Sex difference and the role of leptin in the association between high-sensitivity C-reactive protein and adiposity in two different populations.

Elevated high-sensitivity C-reactive protein (hs-CRP) concentration is associated with an increased risk of cardiovascular disease but this association seems to be largely mediated via conventional cardiovascular risk factors. In particular, the association between hs-CRP and obesity has been extensively demonstrated and correlations are stronger in women than men. We used fractional polynomials-a method that allows flexible modeling of non linear relations-to investigate the dose/response mathematical relationship between hs-CRP and several indicators of adiposity in Caucasians (Switzerland) and Africans (Seychelles) surveyed in two population-based studies. This relationship was non-linear exhibiting a steeper slope for low levels of hs-CRP and a higher level in women. The observed sex difference in the relationship between hs-CRP and adiposity almost disappeared upon adjustment for leptin, suggesting that these sex differences might be partially mediated, by leptin. All these relationship were similar in Caucasians and Africans. This is the first report on a non-linear relation, stratified by gender, between hs-CRP and adiposity.

Detecting epistasis with restricted response patterns in pairs of biallelic loci.

Well-established examples of genetic epistasis between a pair of loci typically show characteristic patterns of phenotypic distributions in joint genotype tables. However, inferring epistasis given such data is difficult due to the lack of power in commonly used approaches, which decompose the epistatic patterns into main plus interaction effects followed by testing the interaction term. Testing additive-only or all terms may have more power, but they are sensitive to nonepistatic patterns. Alternatively, the epistatic patterns of interest can be enumerated and the best matching one is found by searching through the possibilities. Although this approach requires multiple testing correction over possible patterns, each pattern can be fitted with a regression model with just one degree of freedom and thus the overall power can still be high, if the number of possible patterns is limited. Here we compare the power of the linear decomposition and pattern search methods, by applying them to simulated data generated under several patterns of joint genotype effects with simple biological interpretations. Interaction-only tests are the least powerful; while pattern search approach is the most powerful if the range of possibilities is restricted, but still includes the true pattern.

Intraobserver and interobserver variability of ascending aorta diameter as assessed with ECG-gated MDCT: automatic versus manual measurements

Purpose: Recently morphometric measurements of the ascending aorta have been done with ECG-gated MDCT to help the development of future endovascular therapies (TCT) [1]. However, the variability of these measurements remains unknown. It will be interesting to know the impact of CAD (computer aided diagnosis) with automated segmentation of the vessel and automatic measurements of diameter on the management of ascending aorta aneurysms. Methods and Materials: Thirty patients referred for ECG-gated CT thoracic angiography (64-row CT scanner) were evaluated. Measurements of the maximum and minimum ascending aorta diameters were obtained automatically with a commercially available CAD and semi-manually by two observers separately. The CAD algorithms segment the iv-enhanced lumen of the ascending aorta into perpendicular planes along the centreline. The CAD then determines the largest and the smallest diameters. Both observers repeated the automatic measurements and the semimanual measurements during a different session at least one month after the first measurements. The Bland and Altman method was used to study the inter/intraobserver variability. A Wilcoxon signed-rank test was also used to analyse differences between observers. Results: Interobserver variability for semi-manual measurements between the first and second observers was between 1.2 to 1.0 mm for maximal and minimal diameter, respectively. Intraobserver variability of each observer ranged from 0.8 to 1.2 mm, the lowest variability being produced by the more experienced observer. CAD variability could be as low as 0.3 mm, showing that it can perform better than human observers. However, when used in nonoptimal conditions (streak artefacts from contrast in the superior vena cava or weak lumen enhancement), CAD has a variability that can be as high as 0.9 mm, reaching variability of semi-manual measurements. Furthermore, there were significant differences between both observers for maximal and minimal diameter measurements (p<0.001). There was also a significant difference between the first observer and CAD for maximal diameter measurements with the former underestimating the diameter compared to the latter (p<0.001). As for minimal diameters, they were higher when measured by the second observer than when measured by CAD (p<0.001). Neither the difference of mean minimal diameter between the first observer and CAD nor the difference of mean maximal diameter between the second observer and CAD was significant (p=0.20 and 0.06, respectively). Conclusion: CAD algorithms can lessen the variability of diameter measurements in the follow-up of ascending aorta aneurysms. Nevertheless, in non-optimal conditions, it may be necessary to correct manually the measurements. Improvements of the algorithms will help to avoid such a situation.

Attachment among Adoptive Families: Two Emipirical Studies in an International Context

The present dissertation analyzed the construct of attachment at different time points, specifically focusing on two phases of adoptive family life that have so far received little attention from investigators. Study 1 focused on the first months of adoption, and analyzed the development of the attachment relationship to new caregivers. The sample was composed of a small but homogeneous group (n=6) of Korean-born children, adopted by Italian parents. The Parent Attachment Diary (Dozier & Stovall, 1997) was utilized to assess the child's attachment behavior. We assessed these behavior for the first 3 months after placement into adoption. Results showed a double variability of attachment behavior: within subjects during the 3-months, and between subjects, with just half of the children developing a stable pattern of attachment. In order to test the growth trajectories of attachment behavior, Hierarchical Linear Models (Bryk & Raudenbush, 1992) were also applied, but no significant population trend was identified. Study 2 analyzed attachment among adoptees during the sensitive period of adolescence. Data was derived from an international collection (n= 104, from Belgium Italy, and Romania) of semi-structured clinical interviews (with adolescents and with their adoptive parents), as well as from questionnaires. The purpose of this study was to detect the role played by risk and protective factors on the adoptee's behavioral and socio-emotional outcomes. In addition, we tested the possible interactions between the different attachment representations within the adoptive family. Results showed that pre-adoptive risk predicted the adolescent's adjustment; however, parental representations constituted an important moderator of this relationship. Moreover, the adolescent's security of attachment partially mediated the relationship between age at placement and later behavioral problems. In conclusion, the two present attachment studies highlighted the notable rate of change of attachment behavior over time, which showed its underlying plasticity, and thus the possible reparatory value of the adoption practice. Since parents have been proven to play an important role, especially in adolescence, the post-adoption support acquires even more importance in order to help parents promoting a positive and stable relational environment over time. - L'objectif de cette thèse est de décrire la formation des relations d'attachement chez les enfants et les adolescents adoptés, lors de deux phases particulières de la vie de la famille adoptive, qui ont été relativement peu étudiées. L'Étude 1 analyse les premiers mois après l'adoption, avec le but de comprendre si, et comment, une relation d'attachement aux nouveaux parents se développe. L'échantillon est composé d'un petit groupe (n = 6) d'enfants provenant de Corée du Sud, adoptés par des parents Italiens. A l'aide du Parent Attachment Diary (Dozier & Stovall, 1997), des observations des comportements d'attachement de l'enfant ont été recueillies chaque jour au cours des 3 premiers mois après l'arrivée. Les résultats montrent une double variabilité des comportements d'attachement: au niveau inter- et intra-individuel ; au premier de ces niveaux, seuleme la moitié des enfants parvient à développer un pattern stable d'attachement ; au niveau intra-individuel, les trajectoires de développement des comportements d'attachement ont été testées à l'aide de Modèles Linéaires Hiérarchiques (Bryk et Raudenbush, 1992), mais aucune tendance significative n'a pu être révélée. L'Étude 2 vise à analyser l'attachement chez des enfants adoptés dans l'enfance, lors de la période particulièrement sensible de l'adolescence. Les données sont issues d'un base de données internationale (n = 104, Belgique, Italie et Roumanie), composée d' entretiens cliniques semi-structurées (auprès de l'adolescents et des ses parents adoptifs), ainsi que de questionnaires. Les analyses statistiques visent à détecter la présence de facteurs de risque et de protection relativement à l'attachement et aux problèmes de comportement de l'enfant adopté. En outre, la présence d'interactions entre les représentations d'attachement des membres de la famille adoptive est évaluée. Les résultats montrent que les risques associés à la période pré-adoptive prédisent la qualité du bien-être de l'adolescent, mais les représentations parentales constituent un modérateur important de cette relation. En outre, la sécurité de l'attachement du jeune adopté médiatise partiellement la relation entre l'âge au moment du placement et les problèmes de comportement lors de l'adolescence. En conclusion, à l'aide de multiples données relatives à l'attachement, ces deux études soulignent son évolution notable au fil du temps, ce qui sous-tend la présence d'une certaine plasticité, et donc la possible valeur réparatrice de la pratique de l'adoption. Comme les parents semblent jouer un rôle important de ce point de vue, surtout à l'adolescence, cela renforce la notion d'un soutien post-adoption, en vue d'aider les parents à la promotion d'un environnement relationnel favorable et stable. - Il presente lavoro è volto ad analizzare l'attaccamento durante le due fasi della vita della famiglia adottiva che meno sono state indagate dalla letteratura. Lo Studio 1 aveva l'obiettivo di analizzare i primi mesi che seguono il collocamento del bambino, al fine di capire se e come una relazione di attaccamento verso i nuovi genitori si sviluppa. Il campione è composto da un piccolo gruppo (n = 6) di bambini provenienti dalla Corea del Sud e adottati da genitori italiani. Attraverso il Parent Attachment Diary (Stovall e Dozier, 1997) sono stati osservati quotidianamente, e per i primi tre mesi, i comportamenti di attaccamento del bambino. I risultati hanno mostrato una duplice variabilità: a livello intraindividuale (nell'arco dei 3 mesi), ed interindividuale, poiché solo la metà dei bambini ha sviluppato un pattern stabile di attaccamento. Per verificare le traiettorie di sviluppo di tali comportamenti, sono stati applicati i Modelli Lineari Gerarchici (Bryk & Raudenbush, 1992), che però non hanno stimato una tendenza significativa all'interno della popolazione. Obiettivo dello Studio 2 è stato quello di esaminare l'attaccamento nelle famiglie i cui figli adottivi si trovavano nella delicata fase adolescenziale. I dati, provenienti da una raccolta internazionale (n = 104, Belgio, Italia e Romania), erano costituiti da interviste cliniche semi-strutturate (con gli adolescenti e i propri genitori adottivi) e da questionari. Le analisi hanno indagato il ruolo dei fattori di rischio sullo sviluppo socio-emotivo e sugli eventuali problemi comportamentali dei ragazzi. Inoltre, sono state esaminate le possibili interazioni tra le diverse rappresentazioni di attaccamento dei membri della famiglia adottiva. I risultati hanno mostrato che il rischio pre-adottivo predice l'adattamento dell'adolescente, sebbene le rappresentazioni genitoriali costituiscano un importante moderatore di questa relazione. Inoltre, la sicurezza dell'attaccamento dell'adolescente media parzialmente la relazione tra età al momento dell'adozione e problemi comportamentali in adolescenza. In conclusione, attraverso i molteplici dati relativi all'attaccamento, i due studi ne hanno evidenziato il cambiamento nel tempo, a riprova della sua plasticità, e pertanto sottolineano il possibile valore riparativo dell'adozione. Dal momento che i genitori svolgono un ruolo importante, soprattutto in adolescenza, il supporto nel post- adozione diventa centrale per aiutarli a promuovere un ambiente relazionale favorevole e stabile nel tempo.

Job Insecurity and the Timing of Parenthood: A Comparison between Eastern and Western Germany

This article contributes to the ongoing debate on the economic deter- minants of fertility behavior by addressing the role of job insecurity in couples' intentions concerning parenthood and its timing. It starts from the hypothesis that cultural values moderate individuals' reactions to job insecurity and the way it is related to family formation. With a systematic thematic content analysis of a set of semi-structured interviews with childless men and women around the age of 30 in eastern and western Germany, we are able to show that there are substantial dif- ferences in the consequences of job insecurity on intentions to have a first child. In western Germany, a relatively secure job career is expected to precede family formation, and this sequence of transitions is rather rigid, whereas in eastern Germany job security and family formation are thought of and practiced as parallel investments. We suggest that the lack of convergence in family formation patterns between eastern and western Germany after the unification of the country in 1990 is partially related to different attitudes toward job insecurity in the two contexts.

Accuracy profile validation of a new method for carbon monoxide measurement in the human blood using headspace-gas chromatography-mass spectrometry (HS-GC-MS).

The aim of our study was to provide an innovative headspace-gas chromatography-mass spectrometry (HS-GC-MS) method applicable for the routine determination of blood CO concentration in forensic toxicology laboratories. The main drawback of the GC/MS methods discussed in literature for CO measurement is the absence of a specific CO internal standard necessary for performing quantification. Even if stable isotope of CO is commercially available in the gaseous state, it is essential to develop a safer method to limit the manipulation of gaseous CO and to precisely control the injected amount of CO for spiking and calibration. To avoid the manipulation of a stable isotope-labeled gas, we have chosen to generate in a vial in situ, an internal labeled standard gas ((13)CO) formed by the reaction of labeled formic acid formic acid (H(13)COOH) with sulfuric acid. As sulfuric acid can also be employed to liberate the CO reagent from whole blood, the procedure allows for the liberation of CO simultaneously with the generation of (13)CO. This method allows for precise measurement of blood CO concentrations from a small amount of blood (10 μL). Finally, this method was applied to measure the CO concentration of intoxicated human blood samples from autopsies.

Lifelong dynamics of human CD4+CD25+ regulatory T cells: insights from in vivo data and mathematical modeling.

Despite their limited proliferation capacity, regulatory T cells (T(regs)) constitute a population maintained over the entire lifetime of a human organism. The means by which T(regs) sustain a stable pool in vivo are controversial. Using a mathematical model, we address this issue by evaluating several biological scenarios of the origins and the proliferation capacity of two subsets of T(regs): precursor CD4(+)CD25(+)CD45RO(-) and mature CD4(+)CD25(+)CD45RO(+) cells. The lifelong dynamics of T(regs) are described by a set of ordinary differential equations, driven by a stochastic process representing the major immune reactions involving these cells. The model dynamics are validated using data from human donors of different ages. Analysis of the data led to the identification of two properties of the dynamics: (1) the equilibrium in the CD4(+)CD25(+)FoxP3(+)T(regs) population is maintained over both precursor and mature T(regs) pools together, and (2) the ratio between precursor and mature T(regs) is inverted in the early years of adulthood. Then, using the model, we identified three biologically relevant scenarios that have the above properties: (1) the unique source of mature T(regs) is the antigen-driven differentiation of precursors that acquire the mature profile in the periphery and the proliferation of T(regs) is essential for the development and the maintenance of the pool; there exist other sources of mature T(regs), such as (2) a homeostatic density-dependent regulation or (3) thymus- or effector-derived T(regs), and in both cases, antigen-induced proliferation is not necessary for the development of a stable pool of T(regs). This is the first time that a mathematical model built to describe the in vivo dynamics of regulatory T cells is validated using human data. The application of this model provides an invaluable tool in estimating the amount of regulatory T cells as a function of time in the blood of patients that received a solid organ transplant or are suffering from an autoimmune disease.

The average inter-crossing number of equilateral random walks and polygons

In this paper, we study the average inter-crossing number between two random walks and two random polygons in the three-dimensional space. The random walks and polygons in this paper are the so-called equilateral random walks and polygons in which each segment of the walk or polygon is of unit length. We show that the mean average inter-crossing number ICN between two equilateral random walks of the same length n is approximately linear in terms of n and we were able to determine the prefactor of the linear term, which is a = (3 In 2)/(8) approximate to 0.2599. In the case of two random polygons of length n, the mean average inter-crossing number ICN is also linear, but the prefactor of the linear term is different from that of the random walks. These approximations apply when the starting points of the random walks and polygons are of a distance p apart and p is small compared to n. We propose a fitting model that would capture the theoretical asymptotic behaviour of the mean average ICN for large values of p. Our simulation result shows that the model in fact works very well for the entire range of p. We also study the mean ICN between two equilateral random walks and polygons of different lengths. An interesting result is that even if one random walk (polygon) has a fixed length, the mean average ICN between the two random walks (polygons) would still approach infinity if the length of the other random walk (polygon) approached infinity. The data provided by our simulations match our theoretical predictions very well.

Regional abundance of on-premise outlets and drinking patterns among Swiss young men: District level analyses and geographic adjustments.

INTRODUCTION AND AIMS: This study investigated the associations of alcohol outlet density with specific alcohol outcomes (consumption and consequences) among young men in Switzerland and assessed the possible geographically related variations. DESIGN AND METHODS: Alcohol consumption and drinking consequences were measured in a 2010-2011 study assessing substance use risk factors (Cohort Study on Substance Use Risk Factors) among 5519 young Swiss men. Outlet density was based on the number of on- and off-premise outlets in the district of residence. Linear regression models were run separately for drinking level, heavy episodic drinking (HED) and drinking consequences. Geographically weighted regression models were estimated when variations were recorded at the district level. RESULTS: No consistent association was found between outlet density and drinking consequences. A positive association between drinking level and HED with on-premise outlet density was found. Geographically weighted regressions were run for drinking level and HED. The predicted values for HED were higher in the southwest part of Switzerland (French-speaking part). DISCUSSION AND CONCLUSIONS: Among Swiss young men, the density of outlets and, in particular, the abundance of bars, clubs and other on-premise outlets was associated with drinking level and HED, even when drinking consequences were not significantly affected. These findings support the idea that outlet density needs to be considered when developing and implementing regional-based prevention initiatives. [Astudillo M, Kuendig H, Centeno-Gil A, Wicki M, Gmel G. Regional abundance of on-premise outlets and drinking patterns among Swiss young men: District level analyses and geographic adjustments. Drug Alcohol Rev 2014;33:526-33].

Tightness of random knotting.

Long polymers in solution frequently adopt knotted configurations. To understand the physical properties of knotted polymers, it is important to find out whether the knots formed at thermodynamic equilibrium are spread over the whole polymer chain or rather are localized as tight knots. We present here a method to analyze the knottedness of short linear portions of simulated random chains. Using this method, we observe that knot-determining domains are usually very tight, so that, for example, the preferred size of the trefoil-determining portions of knotted polymer chains corresponds to just seven freely jointed segments.

Motivating Employees of the Public Sector: Does Public Service Motivation Matter?

This article analyzes if, and to what extent, the public service motivation (PSM) construct has an added value to explain work motivation in the public sector. In order to address the specificity of PSM when studying work motivation, the theoretical model underlying this empirical study compares PSM with two other explanatory factors: material incentives, such as performance-related pay, and team relations and support, such as recognition by superiors. This theoretical model is then tested with data collected in a national survey of 3,754 civil servants at the Swiss municipal level. Results of a structural equations model clearly show the relevance of PSM. They also provide evidence for the importance of socio-relational motivating factors, whereas material incentives play an anecdotal role.

Genometrics as an essential tool for the assembly of whole genome sequences: the example of the chromosome of Bifidobacterium longum NCC2705.

BACKGROUND: Analysis of the first reported complete genome sequence of Bifidobacterium longum NCC2705, an actinobacterium colonizing the gastrointestinal tract, uncovered its proteomic relatedness to Streptomyces coelicolor and Mycobacterium tuberculosis. However, a rapid scrutiny by genometric methods revealed a genome organization totally different from all so far sequenced high-GC Gram-positive chromosomes. RESULTS: Generally, the cumulative GC- and ORF orientation skew curves of prokaryotic genomes consist of two linear segments of opposite slope: the minimum and the maximum of the curves correspond to the origin and the terminus of chromosome replication, respectively. However, analyses of the B. longum NCC2705 chromosome yielded six, instead of two, linear segments, while its dnaA locus, usually associated with the origin of replication, was not located at the minimum of the curves. Furthermore, the coorientation of gene transcription with replication was very low. Comparison with closely related actinobacteria strongly suggested that the chromosome of B. longum was misassembled, and the identification of two pairs of relatively long homologous DNA sequences offers the possibility for an alternative genome assembly proposed here below. By genometric criteria, this configuration displays all of the characters common to bacteria, in particular to related high-GC Gram-positives. In addition, it is compatible with the partially sequenced genome of DJO10A B. longum strain. Recently, a corrected sequence of B. longum NCC2705, with a configuration similar to the one proposed here below, has been deposited in GenBank, confirming our predictions. CONCLUSION: Genometric analyses, in conjunction with standard bioinformatic tools and knowledge of bacterial chromosome architecture, represent fast and straightforward methods for the evaluation of chromosome assembly.

The expansion of 300 CTG repeats in myotonic dystrophy transgenic mice does not induce sensory or motor neuropathy.

Although many studies have been carried out to verify the involvement of the peripheral nervous system (PNS) in dystrophia myotonica (DM1) patients, the results remain controversial. The generation of DM1 transgenic mice displaying the human DM1 phenotype provides a useful tool to investigate the type and incidence of structural abnormalities in the PNS. In the present study, the morphological and morphometric analysis of semi-thin sections of sciatic and sural nerves, lumbar dorsal root ganglia (DRG) and lumbar spinal cords revealed that in DM1 transgenic mice carrying 300 CTG repeats, there is no change in the number and diameter of myelinated axons compared to wild type. Only a non-significant reduction in the percentage of thin myelinated axons was detected in electron micrographs of ultra-thin sciatic nerve sections. Analysis of the number of neurons did not reveal a loss in number of either sensory neurons in the lumbar DRG or motor neurons in the lumbar spinal cord in these DM1 mice. Furthermore, in hind limb muscle sections, stained with a neurofilament antibody and alpha-bungarotoxin, the intramuscular axon arborization appeared normal in DM1 mice and undistinguishable from that in wild-type mice. Moreover, in DM1 mice, there was no irregularity in the structure or an increase in the endplate area. Also statistical analysis did not show an increase in endplate density or in the concentration of acetylcholine receptors. Altogether, these results suggest that 300 CTG repeats are not sufficient to induce axonopathy, demyelination or neuronopathies in this transgenic mouse model.

Expression of apoptosis and survival genes in human memory T cell populations

RESUME Introduction: Les cellules T mémoires humaines sont classées en trois sous-populations sur la base de l'expression d'un marqueur de surface cellulaire, CD45RA, et du récepteur aux chimiokines, CCR7. Ces sous-populations, nommées cellules mémoires centrales (TcM), mémoires effectrices (TEM) et mémoires effectrices terminales (ITEM), ont des rôles fonctionnels distincts, ainsi que des capacités de prolifération et de régénération différentes. Cependant, la génération de ces différences reste encore mal comprise et on ignore les mécanismes moléculaires impliqués. Matériaux et Méthodes: Des cellules mononucléaires humaines du sang périphérique ont été séparées par cytométrie de flux selon leur expression de CD4, CD8, CD45RA et CCR7 en sous-populations de cellules CD4+ ou CD8+ naïves, TcM, TEM ou ITEM. Dans chacune de ces sous-populations, 14 gènes impliqués dans l'apoptose, la survie ou la capacité proliférative des cellules T ont été quantifiés par RT-PCR en temps réel, relativement à l'expression d'un gène de référence endogène. L'ARN provenant de 450 cellules T a été utilisé par gène et par sous-population. Les gènes analysés (cibles) comprenaient des gènes de survie (BAFF, APRIL, BAFF-R, BCMA, TACI, IL-15Rα, IL-7Rα), des gènes anti-apoptotiques (Bcl-2, BclxL, FLIP), des gènes pro-apoptotiques (Bad, Bax, Fast) et le gène anti-prolifératif, Tob. A l'aide de la méthode comparative delta-delta-CT, le taux d'expression des gènes cibles de chaque sous-population des cellules T mémoires CD4+ et CD8+, à été comparée à leur taux d'expression dans les cellules T naïves CD4+ et CD8+. Résultats: Dans les cellules CD8+, les gènes pro-apoptotiques Bax et Fast étaient surexprimés dans toutes les sous-populations mémoires, tandis que l'expression des facteurs anti-apoptotiques et de survie comme Bcl-2, APRIL et BAFF-R, étaient diminués. Ces deux tendances étaient particulièrement accentuées dans les sous-groupes des cellules mémoires TEM et TTEM. A noter que malgré le fait que leur expression était également diminuée dans les autres cellules mémoires, le facteur de survie IL-7Ra, était sélectivement surexprimé dans la sous-population de cellules TcM et l'expression d'IL-15Ra était sélectivement augmentée dans les TEM. Dans les cellules CD4+, le taux d'expression des gènes analysés était plus variable entre les sujets étudiés que dans les cellules CD8+, ne permettant pas de définir un profil d'expression spécifique. L'expression du gène de survie BAFF par contre, a été significativement augmentée dans toutes les sous-populations mémoire CD4+. Il en va de même pour l'expression d' APRIL et de BAFF-R, bien que dans moindre degré. A remarquer que l'expression du facteur anti-apoptotique Fast a été observée uniquement dans la souspopulation des TTEM. Discussion et Conclusions: Cette étude montre une nette différence entre les cellules CD8+ et CD4+, en ce qui concerne les profils d'expression des gènes impliqués dans la survie et l'apoptose des cellules T mémoires. Ceci pourrait impliquer une régulation cellulaire homéostatique distincte dans ces deux compartiments de cellules T mémoires. Dans les cellules CD8+ l'expression d'un nombre de gènes impliqués dans la survie et la protection de l'apoptose semblerait être diminuée dans les populations TEM et TTEM en comparaison à celle des sous-populations naïves et TEM, tandis que l'expression des gènes pro-apoptotiques semblerait être augmentée. Comme ceci paraît être plus accentué dans les TTEM, cela pourrait indiquer une plus grande disposition à l'apopotose dans les populations CCR7- (effectrices) et une perte de survie parallèlement à l'acquisition de capacités effectrices. Ceci parlerait en faveur d'un modèle de différentiation linéaire dans les cellules CD8+. De plus, l'augmentation sélective de l'expression d'IL-7Ra observée dans le sous-groupe de cellules mémoires TEM, et d'IL-15Ra dans celui des TEM, pourrait indiquer un moyen de sélection pour des réponses immunitaires mémoires à long terme par une réponse distincte à ces cytokines. Dans les cellules CD4+ par contre, aucun profil d'expression n'a pu être déterminé; les résultats suggèrent même une résistance relative à l'apoptose de la part des cellules mémoires. Ceci pourrait favoriser l'existence d'un modèle de différentiation plus flexible avec des possibilités d'interaction multiples. Ainsi, la surexpression sélective de BAFF, APRIL et BAFF-R dans les sous-populations individuelles des cellules mémoires pourrait être un indice de l'interaction de ces sous-groupes avec des cellules B. ABSTRACT Introduction: Based on their surface expression of the CD45 isoform and of the CCR7 chemokine receptor, memory T cells have been divided into the following three subsets: central memory (TAM), effector memory (TEM) and terminal effector memory (ITEM). Distinct functional roles and different proliferative and regenerative capacities have been attributed to each one of these subpopulations. The molecular mechanisms underlying these differences; however, remain poorly understood. Materials and Methods: According to their expression of CD4, CD8, CD45RA and CCR7, human peripheral blood mononuclear cells were sorted by flow-cytometry into CD4+ or CD8+ naïve, TAM, TEM and ITEM subsets. Using real-time PCR, the expression of 14 genes known to be involved in apoptotis, survival or proliferation of T cells was quantified separately in each individual subset, relative to an endogenous reference gene. The RNA equivalent of 450 T cells was used for each gene and subset. The target gene panel included the survival genes BAFF, APRIL, BAFF-R, BCMA, TACI, IL-15Rα and IL-7Rα, the anti-apoptotic genes Bcl2, Bcl-xL and FLIP, the pro-apoptotic genes Bad, Bax and Fast, as well as the antiproliferative gene Tob. Using the comparative CT-method, the expression of the target genes in the three memory T cell subsets of both CD4+ and CD8+ T cell populations was compared to their expression in the naïve T cells. Results: In CD8+ cells, the pro-apoptotic factors Bax and Fast were found to be upregulated in all memory T cell subsets, whereas the survival and anti-apoptotic factors Bcl-2, APRIL and BAFF-R were downregulated. These tendencies were most accentuated in TEM and TTEM subsets. Even though the survival factor IL-7Rα was also downregulated in these subsets, interestingly, it was selectively upregulated in the CD8+ TAM subset. Similarly, IL-15Rαexpression was shown to be selectively upregulated in the CD8+ TEM subset. In CD4+ cells, the expression levels of the analyzed genes showed a greater inter-individual variability than in CD8+ cells, thus suggesting the absence of any particular expression pattern for CD4+ memory T cells. However, the survival factor BAFF was found to be significantly upregulated in all CD4+ memory T cell subsets, as was also the expression of APRIL and BAFF-R, although to a lesser extent. Furthermore, it was noted that the pro-apoptotic gene Fast was only expressed in the TTEM CD4+ subset. Discussion and Conclusions: Genes involved in apoptosis and survival in human memory T cells have been shown to be expressed differently in CD8+ cells as compared to CD4+ cells, suggesting a distinct regulation of cell homeostasis in these two memory T cell compartments. The present study suggests that, in CD8+ T cells, the expression of various survival and antiapoptotic genes is downregulated in TEM and TTEM subsets, while the expression of proapoptotic genes is upregulated in comparison to the naïve and the TAM populations. These characteristics, potentially translating to a greater susceptibility to apoptosis in the CCR7- (effector) memory populations, are accentuated in the TTEM population, suggesting a loss of survival in parallel to the acquisition of effector capacities. This speaks in favour of a linear differentiation model in CD8+ T memory cells. Moreover, the observed selectively increased expression of IL-7Rα in CD8+ TAM cells - as that of IL-15Rα in CD8+ TEM cells -suggest that differential responsiveness to cytokines could confer a selection bias for distinct long-term memory cell responses. Relative to the results for CD8+ T cells, those for CD4+ T cells seem to indicate a certain resistance of the memory subsets to apoptosis, suggesting the possibility of a more flexible differentiation model with multiple checkpoints and potential interaction of CD4+ memory cells with other cells. Thus, the selective upregulation of BAFF, APRIL and BAFF-R in individual memory subsets could imply an interaction of these subsets with B cells.

Impact of different adiposity measures on the relation between serum uric acid and blood pressure in young adults.

Serum uric acid (SUA) concentration is independently associated with blood pressure (BP) in adults. We examined this association in young adults at an age where anti-hypertension treatment, other potential confounding factors and co-morbidity are unlikely to occur. We assessed BP, anthropometric variables including weight, height, waist circumference (WC), body fat percent (using bioimpedance), lifestyle behaviors, SUA and blood lipids in 549 participants aged 19-20 years from a population-based cohort study (Seychelles Child Development Study). Mean (s.d.) SUA was higher in males than females, 0.33 (0.08) and 0.24 (0.07) mmol l(-1), respectively. Body mass index (BMI) was higher in females than males but BP was markedly higher in males than in females. SUA was associated with both systolic and diastolic BP. However, the magnitude of the linear regression coefficients relating BP and SUA decreased by up to 50% upon adjustment for BMI, WC or body fat percent. The association between SUA and BP was not altered upon further adjustment for alcohol intake, smoking, triglycerides or renal function. In fully adjusted models, SUA remained associated with BP (P<0.05) in females. In conclusion, adiposity substantially decreased the association between SUA and BP in young adults, and BP was independently associated with SUA in females. These findings suggest a role of adiposity in the link between hyperuricemia and hypertension.