Body mass index, cigarette smoking, and alcohol consumption and cancers of the oral cavity, pharynx, and larynx: modeling odds ratios in pooled case-control data.

Odds ratios for head and neck cancer increase with greater cigarette and alcohol use and lower body mass index (BMI; weight (kg)/height(2) (m(2))). Using data from the International Head and Neck Cancer Epidemiology Consortium, the authors conducted a formal analysis of BMI as a modifier of smoking- and alcohol-related effects. Analysis of never and current smokers included 6,333 cases, while analysis of never drinkers and consumers of < or =10 drinks/day included 8,452 cases. There were 8,000 or more controls, depending on the analysis. Odds ratios for all sites increased with lower BMI, greater smoking, and greater drinking. In polytomous regression, odds ratios for BMI (P = 0.65), smoking (P = 0.52), and drinking (P = 0.73) were homogeneous for oral cavity and pharyngeal cancers. Odds ratios for BMI and drinking were greater for oral cavity/pharyngeal cancer (P < 0.01), while smoking odds ratios were greater for laryngeal cancer (P < 0.01). Lower BMI enhanced smoking- and drinking-related odds ratios for oral cavity/pharyngeal cancer (P < 0.01), while BMI did not modify smoking and drinking odds ratios for laryngeal cancer. The increased odds ratios for all sites with low BMI may suggest related carcinogenic mechanisms; however, BMI modification of smoking and drinking odds ratios for cancer of the oral cavity/pharynx but not larynx cancer suggests additional factors specific to oral cavity/pharynx cancer.

Genetic association tests: a method for the joint analysis of family and case-control data.

With the trend in molecular epidemiology towards both genome-wide association studies and complex modelling, the need for large sample sizes to detect small effects and to allow for the estimation of many parameters within a model continues to increase. Unfortunately, most methods of association analysis have been restricted to either a family-based or a case-control design, resulting in the lack of synthesis of data from multiple studies. Transmission disequilibrium-type methods for detecting linkage disequilibrium from family data were developed as an effective way of preventing the detection of association due to population stratification. Because these methods condition on parental genotype, however, they have precluded the joint analysis of family and case-control data, although methods for case-control data may not protect against population stratification and do not allow for familial correlations. We present here an extension of a family-based association analysis method for continuous traits that will simultaneously test for, and if necessary control for, population stratification. We further extend this method to analyse binary traits (and therefore family and case-control data together) and accurately to estimate genetic effects in the population, even when using an ascertained family sample. Finally, we present the power of this binary extension for both family-only and joint family and case-control data, and demonstrate the accuracy of the association parameter and variance components in an ascertained family sample.

Probabilistic base calling of Solexa sequencing data.

BACKGROUND: Solexa/Illumina short-read ultra-high throughput DNA sequencing technology produces millions of short tags (up to 36 bases) by parallel sequencing-by-synthesis of DNA colonies. The processing and statistical analysis of such high-throughput data poses new challenges; currently a fair proportion of the tags are routinely discarded due to an inability to match them to a reference sequence, thereby reducing the effective throughput of the technology. RESULTS: We propose a novel base calling algorithm using model-based clustering and probability theory to identify ambiguous bases and code them with IUPAC symbols. We also select optimal sub-tags using a score based on information content to remove uncertain bases towards the ends of the reads. CONCLUSION: We show that the method improves genome coverage and number of usable tags as compared with Solexa's data processing pipeline by an average of 15%. An R package is provided which allows fast and accurate base calling of Solexa's fluorescence intensity files and the production of informative diagnostic plots.

Enhancing the vertical resolution of surface georadar data

There are far-reaching conceptual similarities between bi-static surface georadar and post-stack, "zero-offset" seismic reflection data, which is expressed in largely identical processing flows. One important difference is, however, that standard deconvolution algorithms routinely used to enhance the vertical resolution of seismic data are notoriously problematic or even detrimental to the overall signal quality when applied to surface georadar data. We have explored various options for alleviating this problem and have tested them on a geologically well-constrained surface georadar dataset. Standard stochastic and direct deterministic deconvolution approaches proved to be largely unsatisfactory. While least-squares-type deterministic deconvolution showed some promise, the inherent uncertainties involved in estimating the source wavelet introduced some artificial "ringiness". In contrast, we found spectral balancing approaches to be effective, practical and robust means for enhancing the vertical resolution of surface georadar data, particularly, but not exclusively, in the uppermost part of the georadar section, which is notoriously plagued by the interference of the direct air- and groundwaves. For the data considered in this study, it can be argued that band-limited spectral blueing may provide somewhat better results than standard band-limited spectral whitening, particularly in the uppermost part of the section affected by the interference of the air- and groundwaves. Interestingly, this finding is consistent with the fact that the amplitude spectrum resulting from least-squares-type deterministic deconvolution is characterized by a systematic enhancement of higher frequencies at the expense of lower frequencies and hence is blue rather than white. It is also consistent with increasing evidence that spectral "blueness" is a seemingly universal, albeit enigmatic, property of the distribution of reflection coefficients in the Earth. Our results therefore indicate that spectral balancing techniques in general and spectral blueing in particular represent simple, yet effective means of enhancing the vertical resolution of surface georadar data and, in many cases, could turn out to be a preferable alternative to standard deconvolution approaches.

Dihydroaeruginoic acid synthetase and pyochelin synthetase, products of the pchEF genes, are induced by extracellular pyochelin in Pseudomonas aeruginosa.

The siderophore pyochelin of Pseudomonas aeruginosa is derived from one molecule of salicylate and two molecules of cysteine. Two cotranscribed genes, pchEF, encoding peptide synthetases have been identified and characterized. pchE was required for the conversion of salicylate to dihydroaeruginoate (Dha), the condensation product of salicylate and one cysteine residue and pchF was essential for the synthesis of pyochelin from Dha. The deduced PchE (156 kDa) and PchF (197 kDa) proteins had adenylation, thiolation and condensation/cyclization motifs arranged as modules which are typical of those peptide synthetases forming thiazoline rings. The pchEF genes were coregulated with the pchDCBA operon, which provides enzymes for the synthesis (PchBA) and activation (PchD) of salicylate as well as a putative thioesterase (PchC). Expression of a translational pchE'-'lacZ fusion was strictly dependent on the PchR regulator and was induced by extracellular pyochelin, the end product of the pathway. Iron replete conditions led to Fur (ferric uptake regulator)-dependent repression of the pchE'-'lacZ fusion. A translational pchD'-'lacZ fusion was also positively regulated by PchR and pyochelin and repressed by Fur and iron. Thus, autoinduction by pyochelin (or ferric pyochelin) and repression by iron ensure a sensitive control of the pyochelin pathway in P. aeruginosa.

Fracture imaging within a granitic rock aquifer using multiple-offset single-hole and cross-hole GPR reflection data

The sparsely spaced highly permeable fractures of the granitic rock aquifer at Stang-er-Brune (Brittany, France) form a well-connected fracture network of high permeability but unknown geometry. Previous work based on optical and acoustic logging together with single-hole and cross-hole flowmeter data acquired in 3 neighbouring boreholes (70-100 m deep) has identified the most important permeable fractures crossing the boreholes and their hydraulic connections. To constrain possible flow paths by estimating the geometries of known and previously unknown fractures, we have acquired, processed and interpreted multifold, single- and cross-hole GPR data using 100 and 250 MHz antennas. The GPR data processing scheme consisting of timezero corrections, scaling, bandpass filtering and F-X deconvolution, eigenvector filtering, muting, pre-stack Kirchhoff depth migration and stacking was used to differentiate fluid-filled fracture reflections from source generated noise. The final stacked and pre-stack depth-migrated GPR sections provide high-resolution images of individual fractures (dipping 30-90°) in the surroundings (2-20 m for the 100 MHz antennas; 2-12 m for the 250 MHz antennas) of each borehole in a 2D plane projection that are of superior quality to those obtained from single-offset sections. Most fractures previously identified from hydraulic testing can be correlated to reflections in the single-hole data. Several previously unknown major near vertical fractures have also been identified away from the boreholes.

Characterization of an interaction between fetal hemoglobin and lipid A of LPS resulting in augmented induction of cytokine production in vivo and in vitro.

A previously described extract of sheep fetal liver was reported to reverse many of the cytokine changes associated with aging in mice, including an augmented spleen cell ConA-stimulated production of IL-4 and decreased production of IL-2. Similar effects were not seen with adult liver preparations. These changes were observed in various strains of mice, including BALB/c, DBA/2 and C57BL/6, using mice with ages ranging from 8 to 110 weeks. Preliminary characterization of this crude extract showed evidence for the presence of Hb gamma chain, as well as of lipid A of LPS. We show below that purified preparations of sheep fetal Hb, but not adult Hb, in concert with suboptimally stimulating doses of LPS (lipid A), cooperate in the regulation of production of a number of cytokines, including TNFalpha and IL-6, in vitro. Furthermore, isolated fresh spleen or peritoneal cells from animals treated in vivo with the same combination of Hb and LPS, showed an augmented capacity to produce these cytokines on further culture in vitro. Evidence was also obtained for a further interaction between CLP, LPS and fetal Hb itself in this augmented cytokine production. These data suggest that some of the functional activities in the fetal liver extract reported earlier can be explained in terms of a novel immunomodulatory role of a mixture of LPS (lipid A) and fetal Hb.

Umbilical venous concentrations of estradiol in infants with early-onset neonatal sepsis and chorioamnionitis.

Objective: Fetuses are exposed to high concentrations of estradiol due to placental production. Experimental data suggest that estradiol is an important modulator of the immune response. However, the role of estradiol in the pathogenesis of early-onset neonatal sepsis (EOS) is unknown. The purpose of this pilot study was to determine estradiol levels in umbilical venous blood of newborns with EOS or chorioamnionitis exposure. Methods: Estradiol concentrations were measured by enzyme immunoassay in 37 newborns with EOS, 37 newborns with chorioamnionitis and 37 controls matched for gestational age and gender. Results: Estradiol levels correlated with gestational age, birth weight, gender and mode of delivery (p < 0.05). Multivariate analysis revealed higher estradiol levels in the EOS than in the chorioamnionitis group (odds ratio 8.43, 95% CI 1.63-43.45, p = 0.01) with the highest levels in patients with proven bacteraemia (p = 0.02). No difference was found between the EOS and the control group. Exploratory analysis showed an association between lower estradiol levels and a longer duration of mechanical ventilation (n = 28, p = 0.02). Conclusions: Umbilical venous estradiol levels were similar in EOS compared to controls. Further investigation is needed to evaluate whether high estradiol levels in infants with chorioamnionitis increases the risk of developing EOS.

Adaptive tracking of EEG oscillations.

Neuronal oscillations are an important aspect of EEG recordings. These oscillations are supposed to be involved in several cognitive mechanisms. For instance, oscillatory activity is considered a key component for the top-down control of perception. However, measuring this activity and its influence requires precise extraction of frequency components. This processing is not straightforward. Particularly, difficulties with extracting oscillations arise due to their time-varying characteristics. Moreover, when phase information is needed, it is of the utmost importance to extract narrow-band signals. This paper presents a novel method using adaptive filters for tracking and extracting these time-varying oscillations. This scheme is designed to maximize the oscillatory behavior at the output of the adaptive filter. It is then capable of tracking an oscillation and describing its temporal evolution even during low amplitude time segments. Moreover, this method can be extended in order to track several oscillations simultaneously and to use multiple signals. These two extensions are particularly relevant in the framework of EEG data processing, where oscillations are active at the same time in different frequency bands and signals are recorded with multiple sensors. The presented tracking scheme is first tested with synthetic signals in order to highlight its capabilities. Then it is applied to data recorded during a visual shape discrimination experiment for assessing its usefulness during EEG processing and in detecting functionally relevant changes. This method is an interesting additional processing step for providing alternative information compared to classical time-frequency analyses and for improving the detection and analysis of cross-frequency couplings.

Improved segmentation of deep brain grey matter structures using magnetization transfer (MT) parameter maps.

Basal ganglia and brain stem nuclei are involved in the pathophysiology of various neurological and neuropsychiatric disorders. Currently available structural T1-weighted (T1w) magnetic resonance images do not provide sufficient contrast for reliable automated segmentation of various subcortical grey matter structures. We use a novel, semi-quantitative magnetization transfer (MT) imaging protocol that overcomes limitations in T1w images, which are mainly due to their sensitivity to the high iron content in subcortical grey matter. We demonstrate improved automated segmentation of putamen, pallidum, pulvinar and substantia nigra using MT images. A comparison with segmentation of high-quality T1w images was performed in 49 healthy subjects. Our results show that MT maps are highly suitable for automated segmentation, and so for multi-subject morphometric studies with a focus on subcortical structures.

Iron acquisition with the natural siderophore enantiomers pyochelin and enantio-pyochelin in Pseudomonas species.

The bacterial siderophore pyochelin is composed of salicylate and two cysteine-derived heterocycles, the second of which is modified by reduction and N-methylation during biosynthesis. In Pseudomonas aeruginosa, the first cysteine residue is converted to its D-isoform during thiazoline ring formation, whereas the second cysteine remains in its L-configuration. Stereochemistry is opposite in the Pseudomonas fluorescens siderophore enantio-pyochelin, in which the first ring originates from L-cysteine and the second ring from D-cysteine. Both siderophores promote growth of the producer organism during iron limitation and induce the expression of their biosynthesis genes by activating the transcriptional AraC-type regulator PchR. However, neither siderophore is functional as an iron carrier or as a transcriptional inducer in the other species, demonstrating that both processes are highly stereospecific. Stereospecificity of pyochelin/enantio-pyochelin-mediated iron uptake is ensured at two levels: (i) by the outer membrane siderophore receptors and (ii) by the cytosolic PchR regulators.

Multimodal MRI analysis of structural and functional networks in the human brain : application to two clinical studies : driving abilities under THC intoxication and early white matter changes in FXTAS

Les approches multimodales dans l'imagerie cérébrale non invasive sont de plus en plus considérées comme un outil indispensable pour la compréhension des différents aspects de la structure et de la fonction cérébrale. Grâce aux progrès des techniques d'acquisition des images de Resonance Magnetique et aux nouveaux outils pour le traitement des données, il est désormais possible de mesurer plusieurs paramètres sensibles aux différentes caractéristiques des tissues cérébraux. Ces progrès permettent, par exemple, d'étudier les substrats anatomiques qui sont à la base des processus cognitifs ou de discerner au niveau purement structurel les phénomènes dégénératifs et développementaux. Cette thèse met en évidence l'importance de l'utilisation d'une approche multimodale pour étudier les différents aspects de la dynamique cérébrale grâce à l'application de cette approche à deux études cliniques: l'évaluation structurelle et fonctionnelle des effets aigus du cannabis fumé chez des consommateurs réguliers et occasionnels, et l'évaluation de l'intégrité de la substance grise et blanche chez des jeunes porteurs de la prémutations du gène FMR1 à risque de développer le FXTAS (Fragile-X Tremor Ataxia Syndrome). Nous avons montré que chez les fumeurs occasionnels de cannabis, même à faible concentration du principal composant psychoactif (THC) dans le sang, la performance lors d'une tâche visuo-motrice est fortement diminuée, et qu'il y a des changements dans l'activité des trois réseaux cérébraux impliqués dans les processus cognitifs: le réseau de saillance, le réseau du contrôle exécutif, et le réseau actif par défaut (Default Mode). Les sujets ne sont pas en mesure de saisir les saillances dans l'environnement et de focaliser leur attention sur la tâche. L'augmentation de la réponse hémodynamique dans le cortex cingulaire antérieur suggère une augmentation de l'activité introspective. Une investigation des ef¬fets au niveau cérébral d'une exposition prolongée au cannabis, montre des changements persistants de la substance grise dans les régions associées à la mémoire et au traitement des émotions. Le niveau d'atrophie dans ces structures corrèle avec la consommation de cannabis au cours des trois mois précédant l'étude. Dans la deuxième étude, nous démontrons des altérations structurelles des décennies avant l'apparition du syndrome FXTAS chez des sujets jeunes, asymptomatiques, et porteurs de la prémutation du gène FMR1. Les modifications trouvées peuvent être liées à deux mécanismes différents. Les altérations dans le réseau moteur du cervelet et dans la fimbria de l'hippocampe, suggèrent un effet développemental de la prémutation. Elles incluent aussi une atrophie de la substance grise du lobule VI du cervelet et l'altération des propriétés tissulaires de la substance blanche des projections afférentes correspondantes aux pédoncules cérébelleux moyens. Les lésions diffuses de la substance blanche cérébrale peu¬vent être un marquer précoce du développement de la maladie, car elles sont liées à un phénomène dégénératif qui précède l'apparition des symptômes du FXTAS. - Multimodal brain imaging is becoming a leading tool for understanding different aspects of brain structure and function. Thanks to the advances in Magnetic Resonance imaging (MRI) acquisition schemes and data processing techniques, it is now possible to measure different parameters sensitive to different tissue characteristics. This allows for example to investigate anatomical substrates underlying cognitive processing, or to disentangle, at a pure structural level degeneration and developmental processes. This thesis highlights the importance of using a multimodal approach for investigating different aspects of brain dynamics by applying this approach to two clinical studies: functional and structural assessment of the acute effects of cannabis smoking in regular and occasional users, and grey and white matter assessment in young FMR1 premutation carriers at risk of developing FXTAS. We demonstrate that in occasional smokers cannabis smoking, even at low concentration of the main psychoactive component (THC) in the blood, strongly decrease subjects' performance on a visuo-motor tracking task, and globally alters the activity of the three brain networks involved in cognitive processing: the Salience, the Control Executive, and the Default Mode networks. Subjects are unable to capture saliences in the environment and to orient attention to the task; the increase in Hemodynamic Response in the Anterior Cingulate Cortex suggests an increase in self-oriented mental activity. A further investigation on long term exposure to cannabis, shows a persistent grey matter modification in brain regions associated with memory and affective processing. The degree of atrophy in these structures also correlates with the estimation of drug use in the three months prior the participation to the study. In the second study we demonstrate structural changes in young asymptomatic premutation carriers decades before the onset of FXTAS that might be related to two different mechanisms. Alteration of the cerebellar motor network and of the hippocampal fimbria/ fornix, may reflect a potential neurodevelopmental effect of the premutation. These include grey matter atrophy in lobule VI and modification of white matter tissue property in the corresponding afferent projections through the Middle Cerebellar Peduncles. Diffuse hemispheric white matter lesions that seem to appear closer to the onset of FXTAS and be related to a neurodegenerative phenomenon may mark the imminent onset of FXTAS.

Epidemiology of multiple congenital anomalies in Europe: a EUROCAT population-based registry study.

BACKGROUND: This study describes the prevalence, associated anomalies, and demographic characteristics of cases of multiple congenital anomalies (MCA) in 19 population-based European registries (EUROCAT) covering 959,446 births in 2004 and 2010. METHODS: EUROCAT implemented a computer algorithm for classification of congenital anomaly cases followed by manual review of potential MCA cases by geneticists. MCA cases are defined as cases with two or more major anomalies of different organ systems, excluding sequences, chromosomal and monogenic syndromes. RESULTS: The combination of an epidemiological and clinical approach for classification of cases has improved the quality and accuracy of the MCA data. Total prevalence of MCA cases was 15.8 per 10,000 births. Fetal deaths and termination of pregnancy were significantly more frequent in MCA cases compared with isolated cases (p < 0.001) and MCA cases were more frequently prenatally diagnosed (p < 0.001). Live born infants with MCA were more often born preterm (p < 0.01) and with birth weight < 2500 grams (p < 0.01). Respiratory and ear, face, and neck anomalies were the most likely to occur with other anomalies (34% and 32%) and congenital heart defects and limb anomalies were the least likely to occur with other anomalies (13%) (p < 0.01). However, due to their high prevalence, congenital heart defects were present in half of all MCA cases. Among males with MCA, the frequency of genital anomalies was significantly greater than the frequency of genital anomalies among females with MCA (p < 0.001). CONCLUSION: Although rare, MCA cases are an important public health issue, because of their severity. The EUROCAT database of MCA cases will allow future investigation on the epidemiology of these conditions and related clinical and diagnostic problems.

La gravimétrie expéditive appliquée à la recherche d'aquifères en zone aride. Cas de la nappe alluviale du Teloua (Agadez, Niger)

This paper illustrates the practicality and efficiency of gravimetry for aquifer prospecting in arid zones. Known for the long and tedious data-processing it requires, this method becomes expeditious when simplified as presented here. Its use is then fully justified in a survey of this kind. During the study of the Teloua alluvial aquifer (Agadez, Niger), several ancient channels were clearly and rapidly located. Comparison of the results obtained here with those from previous studies demonstrates anew that for comprehensive prospecting, several complementary geophysical methods should always be employed.