Sélection et suivi prétransplantation des patients candidats à la greffe cardiaque en Suisse romande [Selection and preoperative follow-up of heart transplantation candidates in the French part of Switzerland].

Heart transplantation (HTx) started in 1987 at two university hospitals (CHUV, HUG) in the western part of Switzerland, with 223 HTx performed at the CHUV until December 2010. Between 1987 and 2003, 106 HTx were realized at the HUG resulting in a total of 329 HTx in the western part of Switzerland. After the relocation of organ transplantation activity in the western part of Switzerland in 2003, the surgical part and the early postoperative care of HTx remained limited to the CHUV. However, every other HTx activity are pursued at the two university hospitals (CHUV, HUG). This article summarizes the actual protocols for selection and pre-transplant follow-up of HTx candidates in the western part of Switzerland, permitting a uniform structure of pretransplant follow-up in the western part of Switzerland.

An adult thymic stromal-cell suspension model for in vitro positive selection.

Presented here is a cell-suspension model for positive selection using thymocytes from alphabeta-TCR (H-2Db-restricted) transgenic mice specific to the lymphocytic choriomeningitis virus (LCMV) on a nonselecting MHC background (H-2d or TAP-1 -/-), cocultured with freshly isolated adult thymus stromal cells of the selecting MHC type. The thymic stromal cells alone induced positive selection of functional CD4- CD8+ cells whose kinetics and efficiency were enhanced by nominal peptide. Fibroblasts expressing the selecting MHC alone did not induce positive selection; however, together with nonselecting stroma and nominal peptide, there was inefficient positive. These results suggest multiple signaling in positive selection with selection events able to occur on multiple-cell types. The ease with which this model can be manipulated should greatly facilitate the resolution of the mechanisms of positive selection in normal and pathological states.

A limited role for beta-selection during gamma delta T cell development.

T cells belong to two distinct lineages expressing either alpha beta or gamma delta TCR. During alpha beta T cell development, it is clearly established that productive rearrangement at the TCR beta locus in immature precursor cells leads to the expression of a pre-TCR complex. Signaling through the pre-TCR results in the selective proliferation and maturation of TCR beta+ cells, a process that is known as beta-selection. However, the potential role of beta-selection during gamma delta T cell development is controversial. Whereas PCR-RFLP and sequencing techniques have provided evidence for a bias toward in-frame VDJ beta rearrangements in gamma delta cells (consistent with beta-selection), gamma delta cells apparently develop normally in mice that are unable to assemble a pre-TCR complex due to a deficiency in TCR beta or pT alpha genes. In this report, we have directly addressed the physiologic significance of beta-selection during gamma delta cell development in normal mice by quantitating intracellular TCR beta protein in gamma delta cells and correlating its presence with cell cycle status. Our results indicate that beta-selection plays a significant (although limited) role in gamma delta cell development by selectively amplifying a minor subset of gamma delta precursor cells with productively rearranged TCR beta genes.

Designing phase III or IV trials for vaccines: choosing between individual or cluster randomised trial designs.

The choice of design between individual randomisation, cluster or pseudo-cluster randomisation is often made difficult. Clear methodological guidelines have been given for trials in general practice, but not for vaccine trials. This article proposes a decisional flow-chart to choose the most adapted design for evaluating the effectiveness of a vaccine in large-scale studies. Six criteria have been identified: importance of herd immunity or herd protection, ability to delimit epidemiological units, homogeneity of transmission probability across sub-populations, population's acceptability of randomisation, availability of logistical resources, and estimated sample size. This easy to use decisional method could help sponsors, trial steering committees and ethical committees adopt the most suitable design.

The automatic selection of ventilation parameters during the initial phase of mechanical ventilation.

OBJECTIVE: To test a method that allows automatic set-up of the ventilator controls at the onset of ventilation. DESIGN: Prospective randomized crossover study. SETTING: ICUs in one adult and one children's hospital in Switzerland. PATIENTS: Thirty intubated stable, critically ill patients (20 adults and 10 children). INTERVENTIONS: The patients were ventilated during two 20-min periods using a modified Hamilton AMADEUS ventilator. During the control period the ventilator settings were chosen immediately prior to the study. During the other period individual settings were automatically determined by the ventilatior (AutoInit). MEASUREMENTS AND RESULTS: Pressure, flow, and instantaneous CO2 concentration were measured at the airway opening. From these measurements, series dead space (V(DS)), expiratory time constant (RC), tidal volume (VT, total respiratory frequency (f(tot), minute ventilation (MV), and maximal and mean airway pressure (Paw, max and Paw, mean) were calculated. Arterial blood gases were analyzed at the end of each period. Paw, max was significantly less with the AutoInit ventilator settings while f(tot) was significantly greater (P < 0.05). The other values were not statistically significant. CONCLUSIONS: The AutoInit ventilator settings, which were automatically derived, were acceptable for all patients for a period of 20 min and were not found to be inferior to the control ventilator settings. This makes the AutoInit method potentially useful as an automatic start-up procedure for mechanical ventilation.

Monoclonal antibodies to carcinoembryonic antigen: ionic strength as a factor in the selection of antibodies for immunoscintigraphy.

As part of an ongoing effort to improve the technique of immunoscintigraphy for the detection of human carcinomas with radiolabeled monoclonal antibodies (MABs) to carcinoembryonic antigen (CEA), we have developed a series of MABs to CEA and have studied the effects of low- and physiological molarity buffers on their CEA binding and affinity, as well as their cross-reactivity with granulocyte glycoprotein(s). These in vitro results in different buffer systems were then correlated with the use of these MABs to CEA in the detection of human colon carcinoma grafts in nude mice. Our results show that the binding of CEA by some MABs is influenced by ionic strength and that this may be an important factor in their successful use for the immunolocalization of carcinomas in vivo.

Time Series Input Selection using Multiple Kernel Learning

In this paper we study the relevance of multiple kernel learning (MKL) for the automatic selection of time series inputs. Recently, MKL has gained great attention in the machine learning community due to its flexibility in modelling complex patterns and performing feature selection. In general, MKL constructs the kernel as a weighted linear combination of basis kernels, exploiting different sources of information. An efficient algorithm wrapping a Support Vector Regression model for optimizing the MKL weights, named SimpleMKL, is used for the analysis. In this sense, MKL performs feature selection by discarding inputs/kernels with low or null weights. The approach proposed is tested with simulated linear and nonlinear time series (AutoRegressive, Henon and Lorenz series).

Myocardial flow reserve by Rb-82 cardiac PET improves the selection of patients eligible for invasive coronary angiography

Aim: We asked whether myocardial flow reserve (MFR) by Rb-82 cardiac PET improve the selection of patients eligible for invasive coronary angiography (ICA). Material and Methods: We enrolled 26 consecutive patients with suspected or known coronary artery disease who performed dynamic Rb-82 PET/CT and (ICA) within 60 days; 4 patients who underwent revascularization or had any cardiovascular events between PET and ICA were excluded. Myocardial blood flow at rest (rMBF), at stress with adenosine (sMBF) and myocardial flow reserve (MFR=sMBF/rMBF) were estimated using the 1-compartment Lortie model (FlowQuant) for each coronary arteries territories. Stenosis severity was assessed using computer-based automated edge detection (QCA). MFR was divided in 3 groups: G1:MFR<1.5, G2:1.5≤MFR<2 and G3:2≤MFR. Stenosis severity was graded as non-significant (<50% or FFR ≥0.8), intermediate (50%≤stenosis<70%) and severe (≥70%). Correlation between MFR and percentage of stenosis were assessed using a non-parametric Spearman test. Results: In G1 (44 vessels), 17 vessels (39%) had a severe stenosis, 11 (25%) an intermediate one, and 16 (36%) no significant stenosis. In G2 (13 vessels), 2 (15%) vessels presented a severe stenosis, 7 (54%) an intermediate one, and 4 (31%) no significant stenosis. In G3 (9 vessels), 0 vessel presented a severe stenosis, 1 (11%) an intermediate one, and 8 (89%) no significant stenosis. Of note, among 11 patients with 3-vessel low MFR<1.5 (G1), 9/11 (82%) had at least one severe stenosis and 2/11 (18%) had at least one intermediate stenosis. There was a significant inverse correlation between stenosis severity and MFR among all 66 territories analyzed (rho= -0.38, p=0.002). Conclusion: Patients with MFR>2 could avoid ICA. Low MFR (G1, G2) on a vessel-based analysis seems to be a poor predictor of severe stenosis severity. Patients with 3-vessel low MFR would benefit from ICA as they are likely to present a significant stenosis in at least one vessel.

The role of gene duplication in the origin and evolution of new biological functions

Abstract : Gene duplication is an essential source of material for the origin of genetic novelty and the evolution of lineage- or species-specific phenotypic traits. The reverse transcription of source gene mRNA followed by the genomic insertion of the resulting cDNA - retroposition - has provided the human genome with a significant number of gene copies during the last ~63 million years (MYA) of primate evolution. We estimated that at least 1 new functional gene (retrogene) per MYA emerged by retroposition in the primate lineage leading to humans. Using a combination of comparative sequencing and evolutionary simulations, we obtained strong evidence of functionality for 7 primate specific retrogenes. Most of these genes are specifically expressed in testis suggesting that retroposition has contributed with genetic raw material necessary for the evolution ofmale-specific functions in primates. We characterized CDC14Bretro (identified in the previous survey) that originated from the retroposition of a cell cycle gene - CDC14B - in the common ancestor of humans and apes. We demonstrate that CDC14Bretro experienced a period of intense positive selection in the African ape ancestor. By virtue of the amino acid substitutions that occurred during this period CDC 14Bretro adapted to a new subcellular compartment in African apes. Further analyses indicate that this subcellular shift reflects the evolution of anew functional role of CDC 14Bretro. Prompted by this result, we used yeast (Saccharomyces cerevisiae) to investigate on a global scale the extent of functional diversification of duplicate genes through the subcellular adaptation of their encoded proteins. We found that duplicate proteins frequently evolved new cellular localization patterns, either by partitioning of ancestral localizations ("sublocalization"), or more frequently by relocalization to previously unoccupied compartments ("neolocalization"). Interestingly, proteins involved in processes with a wider subcellular distribution more frequently evolved new localization patterns suggesting that subcellular localization changes are dependent on progenitor gene functions. Relocated proteins adapted to their new subcellular environments and evolved new functional roles through changes of their physio-chemical properties, expression levels, and interaction partners. Our work suggests an important role of subcellular adaptation for the emergence of new gene functions.

Analysis of susceptibility to human immunodeficiency virus 1 (HIV-1) by comparative genetics

Summary [résumé français voir ci-dessous] From the beginning of the 20th century the world population has been confronted with the human immune deficiency virus 1 (HIV-1). This virus has the particularity to mutate fast, and could thus evade and adapt to the human host. Our closest evolutionary related organisms, the non-human primates, are less susceptible to HIV-1. In a broader sense, primates are differentially susceptible to various retrovirus. Species specificity may be due to genetic differences among primates. In the present study we applied evolutionary and comparative genetic techniques to characterize the evolutionary pattern of host cellular determinants of HIV-1 pathogenesis. The study of the evolution of genes coding for proteins participating to the restriction or pathogenesis of HIV-1 may help understanding the genetic basis of modern human susceptibility to infection. To perform comparative genetics analysis, we constituted a collection of primate DNA and RNA to allow generation of de novo sequence of gene orthologs. More recently, release to the public domain of two new primate complete genomes (bornean orang-utan and common marmoset) in addition of the three previously available genomes (human, chimpanzee and Rhesus monkey) help scaling up the evolutionary and comparative genome analysis. Sequence analysis used phylogenetic and statistical methods for detecting molecular adaptation. We identified different selective pressures acting on host proteins involved in HIV-1 pathogenesis. Proteins with HIV-1 restriction properties in non-human primates were under strong positive selection, in particular in regions of interaction with viral proteins. These regions carried key residues for the antiviral activity. Proteins of the innate immunity presented an evolutionary pattern of conservation (purifying selection) but with signals of relaxed constrain if we compared them to the average profile of purifying selection of the primate genomes. Large scale analysis resulted in patterns of evolutionary pressures according to molecular function, biological process and cellular distribution. The data generated by various analyses served to guide the ancestral reconstruction of TRIM5a a potent antiviral host factor. The resurrected TRIM5a from the common ancestor of Old world monkeys was effective against HIV-1 and the recent resurrected hominoid variants were more effective against other retrovirus. Thus, as the result of trade-offs in the ability to restrict different retrovirus, human might have been exposed to HIV-1 at a time when TRIM5a lacked the appropriate specific restriction activity. The application of evolutionary and comparative genetic tools should be considered for the systematical assessment of host proteins relevant in viral pathogenesis, and to guide biological and functional studies. Résumé La population mondiale est confrontée depuis le début du vingtième siècle au virus de l'immunodéficience humaine 1 (VIH-1). Ce virus a un taux de mutation particulièrement élevé, il peut donc s'évader et s'adapter très efficacement à son hôte. Les organismes évolutivement le plus proches de l'homme les primates nonhumains sont moins susceptibles au VIH-1. De façon générale, les primates répondent différemment aux rétrovirus. Cette spécificité entre espèces doit résider dans les différences génétiques entre primates. Dans cette étude nous avons appliqué des techniques d'évolution et de génétique comparative pour caractériser le modèle évolutif des déterminants cellulaires impliqués dans la pathogenèse du VIH- 1. L'étude de l'évolution des gènes, codant pour des protéines impliquées dans la restriction ou la pathogenèse du VIH-1, aidera à la compréhension des bases génétiques ayant récemment rendu l'homme susceptible. Pour les analyses de génétique comparative, nous avons constitué une collection d'ADN et d'ARN de primates dans le but d'obtenir des nouvelles séquences de gènes orthologues. Récemment deux nouveaux génomes complets ont été publiés (l'orang-outan du Bornéo et Marmoset commun) en plus des trois génomes déjà disponibles (humain, chimpanzé, macaque rhésus). Ceci a permis d'améliorer considérablement l'étendue de l'analyse. Pour détecter l'adaptation moléculaire nous avons analysé les séquences à l'aide de méthodes phylogénétiques et statistiques. Nous avons identifié différentes pressions de sélection agissant sur les protéines impliquées dans la pathogenèse du VIH-1. Des protéines avec des propriétés de restriction du VIH-1 dans les primates non-humains présentent un taux particulièrement haut de remplacement d'acides aminés (sélection positive). En particulier dans les régions d'interaction avec les protéines virales. Ces régions incluent des acides aminés clé pour l'activité de restriction. Les protéines appartenant à l'immunité inné présentent un modèle d'évolution de conservation (sélection purifiante) mais avec des traces de "relaxation" comparé au profil général de sélection purifiante du génome des primates. Une analyse à grande échelle a permis de classifier les modèles de pression évolutive selon leur fonction moléculaire, processus biologique et distribution cellulaire. Les données générées par les différentes analyses ont permis la reconstruction ancestrale de TRIM5a, un puissant facteur antiretroviral. Le TRIM5a ressuscité, correspondant à l'ancêtre commun entre les grands singes et les groupe des catarrhiniens, est efficace contre le VIH-1 moderne. Les TRIM5a ressuscités plus récents, correspondant aux ancêtres des grands singes, sont plus efficaces contre d'autres rétrovirus. Ainsi, trouver un compromis dans la capacité de restreindre différents rétrovirus, l'homme aurait été exposé au VIH-1 à une période où TRIM5a manquait d'activité de restriction spécifique contre celui-ci. L'application de techniques d'évolution et de génétique comparative devraient être considérées pour l'évaluation systématique de protéines impliquées dans la pathogenèse virale, ainsi que pour guider des études biologiques et fonctionnelles

Development of appropriateness criteria for the surgical treatment of symptomatic lumbar degenerative spondylolisthesis (LDS).

PURPOSE: Spine surgery rates are increasing worldwide. Treatment failures are often attributed to poor patient selection and inappropriate treatment, but for many spinal disorders there is little consensus on the precise indications for surgery. With an aging population, more patients with lumbar degenerative spondylolisthesis (LDS) will present for surgery. The aim of this study was to develop criteria for the appropriateness of surgery in symptomatic LDS. METHODS: A systematic review was carried out to summarize the current level of evidence for the treatment of LDS. Clinical scenarios were generated comprising combinations of signs and symptoms in LDS and other relevant variables. Based on the systematic review and their own clinical experience, twelve multidisciplinary international experts rated each scenario on a 9-point scale (1 highly inappropriate, 9 highly appropriate) with respect to performing decompression only, fusion, and instrumented fusion. Surgery for each theoretical scenario was classified as appropriate, inappropriate, or uncertain based on the median ratings and disagreement in the ratings. RESULTS: 744 hypothetical scenarios were generated; overall, surgery (of some type) was rated appropriate in 27 %, uncertain in 41 % and inappropriate in 31 %. Frank panel disagreement was low (7 % scenarios). Face validity was shown by the logical relationship between each variable's subcategories and the appropriateness ratings, e.g., no/mild disability had a mean appropriateness rating of 2.3 ± 1.5, whereas the rating for moderate disability was 5.0 ± 1.6 and for severe disability, 6.6 ± 1.6. Similarly, the average rating for no/minimal neurological abnormality was 2.3 ± 1.5, increasing to 4.3 ± 2.4 for moderate and 5.9 ± 1.7 for severe abnormality. The three variables most likely (p < 0.0001) to be components of scenarios rated "appropriate" were: severe disability, no yellow flags, and severe neurological deficit. CONCLUSION: This is the first study to report criteria for determining candidacy for surgery in LDS developed by a multidisciplinary international panel using a validated method (RAM). The panel ratings followed logical clinical rationale, indicating good face validity. The work refines clinical classification and the phenotype of degenerative spondylolisthesis. The predictive validity of the criteria should be evaluated prospectively to examine whether patients treated "appropriately" have better clinical outcomes.

Genetic team composition and level of selection in the evolution of cooperation

In cooperative multiagent systems, agents interac to solve tasks. Global dynamics of multiagent teams result from local agent interactions, and are complex and difficult to predict. Evolutionary computation has proven a promising approach to the design of such teams. The majority of current studies use teams composed of agents with identical control rules ("geneti- cally homogeneous teams") and select behavior at the team level ("team-level selection"). Here we extend current approaches to include four combinations of genetic team composition and level of selection. We compare the performance of genetically homo- geneous teams evolved with individual-level selection, genetically homogeneous teams evolved with team-level selection, genetically heterogeneous teams evolved with individual-level selection, and genetically heterogeneous teams evolved with team-level selection. We use a simulated foraging task to show that the optimal combination depends on the amount of cooperation required by the task. Accordingly, we distinguish between three types of cooperative tasks and suggest guidelines for the optimal choice of genetic team composition and level of selection