Oligogalacturonide defense signals in plants: large fragments interact with the plasma membrane in vitro.

Oligogalacturonides are plant cell wall-derived regulatory molecules which stimulate defense gene expression during pathogenesis. In vitro, these compounds enhance the phosphorylation of an approximately 34-kDa protein (pp34) in purified plasma membranes from potato and tomato leaves. We now show that polygalacturonate-enhanced phosphorylation of pp34 occurs in plasma membranes purified from tomato roots, hypocotyls, and stems and from undifferentiated potato cells. Furthermore, a similar phosphorylation is detected in leaf plasma membranes from soybean, a plant distantly related to tomato. Purified oligogalacturonides 13 to at least 26 residues long stimulate pp34 thiophosphorylation in vitro. This stimulation pattern differs from the induction of many known defense responses in vivo, where a narrower range of smaller fragments, between approximately 10 and 15 residues long, are active. On the basis of these differences we suggest that observed effects of applied exogenous oligogalacturonides on defense responses may not necessarily reflect the situation during pathogenesis. The cell wall could act as a barrier to many exogenous oligo- and polygalacturonides as well as other large regulatory ligands.

Complications of different ventilation strategies in endoscopic laryngeal surgery: a 10-year review.

BACKGROUND: Spontaneous ventilation, mechanical controlled ventilation, apneic intermittent ventilation, and jet ventilation are commonly used during interventional suspension microlaryngoscopy. The aim of this study was to investigate specific complications of each technique, with special emphasis on transtracheal and transglottal jet ventilation. METHODS: The authors performed a retrospective single-institution analysis of a case series of 1,093 microlaryngoscopies performed in 661 patients between January 1994 and January 2004. Data were collected from two separate prospective databases. Feasibility and complications encountered with each technique of ventilation were analyzed as main outcome measures. RESULTS: During 1,093 suspension microlaryngoscopies, ventilation was supplied by mechanical controlled ventilation via small endotracheal tubes (n = 200), intermittent apneic ventilation (n = 159), transtracheal jet ventilation (n = 265), or transglottal jet ventilation (n = 469). Twenty-nine minor and 4 major complications occurred. Seventy-five percent of the patients with major events had an American Society of Anesthesiologists physical status classification of III. Five laryngospasms were observed with apneic intermittent ventilation. All other 24 complications (including 7 barotrauma) occurred during jet ventilation. Transtracheal jet ventilation was associated with a significantly higher complication rate than transglottal jet ventilation (P < 0.0001; odds ratio, 4.3 [95% confidence interval, 1.9-10.0]). All severe complications were related to barotraumas resulting from airway outflow obstruction during jet ventilation, most often laryngospasms. CONCLUSIONS: The use of a transtracheal cannula was the major independent risk factor for complications during jet ventilation for interventional microlaryngoscopy. The anesthetist's vigilance in clinically detecting and preventing outflow airway obstruction remains the best prevention of barotrauma during subglottic jet ventilation.

The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia.

Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, and sepsis. Pneumococci can be divided into >90 serotypes that show differences in the pathogenicity and invasiveness. We tested the hypotheses that the innate immune inflammasome pathway is involved in fighting pneumococcal pneumonia and that some invasive pneumococcal types are not recognized by this pathway. We show that human and murine mononuclear cells responded to S. pneumoniae expressing hemolytic pneumolysin by producing IL-1β. This IL-1β production depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Some serotype 1, serotype 8, and serotype 7F bacteria, which have previously been associated with increased invasiveness and with production of toxins with reduced hemolytic activity, or bacterial mutants lacking pneumolysin did not stimulate notable IL-1β production. We further found that NLRP3 was beneficial for mice during pneumonia caused by pneumococci expressing hemolytic pneumolysin and was involved in cytokine production and maintenance of the pulmonary microvascular barrier. Overall, the inflammasome pathway is protective in pneumonia caused by pneumococci expressing hemolytic toxin but is not activated by clinically important pneumococcal sequence types causing invasive disease. The study indicates that a virulence factor polymorphism may substantially affect the recognition of bacteria by the innate immune system.

Stratégies thérapeutiques en présence d'un diabète de type 2 [Therapeutic strategies in type 2 diabetes]

UKPDS and DCCT studies have demonstrated the critical role of tight glycaemic control to reduce the micro- and macro-vascular damage linked to diabetes. Unfortunately, the insulin requirement of type 2 diabetic patients remains elevated since 5 to 7% of these patients will required, yearly, a change from oral antidiabetic drug to insulin treatment to maintain a good glycaemic control. This manuscript is intended to review the currently available oral antidiabetic drugs, their benefits as well as potential arms and to propose a simplified therapeutic strategy in presence of type 2 diabetes.

Melanin-specific life-history strategies.

Abstract The maintenance of genetic variation is a long-standing issue because the adaptive value of life-history strategies associated with each genetic variant is usually unknown. However, evidence for the coexistence of alternative evolutionary fixed strategies at the population level remains scarce. Because in the tawny owl (Strix aluco) heritable melanin-based coloration shows different physiological and behavioral norms of reaction, we investigated whether coloration is associated with investment in maintenance and reproduction. Light melanic owls had lower adult survival compared to dark melanic conspecifics, and color variation was related to the trade-off between offspring number and quality. When we experimentally enlarged brood size, light melanic males produced more fledglings but in poorer condition, and they were less often recruited in the local breeding population than those of darker melanic conspecifics. Our results also suggest that dark melanic males allocate a constant effort to raise their brood independently of environmental conditions, whereas lighter melanic males finely adjust reproductive effort in relation to changes in environmental conditions. Color traits can therefore be associated with life-history strategies, and stochastic environmental perturbation can temporarily favor one phenotype over others. The existence of fixed strategies implies that some phenotypes can sometimes display a "maladapted" strategy. Long-term population monitoring is therefore vital for a full understanding of how different genotypes deal with trade-offs.

On optimal dividend strategies with deficit or incomplete information

Rapport de synthèse Cette thèse consiste en trois essais sur les stratégies optimales de dividendes. Chaque essai correspond à un chapitre. Les deux premiers essais ont été écrits en collaboration avec les Professeurs Hans Ulrich Gerber et Elias S. W. Shiu et ils ont été publiés; voir Gerber et al. (2006b) ainsi que Gerber et al. (2008). Le troisième essai a été écrit en collaboration avec le Professeur Hans Ulrich Gerber. Le problème des stratégies optimales de dividendes remonte à de Finetti (1957). Il se pose comme suit: considérant le surplus d'une société, déterminer la stratégie optimale de distribution des dividendes. Le critère utilisé consiste à maximiser la somme des dividendes escomptés versés aux actionnaires jusqu'à la ruine2 de la société. Depuis de Finetti (1957), le problème a pris plusieurs formes et a été résolu pour différents modèles. Dans le modèle classique de théorie de la ruine, le problème a été résolu par Gerber (1969) et plus récemment, en utilisant une autre approche, par Azcue and Muler (2005) ou Schmidli (2008). Dans le modèle classique, il y a un flux continu et constant d'entrées d'argent. Quant aux sorties d'argent, elles sont aléatoires. Elles suivent un processus à sauts, à savoir un processus de Poisson composé. Un exemple qui correspond bien à un tel modèle est la valeur du surplus d'une compagnie d'assurance pour lequel les entrées et les sorties sont respectivement les primes et les sinistres. Le premier graphique de la Figure 1 en illustre un exemple. Dans cette thèse, seules les stratégies de barrière sont considérées, c'est-à-dire quand le surplus dépasse le niveau b de la barrière, l'excédent est distribué aux actionnaires comme dividendes. Le deuxième graphique de la Figure 1 montre le même exemple du surplus quand une barrière de niveau b est introduite, et le troisième graphique de cette figure montre, quand à lui, les dividendes cumulés. Chapitre l: "Maximizing dividends without bankruptcy" Dans ce premier essai, les barrières optimales sont calculées pour différentes distributions du montant des sinistres selon deux critères: I) La barrière optimale est calculée en utilisant le critère usuel qui consiste à maximiser l'espérance des dividendes escomptés jusqu'à la ruine. II) La barrière optimale est calculée en utilisant le second critère qui consiste, quant à lui, à maximiser l'espérance de la différence entre les dividendes escomptés jusqu'à la ruine et le déficit au moment de la ruine. Cet essai est inspiré par Dickson and Waters (2004), dont l'idée est de faire supporter aux actionnaires le déficit au moment de la ruine. Ceci est d'autant plus vrai dans le cas d'une compagnie d'assurance dont la ruine doit être évitée. Dans l'exemple de la Figure 1, le déficit au moment de la ruine est noté R. Des exemples numériques nous permettent de comparer le niveau des barrières optimales dans les situations I et II. Cette idée, d'ajouter une pénalité au moment de la ruine, a été généralisée dans Gerber et al. (2006a). Chapitre 2: "Methods for estimating the optimal dividend barrier and the probability of ruin" Dans ce second essai, du fait qu'en pratique on n'a jamais toute l'information nécessaire sur la distribution du montant des sinistres, on suppose que seuls les premiers moments de cette fonction sont connus. Cet essai développe et examine des méthodes qui permettent d'approximer, dans cette situation, le niveau de la barrière optimale, selon le critère usuel (cas I ci-dessus). Les approximations "de Vylder" et "diffusion" sont expliquées et examinées: Certaines de ces approximations utilisent deux, trois ou quatre des premiers moments. Des exemples numériques nous permettent de comparer les approximations du niveau de la barrière optimale, non seulement avec les valeurs exactes mais également entre elles. Chapitre 3: "Optimal dividends with incomplete information" Dans ce troisième et dernier essai, on s'intéresse à nouveau aux méthodes d'approximation du niveau de la barrière optimale quand seuls les premiers moments de la distribution du montant des sauts sont connus. Cette fois, on considère le modèle dual. Comme pour le modèle classique, dans un sens il y a un flux continu et dans l'autre un processus à sauts. A l'inverse du modèle classique, les gains suivent un processus de Poisson composé et les pertes sont constantes et continues; voir la Figure 2. Un tel modèle conviendrait pour une caisse de pension ou une société qui se spécialise dans les découvertes ou inventions. Ainsi, tant les approximations "de Vylder" et "diffusion" que les nouvelles approximations "gamma" et "gamma process" sont expliquées et analysées. Ces nouvelles approximations semblent donner de meilleurs résultats dans certains cas.

Stratégies thérapeutiques pour le traitement des gliomes [Therapeutic strategies for the management of gliomas]

The management of gliomas remains challenging and requires a multidisciplinary approach that involves neurosurgeons, radiation therapists and oncologists. For patients with glioblastomas, progress has been made in recent years with the introduction of a combined modality treatment associating radiation therapy and concomitant chemotherapy with the novel alkylating agent temozolomide. This combination resulted in a significant prolongation of survival and increase in the number of patients with survival well beyond two years. Since then, interest in developing new agents in this disease has dramatically increased. In parallel, molecular markers, such as methylation status of MGMT or identification of the translocation of 1p and 19q in oligodendrogliomas have allowed to identify distinct subtypes with exquisite response to treatment or different prognosis. These developments have implications for the development of clinical trials of new potential drug treatments. In this article, we provide a review of the current management of low- and high-grade gliomas, including astrocytomas, oligodendrogliomas and glioblastomas and provide an outlook into future potential therapies.

Optimization strategies for fast detection of positive selection on phylogenetic trees.

MOTIVATION: The detection of positive selection is widely used to study gene and genome evolution, but its application remains limited by the high computational cost of existing implementations. We present a series of computational optimizations for more efficient estimation of the likelihood function on large-scale phylogenetic problems. We illustrate our approach using the branch-site model of codon evolution. RESULTS: We introduce novel optimization techniques that substantially outperform both CodeML from the PAML package and our previously optimized sequential version SlimCodeML. These techniques can also be applied to other likelihood-based phylogeny software. Our implementation scales well for large numbers of codons and/or species. It can therefore analyse substantially larger datasets than CodeML. We evaluated FastCodeML on different platforms and measured average sequential speedups of FastCodeML (single-threaded) versus CodeML of up to 5.8, average speedups of FastCodeML (multi-threaded) versus CodeML on a single node (shared memory) of up to 36.9 for 12 CPU cores, and average speedups of the distributed FastCodeML versus CodeML of up to 170.9 on eight nodes (96 CPU cores in total).Availability and implementation: ftp://ftp.vital-it.ch/tools/FastCodeML/. CONTACT: selectome@unil.ch or nicolas.salamin@unil.ch.

Public health impact of statin prescribing strategies based on JUPITER Modeling study from a population-based study.

OBJECTIVE: To evaluate the public health impact of statin prescribing strategies based on the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin Study (JUPITER). METHODS: We studied 2268 adults aged 35-75 without cardiovascular disease in a population-based study in Switzerland in 2003-2006. We assessed the eligibility for statins according to the Adult Treatment Panel III (ATPIII) guidelines, and by adding "strict" (hs-CRP≥2.0mg/L and LDL-cholesterol <3.4mmol/L), and "extended" (hs-CRP≥2.0mg/L alone) JUPITER-like criteria. We estimated the proportion of CHD deaths potentially prevented over 10years in the Swiss population. RESULTS: Fifteen % were already taking statins, 42% were eligible by ATPIII guidelines, 53% by adding "strict", and 62% by adding "extended" criteria, with a total of 19% newly eligible. The number needed to treat with statins to avoid one CHD death over 10years was 38 for ATPIII, 84 for "strict" and 92 for "extended" JUPITER-like criteria. ATPIII would prevent 17% of CHD deaths, compared with 20% for ATPIII+"strict" and 23% for ATPIII + "extended" criteria (+6%). CONCLUSION: Implementing JUPITER-like strategies would make statin prescribing for primary prevention more common and less efficient than it is with current guidelines.

Stratégies destinées a optimiser l'utilisation des antibiotiques en réanimation [Strategies targeted at optimising antimicrobial therapy in critically ill patients]

Antibiotics are widely used in critical care and adequate empirical treatments has a significant impact on the outcome of many patients. Most nosocomial infections may be due to multidrug-resistant pathogens and requires empirical borad spectrum coverage before identification of the etiologic agents. This is associated with overuse of antibiotics which contributes to the further increase in multidrug-resistances. In this context, new strategies targeted at antibiotic control, such as guidelines and de-escalation are needed to control this evolution.