimensionnes ou des complexes de protéines. Nous avons choisi Escherichia coli comme système d'expression pour sa capacité de pousser dans des conditions très hostiles comme des solutions 100%-D2O. Pour surmonter les difficultés habituellement rencontrées lors de l'expression des GPCRs, nous avons appliqué un protocole innovant qui cible l'expression de GPCRs directement aux corps d'inclusion. Ceci permet la production des bonnes quantités de protéines (jusqu’à 6 mg/litres de culture de pur 13CH3-u-2H-GPCRs). Une fois purifié, le récepteur est foldé en amphipols et transféré ensuite à une double couche lipidique appelée nanometric lipid bilayer ou nanodisc (NLB). De façon très important, les mesures pharmacologiques quantitatives indiquent que les récepteurs incorporés dans des NLBs après ce protocole sont stables et entièrement actifs dans les conditions des expériences de NMR.Les investigations par RMN conduites sur le GPCR en NLB ont donné lieu à une résolution jamais obtenue dans le domaine, grâce à la biochimie finement accordée et à la perdeuteration du récepteur. Selon les données obtenues, notre récepteur modèle, le récepteur 2 pour le leukotriene B4 (BLT2), est capable d'explorer plusieurs conformations différentes, même dans l'état pas lié aux ligands, y compris l'état actif. Ce paysage conformationnel est également modulé par des ligands et des lipides. Dans le cas spécifiques, nous avons observé que un incrément dans le contenu de stérol dans la membrane modifie la distribution des différents états conformationnels du récepteur, en favorisant l'état actif, qui indique une régulation allosteric positif du stérol sur l'activation de ce récepteur, comme confirmé aussi par les mesures de liaison du GTP à la protéine G. Cette propriété du stérol est probablement importante pour le contrôle de mécanisme de signalisation de GPCRs
G protein-coupled receptors (GPCRs) are the largest family of integral membrane protein receptors present in most eukaryotic cells. They play a key role in signal transduction and understanding their signalling mechanism represents one of the main issues in biology today. In the characterization of the energy landscape of these receptors, at the atomic scale, X-ray crystal atomic structures published during the last decade represent the major breakthrough and contribution in the structural biology of GPCRs. They represent a precious starting point in the understanding of the mechanism of signal transduction by placing structures in the conformational ensemble of these receptors along the activation pathway. To complete these static snapshots that correspond to low energy and highly populated states, a characterization of the whole conformational ensemble and associated kinetic barriers is fundamental to complete the picture. To this aim we proposed an innovative approach to observe GPCRs dynamic conformational landscape and how it is modulated by ligands and lipids, that are known to play a key role in membrane protein structures and functions (e.g.). One of the most appropriate tool to explore GPCR kinetic barriers is solution state NMR. To do so, we used 13CH3 probes immersed in a perdeuterated environment, the most appropriate isotope-labelling scheme to investigate conformational landscapes of large proteins or protein complexes with this spectroscopy. We chose Escherichia coli as expression system for its ability to grow in very hostile conditions like 100%-D2O solutions. In order to overcome the usual expression issues concerning GPCRs, we applied an innovative protocol which targets the expression directly to inclusion bodies. This allows the production of high amounts of proteins (up to 6 mg/litre of culture of pure 13CH3-u-2H-GPCRs). Once purified, receptors are folded in amphipols and then transferred to nanometric lipid bilayers or nanodiscs. Importantly quantitative pharmacological measurements indicate that receptors embedded in NLBs following this protocol are stable and fully active in the conditions of the NMR experiments. NMR investigation of a GPCR in a NLB gave rise to a resolution never achieved in the field thanks to a fine tuned biochemistry and a perdeuteration of the receptor. According to our data, the prototypical receptor, the leukotriene B4 receptor (BLT2), is able to explore multiple different conformations, even in the unliganded state, including the active state. This conformational landscape is further modulated by ligands and lipids. In particular, we observed that an increment in the sterol content of the membrane modifies the distribution of the different conformational states of the receptor in favour of the active one, indicating a positive allosteric regulation of the sterol on the activation of this receptor, as confirmed by GTP-to-G protein binding measurements. This property of the sterol is likely important for the control of the signalling properties of GPCRs

Une solution prometteuse pour diminuer les émissions anthropogéniques de gaz à effet de serre consiste à injecter une partie des rejets industriels de CO2 dans des formations souterraines. Celles-ci comportent un réservoir entouré de roches de couverture, qui constituent la première barrière à la migration des fluides. La caractérisation de leurs propriétés de confinement et de leur évolution en présence de CO2 est donc un élément clé de la sécurité d’un site de stockage. Le travail présenté propose une méthodologie, appliquée ici à des roches carbonatées du bassin parisien, permettant de mesurer les paramètres de transport de roches de couverture et les conséquences d’un vieillissement en conditions représentatives de celles d’un stockage en aquifère profond. La pression de percée, le coefficient de diffusion des produits de dissolution du CO2, et la perméabilité, paramètres contrôlant les principaux mécanismes de fuite, ont été mesurés avant et après altération des matériaux par réaction avec une saumure saturée en CO2 dans des conditions thermodynamiques typiques d’un réservoir (environ 80°C et 100 bar). Les résultats obtenus ont révélé un bon comportement global des roches, mais également une forte diminution du potentiel de confinement en présence de défauts structurels initiaux (fractures rebouchées, pores de grand diamètre...). Une simulation numérique décrivant les évolutions de la formation rocheuse non-fissurée sur une durée de 1000 ans a été réalisée en s’appuyant sur des paramètres mesurés directement ou obtenus par modélisation des essais d’altération. Elle a montré que les transformations engendrées par le stockage de CO2 sous une roche de couverture homogène restent très limitées spatialement
A promising solution to reduce anthropogenic emissions of greenhouse effect gases consists in the injection and long-term storage of a part of the industrial carbon dioxide discharges in underground formations. These formations must be composed of a reservoir surrounded by tight caprocks, which represent the first barrier preventing fluids migration. The characterization of their confining properties and of their evolution in presence of CO2 is thus a key element regarding a storage site security. This work presents a methodology allowing the measurement of caprocks transport parameters and the consequences of an alteration under representative conditions of deep aquifers storage. This methodology was applied to carbonate rocks from the Paris basin. The breakthrough pressure, the diffusion coefficient of CO2 dissolution products, and the permeability, controlling parameters of leakage mechanisms, were measured before and after alteration of the materials by reaction with a CO2-saturated brine under reservoir thermodynamic conditions (about 80°C and 100 bar). Results revealed a satisfactory global behaviour under these aggressive conditions, but also a strong diminution of the confinement potential in presence of initial structural faults (sealed fractures, large-diameter pores…) forming higher-permeability zones. A numeric simulation describing the evolution of a homogeneous rock formation during 1000 years was also realized based on parameters directly measured or obtained by modelling of the alteration experiments. It showed that the transformations brought by the CO2 storage under a rock formation with no initial faults remain very localized spatially

Chez l'homme, de nombreuses pathologies sont liees a des dysfonctionnements du transport cellulaire du d-glucose. Les techniques d'imagerie etant un outil precieux pour detecter ces anomalies de transport, la synthese d'analogues du d-glucose radiomarques a l'iode (emetteur gamma) et utilisables en imagerie spect, a ete entreprise selon deux approches : la premiere repose sur l'utilisation du motif beta-iodoethoxyle qui a ete introduit sur diverses positions (1, 4, 5 et 6) du glucose. La seconde consiste a conserver tous les hydroxyles du glucose en introduisant le motif iode a partir des carbones du squelette. Ceci a ete effectue avec un motif iodomethyle sur les positions 3 et 6 ainsi que para-iodophenyle sur cette derniere. Tous les derives prepares ont fait l'objet d'une evaluation biologique, au moins preliminaire, sans toutefois presenter les proprietes d'un traceur du d-glucose, a l'exception du 6-deoxy-6-iodo-d-glucose (6-dig). Ce dernier, dont l'evaluation biologique sera poursuivie, a pu etre prepare a une echelle multi-grammes.

Synthese de ligands macrocycles tetraphores, complexants potentiels de cations paramagnetiques (gd**(3+), fe**(3+)) et de nucleide radioactifs. Etude de la reactivite de ces ligands et des essais de complexation

La gestion de la ressource en eau en milieu alluvionnaire de montagne, nécessite une définition à la fois de l'origine et de la dynamique des écoulements souterrains dans ce type d'aquifère. Cette définition implique par conséquent la prise en considération des autres compartiments du système hydrologique du domaine montagnard, c'est-à-dire les précipitations, le réseau de surface et les aquifères de versant. L'étude hydrogéologique de l'aquifère alluvial de la plaine d’Aoste (Italie), pris comme référence pour les alpes italo-franco-suisses, s'appuie en particulier sur l'utilisation de deux isotopes de la molécule d'eau: l'oxygene-18 et le tritium. Le signal d'entrée en oxygene-18 fourni par les precipitations présente une grande variabilité due au contexte orographique et climatique. Dans les aquifères de versant, les circulations préférentielles liées à une fracturation plus ou moins profonde, réalisent une homogénéisation aboutissant à un signal de sortie très tamponné, ce qui explique la stabilité et l'uniformité des valeurs relevées dans le milieu alluvial. L'outil principal permettant une distinction entre les différentes circulations s'est avéré être le tritium, dont les variations saisonnières constituent un excellent traceur des écoulements souterrains.

Strontium 90 (90Sr) is a radionuclide of anthropogenic origin released in large quantities in the environment as a result of nuclear atmospheric tests or accidents at nuclear facilities. 90Sr persists on a long-term basis in the environment, leading to chronic contamination by ingestion of populations living on contaminated territories. The induction of bone tumours associated with the fixation of 90Sr has been widely described. However, the occurrence of non-cancer effects is much less known. We used a mouse model with chronic contamination by ingestion of water containing 20 kBq/l of 90Sr. A biokinetic study confirmed the accumulation of 90Sr in the bones, with an increased rate of accumulation during bone growth. This accumulation was higher in the bones of females than in males. The whole-body absorbed doses ranged from 0.33 ± 0.06 mGy (birth) to 10.6 ± 0.1 mGy (20 weeks). The absorbed dose for the skeleton was up to 55 mGy. Ingestion of 90Sr induced a change in the expression of genes inducing an imbalance in favour of bone resorption, but without effect on bone morphology. No significant effect was observed for the hematopoietic system. On the other hand, minor modifications were observed for the immune system. To evaluate the functionality of the immune system, a vaccination test with TT and KLH antigens was used. Results showed in contaminated animals a significant decrease in the production of specific immunoglobulins, changes in the Th1/Th2 balance in the spleen and a disrupted B lymphocyte differentiation. These results improve the understanding of some of the non-cancerous consequences of chronic exposure at low dose of radionuclides with a long half-life, which can be accidentally released.

Description de la méthode expérimentales de traceur radioactif et de sectionnement permettant la mesure précise des coefficients de diffusion de (204)TL dans TL-beta. Détermination de la précision atteinte sur la mesure du coefficient de diffusion. Détection d'une courbure positive dans le graphe d’Arrhenius. Explication des résultats.

Les effets d'amelioration des capacites de passivation apportees par le molybdene et les effets de depassivation induits par le soufre adsorbe et en solution solide ont ete etudies en milieu h::(2)so::(4) sur des alliages monocristallins a base de nickel contenant 2% et 6% de molybdene, a l'aide de techniques electrochimiques et radiochimiques (traceur s**(35))

Un dosage radioimmunologique specifique du zinniol a ete au point; les etapes de ce travail ont ete les suivantes: - synthese d'une molecule immunogene (conjugue zinniol-proteine porteuse). - obtention d'anticorps specifique (4 ci/mmole). - mise au point du dosage radioimmunologique valide du point de vue de sa specificite, de sa reproductibilite et de sa sensibilite (limite de detection 0,14 nn/essai). Cet outil a permis de realiser des dosages sur des plantes infectees. Ces resultats inedits montrent que la molecule est emise tres rapidement dans les tissus infectes (12 h apres inoculation).

Thesis (Ph. D.)--Florida State University, 2005.
Advisor: Dr. William C. Burnett, Florida State University, College of Arts and Sciences, Department of Oceanography. Title and description from dissertation home page (viewed Sept. 15, 2005). Document formatted into pages; contains xvi, 132 pages. Includes bibliographical references.

A thesis submitted to the faculty of Engineering, University of the Witwatersrand, Johannesburg , in fulfillment of the requirements for the degree of Doctor of Philosophy. Johannesburg, November 1994
Organ function is often characterised using imaging techniques. In particular a tracer is often used which does not react with tissue, is low in concentration, follows body fluid flows and is distinguishable from the observed system and thus measurable. These requirements ensure linear characteristics of the tracer. In this thesis, these linear characteristics are used to develop a generalised mathematical theory to determine organ function from imaged tracer experiments. The theory is based on anatomical and physiological information for single and multiple input organs. [Abbreviated Abstract. Open document to view full version]
MT2018

Thesis (Ph. D.)--Massachusetts Institute of Technology and Woods Hole Oceanographic Institution, 2007.
"September 2007". "Joint Program in Oceanography/Applied Ocean Science and Engineering"--Cover. Title from Web page (viewed on Mar. 24, 2008). Includes bibliographical references (p. 215-225).

A research report submitted to the Faculty of Science school of Geosciences in partial fulfillment of the requirements for the degree of Masters of Science in Hydrogeology. Johannesburg, June 2017.
The Masama Sandstone Aquifer is located in a semi-arid region of south-eastern Botswana where there are no perennial rivers. Groundwater is the main source of water supply for the communities. Historically many water drilling programs have been carried out in this area and the hydrogeological system has been conceptualized. An integrated approach coupling environmental isotopes, radioisotopes and multivariate statistical analysis of the hydrochemical variables was employed to study the origin, age, recharge conditions, rock-water interaction and the hydrological link between the aquifer and geological structures. The major ions in this area are Na+, Ca2+, Mg2+ and HCO-3. Groundwater in the Masama area fall in the transition from a Na-HCO-3 –type through Ca-Na-HCO-3 to Ca-Mg-HCO-3 -type waters from the western to the eastern part of the area. The water types are as a result of cation exchange, carbonate dissolution and rock-weathering processes. The δ18O and δ2H values vary spatially depending on the source of moisture, rainfall season, geology, topography and groundwater circulation depth. Deep circulating groundwaters are isotopically depleted whilst shallow circulating groundwaters are isotopically enriched with respect to winter rain. Low tritium values < 0.8TU and 14C values < 80pmc testifies for recharge. Recent rainfall amount in the area is not sufficient enough to make a profound replenishment in the aquifer. Tritium, 14C and Chloride Mass Balance helped in identifying recharge location and hydrologic connections between structures and the sandstone aquifer elucidating that recharge zones are in the NE and NW of the study area. High recharge rates occur in the north-eastern part and the Makhujwane fault act as a conduit for groundwater recharge. This study provides a better understanding of the aquifer and the information contained herein can be incorporated into future works for sustainable use of the groundwater resource.
XL2017

Thesis (Ph.D.)--University of Alberta, 2009.
A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Oncology. Title from pdf file main screen (viewed on January 30, 2010). Includes bibliographical references.

La progression d’un individu au travers d’un environnement diversifié dépend des informations visuelles qui lui permettent d’évaluer la taille, la forme ou même la distance et le temps de contact avec les obstacles dans son chemin. Il peut ainsi planifier en avance les modifications nécessaires de son patron locomoteur afin d’éviter ou enjamber ces entraves. Ce concept est aussi applicable lorsque le sujet doit atteindre une cible, comme un prédateur tentant d’attraper sa proie en pleine course. Les structures neurales impliquées dans la genèse des modifications volontaires de mouvements locomoteurs ont été largement étudiées, mais relativement peu d’information est présentement disponible sur les processus intégrant l’information visuelle afin de planifier ces mouvements. De nombreux travaux chez le primate suggèrent que le cortex pariétal postérieur (CPP) semble jouer un rôle important dans la préparation et l’exécution de mouvements d’atteinte visuellement guidés. Dans cette thèse, nous avons investigué la proposition que le CPP participe similairement dans la planification et le contrôle de la locomotion sous guidage visuel chez le chat. Dans notre première étude, nous avons examiné l’étendue des connexions cortico-corticales entre le CPP et les aires motrices plus frontales, particulièrement le cortex moteur, à l’aide d’injections de traceurs fluorescents rétrogrades. Nous avons cartographié la surface du cortex moteur de chats anesthésiés afin d’identifier les représentations somatotopiques distales et proximales du membre antérieur dans la partie rostrale du cortex moteur, la représentation du membre antérieur située dans la partie caudale de l’aire motrice, et enfin la représentation du membre postérieur. L’injection de différents traceurs rétrogrades dans deux régions motrices sélectionnées par chat nous a permis de visualiser la densité des projections divergentes et convergentes pariétales, dirigées vers ces sites moteurs. Notre analyse a révélé une organisation topographique distincte de connexions du CPP avec toutes les régions motrices identifiées. En particulier, nous avons noté que la représentation caudale du membre antérieur reçoit majoritairement des projections du côté rostral du sillon pariétal, tandis que la partie caudale du CPP projette fortement vers la représentation rostrale du membre antérieur. Cette dernière observation est particulièrement intéressante, parce que le côté caudal du sillon pariétal reçoit de nombreux inputs visuels et sa cible principale, la région motrice rostrale, est bien connue pour être impliquée dans les fonctions motrices volontaires. Ainsi, cette étude anatomique suggère que le CPP, au travers de connexions étendues avec les différentes régions somatotopiques du cortex moteur, pourrait participer à l’élaboration d’un substrat neural idéal pour des processus tels que la coordination inter-membre, intra-membre et aussi la modulation de mouvements volontaires sous guidage visuel. Notre deuxième étude a testé l’hypothèse que le CPP participe dans la modulation et la planification de la locomotion visuellement guidée chez le chat. En nous référant à la cartographie corticale obtenue dans nos travaux anatomiques, nous avons enregistré l’activité de neurones pariétaux, situés dans les portions des aires 5a et 5b qui ont de fortes connexions avec les régions motrices impliquées dans les mouvements de la patte antérieure. Ces enregistrements ont été effectués pendant une tâche de locomotion qui requiert l’enjambement d’obstacles de différentes tailles. En dissociant la vitesse des obstacles de celle du tapis sur lequel le chat marche, notre protocole expérimental nous a aussi permit de mettre plus d’emphase sur l’importance de l’information visuelle et de la séparer de l’influx proprioceptif généré pendant la locomotion. Nos enregistrements ont révélé deux groupes de cellules pariétales activées en relation avec l’enjambement de l’obstacle: une population, principalement située dans l’aire 5a, qui décharge seulement pendant le passage du membre au dessus del’entrave (cellules spécifiques au mouvement) et une autre, surtout localisée dans l’aire 5b, qui est activée au moins un cycle de marche avant l’enjambement (cellules anticipatrices). De plus, nous avons observé que l’activité de ces groupes neuronaux, particulièrement les cellules anticipatrices, était amplifiée lorsque la vitesse des obstacles était dissociée de celle du tapis roulant, démontrant l’importance grandissante de la vision lorsque la tâche devient plus difficile. Enfin, un grand nombre des cellules activées spécifiquement pendant l’enjambement démontraient une corrélation soutenue de leur activité avec le membre controlatéral, même s’il ne menait pas dans le mouvement (cellules unilatérales). Inversement, nous avons noté que la majorité des cellules anticipatrices avaient plutôt tendance à maintenir leur décharge en phase avec l’activité musculaire du premier membre à enjamber l’obstacle, indépendamment de sa position par rapport au site d’enregistrement (cellules bilatérales). Nous suggérons que cette disparité additionnelle démontre une fonction diversifiée de l’activité du CPP. Par exemple, les cellules unilatérales pourraient moduler le mouvement du membre controlatéral au-dessus de l’obstacle, qu’il mène ou suive dans l’ordre d’enjambement, tandis que les neurones bilatéraux sembleraient plutôt spécifier le type de mouvement volontaire requis pour éviter l’entrave. Ensembles, nos observations indiquent que le CPP a le potentiel de moduler l’activité des centres moteurs au travers de réseaux corticaux étendus et contribue à différents aspects de la locomotion sous guidage visuel, notamment l’initiation et l’ajustement de mouvements volontaires des membres antérieurs, mais aussi la planification de ces actions afin d’adapter la progression de l’individu au travers d’un environnement complexe.
When progressing through a varied environment, an individual will depend on visual information to evaluate the size, shape or the distance and time to contact of objects in his path. This will allow him to plan in advance the gait requirements necessary to avoid or step over these obstacles. This concept is also applicable in situations where the subject must reach a target, as with a predator chasing down its prey. The neural structures involved in generating voluntary gait modifications during locomotion have been extensively studied, but relatively little information is available on the processes that integrate visual information to plan these movements. Numerous studies in the primate suggest that the posterior parietal cortex (PPC) plays an important role in the preparation and execution of visually-guided reaching movements. In this thesis, we investigated the proposition that the PPC is similarly involved in the planning and control of visually-guided locomotion in the cat. Our first study examined the extent of cortico-cortical connections between the PPC and the more frontal motor areas, particularly the motor cortex, using injections of fluorescent retrograde tracers. We mapped the cortical surface of anaesthetized cats to identify the somatotopical representations of the distal and proximal forelimb in the rostral portion of the motor cortex, the forelimb representation in the caudal motor area, and also the hindlimb representation. The injection of different tracers in two selected regions, for every cat, allowed us to visualize the density of divergent and convergent parietal projections to these motor sites. Our analysis revealed a distinct topographical organization of parietal connections with all of the identified motor regions. In particular, the caudal motor representation of the forelimb primarily received projections from the rostral bank of the parietal cortex, while the caudal portion of the PPC strongly projected to the rostral forelimb representation. The latter observation is particularly interesting, since the caudal bank of the PPC receives numerous visual inputs and its target, the rostral motor region, is well-known for its involvement in voluntary motor functions. Therefore, this study suggests that the PPC, through extensive connections with the different somatotopic representations of the motor cortex, could constitute an ideal neural substrate for processes such as inter- and intra-limb coordination, as well as the modulation of visually-guided voluntary movements. Our second study tested the hypothesis that the PPC participates in the modulation and planning of voluntary gait modifications during locomotion in the cat. Using the cortical mapping established in our anatomical study, we recorded the activity of parietal neurons, localized in parts of areas 5a and 5b which are known to project strongly towards motor regions involved in forelimb movements. These recordings were obtained during a locomotion task requiring the cat to step over several obstacles of different sizes. By dissociating the speed of the obstacles from that of the treadmill onto which the cat is walking, our experimental protocol also allows us to increase the importance of visual information from the obstacles and to separate it from the influx of proprioceptive influx generated during locomotion. Our recordings revealed two groups of parietal cells on the basis of their activity in relation with the step over the obstacle: one population, mostly localized in area 5a, discharged solely as the lead forelimb passed over the obstacle (step-related cells), and another group, mainly found in area 5b, that showed significant activity at least one step cycle before the gait modification (step-advanced cells). Additionally, we observed an increase of cell activity in these groups, but particularly in step-advanced cells, when the speed of the obstacles was dissociated from that of the treadmill, demonstrating the growing importance of visual information as the task’s difficulty is increased. Finally, a great number of step-related cells were found to discharge specifically in correlation with muscle activity in the contralateral forelimb, regardless of whether or not it led over the obstacle (limb-specific cells). Inversely, the majority of step-advanced neurons tended to maintain their discharge in phase with the leading limb during the gait modification, independently of its position in relation with the recording site (limb-independent cells). We suggest that this additional disparity indicates diversified functions in PPC activity. For example, limb-specific cells could be involved in modulating the movement of the contralateral forelimb over the obstacle, regardless of its order of passage, while limb-independent neurons could instead specify the type of voluntary movement required to overcome the obstacle. Together, our observations indicate that the PPC can potentially influence the activity of motor centers through extensive cortical networks, and contributes to different aspects of visually-guided locomotion, such as initiation and modulation of voluntary forelimb movements, as well as the planning of these gait modifications to allow an individual to walk through a complex environment.