Développement d'un nouveau critère pour déterminer les limites d'utilisation des détecteurs en dosimétrie non standard

Depuis quelques années, il y a un intérêt de la communauté en dosimétrie d'actualiser les protocoles de dosimétrie des faisceaux larges tels que le TG-51 (AAPM) et le TRS-398 (IAEA) aux champs non standard qui requièrent un facteur de correction additionnel. Or, ces facteurs de correction sont difficiles à déterminer précisément dans un temps acceptable. Pour les petits champs, ces facteurs augmentent rapidement avec la taille de champ tandis que pour les champs d'IMRT, les incertitudes de positionnement du détecteur rendent une correction cas par cas impraticable. Dans cette étude, un critère théorique basé sur la fonction de réponse dosimétrique des détecteurs est développé pour déterminer dans quelles situations les dosimètres peuvent être utilisés sans correction. Les réponses de quatre chambres à ionisation, d'une chambre liquide, d'un détecteur au diamant, d'une diode, d'un détecteur à l'alanine et d'un détecteur à scintillation sont caractérisées à 6 MV et 25 MV. Plusieurs stratégies sont également suggérées pour diminuer/éliminer les facteurs de correction telles que de rapporter la dose absorbée à un volume et de modifier les matériaux non sensibles du détecteur pour pallier l'effet de densité massique. Une nouvelle méthode de compensation de la densité basée sur une fonction de perturbation est présentée. Finalement, les résultats démontrent que le détecteur à scintillation peut mesurer les champs non standard utilisés en clinique avec une correction inférieure à 1%.

Cell lines and animal model in the analysis of pharmacogenomics markers in childhood acute lymphoblastic leukemia

La leucémie aiguë lymphoblastique (LAL) est le cancer pédiatrique le plus fréquent. Elle est la cause principale de mortalité liée au cancer chez les enfants due à un groupe de patient ne répondant pas au traitement. Les patients peuvent aussi souffrir de plusieurs toxicités associées à un traitement intensif de chimiothérapie. Les études en pharmacogénétique de notre groupe ont montré une corrélation tant individuelle que combinée entre les variants génétiques particuliers d’enzymes dépendantes du folate, particulièrement la dihydrofolate réductase (DHFR) ainsi que la thymidylate synthase (TS), principales cibles du méthotrexate (MTX) et le risque élevé de rechute chez les patients atteints de la LAL. En outre, des variations dans le gène ATF5 impliqué dans la régulation de l’asparagine synthetase (ASNS) sont associées à un risque plus élevé de rechute ou à une toxicité ASNase dépendante chez les patients ayant reçu de l’asparaginase d’E.coli (ASNase). Le but principal de mon projet de thèse est de comprendre davantage d’un point de vue fonctionnel, le rôle de variations génétiques dans la réponse thérapeutique chez les patients atteints de la LAL, en se concentrant sur deux composants majeurs du traitement de la LAL soit le MTX ainsi que l’ASNase. Mon objectif spécifique était d’analyser une association trouvée dans des paramètres cliniques par le biais d’essais de prolifération cellulaire de lignées cellulaires lymphoblastoïdes (LCLs, n=93) et d’un modèle murin de xénogreffe de la LAL. Une variation génétique dans le polymorphisme TS (homozygosité de l’allèle de la répétition triple 3R) ainsi que l’haplotype *1b de DHFR (défini par une combinaison particulière d’allèle dérivé de six sites polymorphiques dans le promoteur majeur et mineur de DHFR) et de leurs effets sur la sensibilité au MTX ont été évalués par le biais d’essais de prolifération cellulaire. Des essais in vitro similaires sur la réponse à l’ASNase de E. Coli ont permis d’évaluer l’effet de la variation T1562C de la région 5’UTR de ATF5 ainsi que des haplotypes particuliers du gène ASNS (définis par deux variations génétiques et arbitrairement appelés haplotype *1). Le modèle murin de xénogreffe ont été utilisé pour évaluer l’effet du génotype 3R3R du gène TS. L’analyse de polymorphismes additionnels dans le gène ASNS a révélé une diversification de l’haplotype *1 en 5 sous-types définis par deux polymorphismes (rs10486009 et rs6971012,) et corrélé avec la sensibilité in vitro à l’ASNase et l’un d’eux (rs10486009) semble particulièrement important dans la réduction de la sensibilité in vitro à l’ASNase, pouvant expliquer une sensibilité réduite de l’haplotype *1 dans des paramètres cliniques. Aucune association entre ATF5 T1562C et des essais de prolifération cellulaire en réponse à ASNase de E.Coli n’a été détectée. Nous n’avons pas détecté une association liée au génotype lors d’analyse in vitro de sensibilité au MTX. Par contre, des résultats in vivo issus de modèle murin de xénogreffe ont montré une relation entre le génotype TS 3R/3R et la résistance de manière dose-dépendante au traitement par MTX. Les résultats obtenus ont permis de fournir une explication concernant un haut risque significatif de rechute rencontré chez les patients au génotype TS 3R/3R et suggèrent que ces patients pourraient recevoir une augmentation de leur dose de MTX. À travers ces expériences, nous avons aussi démontré que les modèles murins de xénogreffe peuvent servir comme outil préclinique afin d’explorer l’option d’un traitement individualisé. En conclusion, la connaissance acquise à travers mon projet de thèse a permis de confirmer et/ou d’identifier quelques variants dans la voix d’action du MTX et de l’ASNase qui pourraient faciliter la mise en place de stratégies d’individualisation de la dose, permettant la sélection d’un traitement optimum ou moduler la thérapie basé sur la génétique individuelle.

Leveraging noisy side information for disentangling of factors of variation in a supervised setting

Ce mémoire est composé de trois articles et présente les résultats de travaux de recherche effectués dans le but d'améliorer les techniques actuelles permettant d'utiliser des données associées à certaines tâches dans le but d'aider à l'entraînement de réseaux de neurones sur une tâche différente. Les deux premiers articles présentent de nouveaux ensembles de données créés pour permettre une meilleure évaluation de ce type de techniques d'apprentissage machine. Le premier article introduit une suite d'ensembles de données pour la tâche de reconnaissance automatique de chiffres écrits à la main. Ces ensembles de données ont été générés à partir d'un ensemble de données déjà existant, MNIST, auquel des nouveaux facteurs de variation ont été ajoutés. Le deuxième article introduit un ensemble de données pour la tâche de reconnaissance automatique d'expressions faciales. Cet ensemble de données est composé d'images de visages qui ont été collectées automatiquement à partir du Web et ensuite étiquetées. Le troisième et dernier article présente deux nouvelles approches, dans le contexte de l'apprentissage multi-tâches, pour tirer avantage de données pour une tâche donnée afin d'améliorer les performances d'un modèle sur une tâche différente. La première approche est une généralisation des neurones Maxout récemment proposées alors que la deuxième consiste en l'application dans un contexte supervisé d'une technique permettant d'inciter des neurones à apprendre des fonctions orthogonales, à l'origine proposée pour utilisation dans un contexte semi-supervisé.

Reliability of a quantitative clinical posture assessment tool among persons with idiopathic scoliosis

Objective To determine overall, test–retest and inter-rater reliability of posture indices among persons with idiopathic scoliosis. Design A reliability study using two raters and two test sessions. Setting Tertiary care paediatric centre. Participants Seventy participants aged between 10 and 20 years with different types of idiopathic scoliosis (Cobb angle 15 to 60°) were recruited from the scoliosis clinic. Main outcome measures Based on the XY co-ordinates of natural reference points (e.g. eyes) as well as markers placed on several anatomical landmarks, 32 angular and linear posture indices taken from digital photographs in the standing position were calculated from a specially developed software program. Generalisability theory served to estimate the reliability and standard error of measurement (SEM) for the overall, test–retest and inter-rater designs. Bland and Altman's method was also used to document agreement between sessions and raters. Results In the random design, dependability coefficients demonstrated a moderate level of reliability for six posture indices (ϕ = 0.51 to 0.72) and a good level of reliability for 26 posture indices out of 32 (ϕ ≥ 0.79). Error attributable to marker placement was negligible for most indices. Limits of agreement and SEM values were larger for shoulder protraction, trunk list, Q angle, cervical lordosis and scoliosis angles. The most reproducible indices were waist angles and knee valgus and varus. Conclusions Posture can be assessed in a global fashion from photographs in persons with idiopathic scoliosis. Despite the good reliability of marker placement, other studies are needed to minimise measurement errors in order to provide a suitable tool for monitoring change in posture over time.

Logique et Sémantique : Critique d’une interprétation non‐standard de la logique déontique

Ce texte porte sur l’analyse sémantique de la logique déontique. Nous analyserons de façon critique un texte de Schotch (1981) portant sur une interprétation de la logique déontique dans le cadre d’une sémantique non-kripkéenne. Nous laisserons de côté les choix relatifs à la syntaxe de son système afin de se concentrer sur l’analyse sémantique qu’il expose contre la logique déontique et sur celle qu’il propose en retour. Avant de voir le détail de son raisonnement, nous présenterons brièvement quelques notions de logique modale afin de faciliter la compréhension de l’argument de Schotch. Nous présenterons ensuite l’argument de l’auteur contre la logique déontique afin de pouvoir exposer sa solution, ce qui ouvrira la porte à une lecture critique de son analyse.

A fiber optic smart sensor for studying the setting characteristics of various grades of cement

A simple, effective and inexpensive fiber optic sensor for investigating the setting characteristics of various grades of cement is described. A finite length of unsheathed multimode optical fiber laid inside the cement mix, is subjected to stress during the setting process. The microbends created on the fiber due to this stress directly influence the intensity of light propagating through the fiber. Continuous monitoring of such variations in the light output transmitted through the fiber gives a clear measure of the setting characteristics of the cement mix, thus providing a simple and elegant technique of great practical importance in the field of civil engineering. The smart fiber optic sensor described above can be incorporated into a building during the construction process itself so that continuous monitoring of the deterioration process for the entire life time of the building can be carried out.

Decimation Filter Design Toolbox for Multi-Standard Wireless Transceivers using MATLAB.

The demand for new telecommunication services requiring higher capacities, data rates and different operating modes have motivated the development of new generation multi-standard wireless transceivers. A multi-standard design often involves extensive system level analysis and architectural partitioning, typically requiring extensive calculations. In this research, a decimation filter design tool for wireless communication standards consisting of GSM, WCDMA, WLANa, WLANb, WLANg and WiMAX is developed in MATLAB® using GUIDE environment for visual analysis. The user can select a required wireless communication standard, and obtain the corresponding multistage decimation filter implementation using this toolbox. The toolbox helps the user or design engineer to perform a quick design and analysis of decimation filter for multiple standards without doing extensive calculation of the underlying methods.

An efficient scheme for the evaluation of coding performance of high speed links incorporating joint error behaviour based on Monte Carlo Method

While channel coding is a standard method of improving a system’s energy efficiency in digital communications, its practice does not extend to high-speed links. Increasing demands in network speeds are placing a large burden on the energy efficiency of high-speed links and render the benefit of channel coding for these systems a timely subject. The low error rates of interest and the presence of residual intersymbol interference (ISI) caused by hardware constraints impede the analysis and simulation of coded high-speed links. Focusing on the residual ISI and combined noise as the dominant error mechanisms, this paper analyses error correlation through concepts of error region, channel signature, and correlation distance. This framework provides a deeper insight into joint error behaviours in high-speed links, extends the range of statistical simulation for coded high-speed links, and provides a case against the use of biased Monte Carlo methods in this setting

Matrix based Key Generation to Enhance Key Avalanche in Advanced Encryption Standard

In symmetric block ciphers, substitution and diffusion operations are performed in multiple rounds using sub-keys generated from a key generation procedure called key schedule. The key schedule plays a very important role in deciding the security of block ciphers. In this paper we propose a complex key generation procedure, based on matrix manipulations, which could be introduced in symmetric ciphers. The proposed key generation procedure offers two advantages. First, the procedure is simple to implement and has complexity in determining the sub-keys through crypt analysis. Secondly, the procedure produces a strong avalanche effect making many bits in the output block of a cipher to undergo changes with one bit change in the secret key. As a case study, matrix based key generation procedure has been introduced in Advanced Encryption Standard (AES) by replacing the existing key schedule of AES. The key avalanche and differential key propagation produced in AES have been observed. The paper describes the matrix based key generation procedure and the enhanced key avalanche and differential key propagation produced in AES. It has been shown that, the key avalanche effect and differential key propagation characteristics of AES have improved by replacing the AES key schedule with the Matrix based key generation procedure

Health, Education and Employment in a Forward-Backward Dichotomy Based on Standard of Living Index for the Tribes in Kerala

The Paper unfolds the paradox that exists in the tribal community with respect to the development indicators and hence tries to cull out the difference in the standard of living of the tribes in a dichotomous framework, forward and backward. Four variables have been considered for ascertaining the standard of living and socio-economic conditions of the tribes. The data for the study is obtained from a primary survey in the three tribal predominant districts of Wayanad, Idukki and Palakkad. Wayanad was selected for studying six tribal communities (Paniya, Adiya, Kuruma, Kurichya, Urali and Kattunaika), Idukki for two communities (Malayarayan and Muthuvan) and Palakkad for one community (Irula). 500 samples from 9 prominent tribal communities of Kerala have been collected according to multistage proportionate random sample framework. The analysis highlights the disproportionate nature of socio-economic indicators within the tribes in Kerala owing to the failure of governmental schemes and assistances meant for their empowerment. The socio-economic variables, such as education, health, and livelihood have been augmented with SLI based on correlation analysis gives interesting inference for policy options as high educated tribal communities are positively correlated with high SLI and livelihood. Further, each of the SLI variable is decomposed using Correlation and Correspondence analysis for understanding the relative standing of the nine tribal sub communities in the three dimensional framework of high, medium and low SLI levels. Tribes with good education and employment (Malayarayan, Kuruma and Kurichya) have a better living standard and hence they can generally be termed as forward tribes whereas those with a low or poor education, employment and living standard indicators (Paniya, Adiya, Urali, Kattunaika, Muthuvans and Irula) are categorized as backward tribes

Standard of Living and Community Perception in the Community Based Ecotourism (CBET) Sites of Kerala: An Inter Zone Analysis

This study is an attempt to situate the quality of life and standard of living of local communities in ecotourism destinations inter alia their perception on forest conservation and the satisfaction level of the local community. 650 EDC/VSS members from Kerala demarcated into three zones constitute the data source. Four variables have been considered for evaluating the quality of life of the stakeholders of ecotourism sites, which is then funneled to the income-education spectrum for hypothesizing into the SLI framework. Zone-wise analysis of the community members working in tourism sector shows that the community members have benefited totally from tourism development in the region as they have got both employments as well as secured livelihood options. Most of the quality of life-indicators of the community in the eco-tourist centres show a promising position. The community perception does not show any negative impact on environment as well as on their local culture.

Provenance, Isolation and Characterisation of Organic Matter in the Cochin Estuarine Sediment-“a Diagenetic Amino Acid Marker Scenario

Cochin estuarine system is among the most productive aquatic environment along the Southwest coast of India, exhibits unique ecological features and possess greater socioeconomic relevance. Serious investigations carried out during the past decades on the hydro biogeochemical variables pointed out variations in the health and ecological functioning of this ecosystem. Characterisation of organic matter in the estuary has been attempted in many investigations. But detailed studies covering the degradation state of organic matter using molecular level approach is not attempted. The thesis entitled Provenance, Isolation and Characterisation of Organic Matter in the Cochin Estuarine Sediment-“ A Diagenetic Amino Acid Marker Scenario” is an integrated approach to evaluate the source, quantity, quality, and degradation state of the organic matter in the surface sediments of Cochin estuarine system with the combined application of bulk and molecular level tools. Sediment and water samples from nine stations situated at Cochin estuary were collected in five seasonal sampling campaigns, for the biogeochemical assessment and their distribution pattern of sedimentary organic matter. The sampling seasons were described and abbreviated as follows: April- 2009 (pre monsoon: PRM09), August-2009 (monsoon: MON09), January-2010 (post monsoon: POM09), April-2010 (pre monsoon: PRM10) and September- 2012 (monsoon: MON12). In order to evaluate the general environmental conditions of the estuary, water samples were analysed for water quality parameters, chlorophyll pigments and nutrients by standard methods. Investigations suggested the fact that hydrographical variables and nutrients in Cochin estuary supports diverse species of flora and fauna. Moreover the sedimentary variables such as pH, Eh, texture, TOC, fractions of nitrogen and phosphorous were determined to assess the general geochemical setting as well as redox status. The periodically fluctuating oxic/ anoxic conditions and texture serve as the most significant variables controlling other variables of the aquatic environment. The organic matter in estuary comprise of a complex mixture of autochthonous as well as allochthonous materials. Autochthonous input is limited or enhanced by the nutrient elements like N and P (in their various fractions), used as a tool to evaluate their bioavailability. Bulk parameter approach like biochemical composition, stoichiometric elemental ratios and stable carbon isotope ratio was also employed to assess the quality and quantity of sedimentary organic matter in the study area. Molecular level charactersation of free sugars and amino acids were carried out by liquid chromatographic techniques. Carbohydrates are the products of primary production and their occurrence in sediments as free sugars can provide information on the estuarine productivity. Amino acid biogeochemistry provided implications on the system productivity, nature of organic matter as well as degradation status of the sedimentary organic matter in the study area. The predominance of carbohydrates over protein indicated faster mineralisation of proteinaceous organic matter in sediments and the estuary behaves as a detrital trap for the accumulation of aged organic matter. The higher lipid content and LPD/CHO ratio pointed towards the better food quality that supports benthic fauna and better accumulation of lipid compounds in the sedimentary environment. Allochthonous addition of carbohydrates via terrestrial run off was responsible for the lower PRT/CHO ratio estimated in thesediments and the lower ratios also denoted a detrital heterotrophic environment. Biopolymeric carbon and the algal contribution to BPC provided important information on the better understanding the trophic state of the estuarine system and the higher values of chlorophyll-a to phaeophytin ratio indicated deposition of phytoplankton to sediment at a rapid rate. The estimated TOC/TN ratios implied the combined input of both terrestrial and autochthonous organic matter to sedimentsAmong the free sugars, depleted levels of glucose in sediments in most of the stations and abundance of mannose at station S5 was observed during the present investigation. Among aldohexoses, concentration of galactose was found to be higher in most of the stationsRelative abundance of AAs in the estuarine sediments based on seasons followed the trend: PRM09-Leucine > Phenylalanine > Argine > Lysine, MON09-Lysine > Aspartic acid > Histidine > Tyrosine > Phenylalanine, POM09-Lysine > Histadine > Phenyalanine > Leucine > Methionine > Serine > Proline > Aspartic acid, PRM10-Valine > Aspartic acid > Histidine > Phenylalanine > Serine > Proline, MON12-Lysine > Phenylalanine > Aspartic acid > Histidine > Valine > Tyrsine > MethionineThe classification of study area into three zones based on salinity was employed in the present study for the sake of simplicity and generalized interpretations. The distribution of AAs in the three zones followed the trend: Fresh water zone (S1, S2):- Phenylalanine > Lysine > Aspartic acid > Methionine > Valine ῀ Leucine > Proline > Histidine > Glycine > Serine > Glutamic acid > Tyrosine > Arginine > Alanine > Threonine > Cysteine > Isoleucine. Estuarine zone (S3, S4, S5, S6):- Lysine > Aspartic acid > Phenylalanine > Leucine > Valine > Histidine > Methionine > Tyrosine > Serine > Glutamic acid > Proline > Glycine > Arginine > Alanine > Isoleucine > Cysteine > Threonine. Riverine /Industrial zone (S7, S8, S9):- Phenylalanine > Lysine > Aspartic acid > Histidine > Serine > Arginine > Tyrosine > Leucine > Methionine > Glutamic acid > Alanine > Glycine > Cysteine > Proline > Isoleucine > Threonine > Valine. The abundance of AAs like glutamic acid, aspartic acid, isoleucine, valine, tyrosine, and phenylalanine in sediments of the study area indicated freshly derived organic matter.

DNA methylation in Dictyostelium discoideum

DNA methyltransferases of type Dnmt2 are a highly conserved protein family with enigmatic function. The aim of this work was to characterize DnmA, the Dnmt2 methyltransferase in Dictyostelium discoideum, and further to investigate its implication in DNA methylation and transcriptional gene silencing. The genome of the social amoeba Dictyostelium encodes DnmA as the sole DNA methyltransferase. The enzyme bears all ten characteristic DNA methyltransferase motifs in its catalytic domain. The DnmA mRNA was found by RT-PCR to be expressed during vegetative growth and down regulated during development. Investigations using fluorescence microscopy showed that both DnmA-myc and DnmA-GFP fusions predominantly localised to the nucleus. The function of DnmA remained initially unclear, but later experiment revealed that the enzyme is an active DNA methyltransferase responsible for all DNA (cytosine) methylation in Dictyostelium. Neither in gel retardation assays, nor by the yeast two hybrid system, clues on the functionality of DnmA could be obtained. However, immunological detection of the methylation mark with an α - 5mC antibody gave initial evidence that the DNA of Dictyostelium was methylated. Furthermore, addition of 5-aza-cytidine as demethylating agent to the Dictyostelium medium and subsequent in vitro incubation of the DNA isolated from these cells with recombinant DnmA showed that the enzyme binds slightly better to this target DNA. In order to investigate further the function of the protein, a gene knock-out for dnmA was generated. The gene was successfully disrupted by homologous recombination, the knock-out strain, however, did not show any obvious phenotype under normal laboratory conditions. To identify specific target sequences for DNA methylation, a microarray analysis was carried out. Setting a threshold of at least 1.5 fold for differences in the strength of gene expression, several such genes in the knock-out strain were chosen for further investigation. Among the up-regulated genes were the ESTs representing the gag and the RT genes respectively of the retrotransposon skipper. In addition Northern blot analysis confirmed the up-regulation of skipper in the DnmA knock-out strain. Bisufite treatment and sequencing of specific DNA stretches from skipper revealed that DnmA is responsible for methylation of mostly asymmetric cytosines. Together with skipper, DIRS-1 retrotransposon was found later also to be methylated but was not present on the microarray. Furthermore, skipper transcription was also up-regulated in strains that had genes disrupted encoding components of the RNA interference pathway. In contrast, DIRS 1 expression was not affected by a loss of DnmA but was strongly increased in the strain that had the RNA directed RNA polymerase gene rrpC disrupted. Strains generated by propagating the usual wild type Ax2 and the DnmA knock-out cells over 16 rounds in development were analyzed for transposon activity. Northern blot analysis revealed activation for skipper expression, but not for DIRS-1. A large number of siRNAs were found to be correspondent to the DIRS-1 sequence, suggesting concerted regulation of DIRS-1 expression by RNAi and DNA methylation. In contrast, no siRNAs corresponding to the standard skipper element were found. The data show that DNA methylation plays a crucial role in epigenetic gene regulation in Dictyostelium and that different, partially overlapping mechanisms control transposon silencing for skipper and DIRS-1. To elucidate the mechanism of targeting the protein to particular genes in the Dictyostelium genome, some more genes which were up-regulated in the DnmA knock-out strain were analyzed by bisulfite sequencing. The chosen genes are involved in the multidrug response in other species, but their function in Dictyostelium is uncertain. Bisulfite data showed that two of these genes were methylated at asymmetrical C-residues in the wild type, but not in DnmA knock-out cells. This suggested that DNA methylation in Dictyostelium is involved not only in transposon regulation but also in transcriptional silencing of specific genes.

Macht das "Setting" den Unterschied?

Im Rahmen einer Voruntersuchung wird eine klassisch pflegeorientierte stationäre Altenpflegeeinrichtung mit einer am Konzept der alltagsnahen Normalität orientierten Einrichtung mit mehreren Wohngruppen verglichen. Daraus werden die Zusammenhänge von personellen, konzeptionellen und räumlichen Bedingungen verschiedener Pflegesettings und der Erhaltung von Selbsthilfefähigkeiten und Wohlfühlen der Bewohner abgeleitet.