Adaptive Continuous time Markov Chain Approximation Model to General Jump-Diusions

We propose a non-equidistant Q rate matrix formula and an adaptive numerical algorithm for a continuous time Markov chain to approximate jump-diffusions with affine or non-affine functional specifications. Our approach also accommodates state-dependent jump intensity and jump distribution, a flexibility that is very hard to achieve with other numerical methods. The Kolmogorov-Smirnov test shows that the proposed Markov chain transition density converges to the one given by the likelihood expansion formula as in Ait-Sahalia (2008). We provide numerical examples for European stock option pricing in Black and Scholes (1973), Merton (1976) and Kou (2002).

The system-wide impacts of the external benefits to higher education on the Scottish economy: An exploratory “micro-to-macro” approach

The private market benefits of education, i.e. the wage premia of graduates, are widely studied at the micro level, although the magnitude of their macroeconomic impact is disputed. However, there are additional benefits of education, which are less well understood but could potentially drive significant macroeconomic impacts. Following the taxonomy of McMahon (2009) we identify four different types of benefits of education. These are: private market benefits (wage premia); private non market benefits (own health, happiness, etc.); external market benefits (productivity spillovers; and external non-market benefits (crime rates, civic society, democratisation, etc.). Drawing on available microeconometric evidence we use a micro-to-macro simulation approach (Hermannsson et al, 2010) to estimate the macroeconomic impacts of external benefits of higher education. We explore four cases: technology spillovers from HEIs; productivity spillovers from more skilled workers in the labour market; reduction in property crime; and the potential overall impact of external and private non-market benefits. Our results suggest that the external economic benefits of higher education could potentially be very large. However, given the dearth of microeconomic evidence this result should be seen as tentative. Our aim is to illustrate the links from education to the wider economy in principle and encourage further research in the field.

Response of photosynthetic organisms to global change: an approach based on marker pigments

Report for the scientific sojourn carried out at the Department of Freshwater Ecology, National Environmetal Research Institute, Denmark, from 2006 to 2008. The main objective of the project was to reconstruct photosynthetic organism community composition using pigmentbased methods and to study their response to natural (e.g. climate) or anthropogenic (e.g. eutrophication) perturbations that took place in the system over time. We performed a study in different locations and at different temporal scales. We analysed the pigment composition in a short sediment record (46 cm sediment depth) of a volcanic lake (Lake Furnas) in the Azores Archipelago (Portugal). The lake has been affected during the last century by successive fish introductions. The specific objective was to reconstruct the lake’s trophic state history and to assess the role of land-use, climate and fish introductions in structuring the lake community. Results obtained suggested that whereas trophic cascade and changes in nutrient concentrations have some clear effects on algal and microbial assemblages, interpreting the effects of changes in climate are not straightforward. This is probably related with the rather constant precipitation in the Azores Islands during the studied period. We also analysed the pigment composition in a long sediment record (1800 cm sediment depth) of Lake Aborre (Denmark) covering ca. 8kyr of lake history. The specific objective was to describe changes in lake primary production and lake trophic state over the Holocene and to determine the photosynthetic organisms involved. Results suggested that external forcing (i.e. land use changes) was responsible of erosion and nutrient run off to the lake that contributed to the reported changes in lake primary production along most of the Holocene.

An affective approach to moral motivation

Over the last few years, there has been a surge of work in a new field called "moral psychology", which uses experimental methods to test the psychological processes underlying human moral activity. In this paper, I shall follow this line of approach with the aim of working out a model of how people form value judgements and how they are motivated to act morally. I call this model an "affective picture": 'picture' because it remains strictly at the descriptive level and 'affective' because it has an important role for affects and emotions. This affective picture is grounded on a number of plausible and empirically supported hypotheses. The main idea is that we should distinguish between various kinds of value judgements by focusing on the sort of state of mind people find themselves in while uttering a judgement. "Reasoned judgements" are products of rational considerations and are based on preliminary acceptance of norms and values. On the contrary, "basic value judgements" are affective, primitive and non-reflective ways of assessing the world. As we shall see, this analysis has some consequences for the traditional internalism-externalism debate in philosophy; it highlights the fact that motivation is primarily linked to "basic value judgements" and that the judgements we openly defend might not have a particular effect on our actions, unless we are inclined to have an emotional attitude that conforms to them.

Optimisation of antiretroviral therapy : pharmacokinetic and pharmacogenetic approaches

Les progrès de la thérapie antirétrovirale ont transformé l'infection par le VIH d'une condition inévitablement fatale à une maladie chronique. En dépit de ce succès, l'échec thérapeutique et la toxicité médicamenteuse restent fréquents. Une réponse inadéquate au traitement est clairement multifactorielle et une individualisation de la posologie des médicaments qui se baserait sur les facteurs démographiques et génétiques des patients et sur les taux sanguins totaux, libres et/ou cellulaires des médicaments pourrait améliorer à la fois l'efficacité et la tolérance de la thérapie, cette dernière étant certainement un enjeu majeur pour un traitement qui se prend à vie.L'objectif global de cette thèse était de mieux comprendre les facteurs pharmacocinétiques (PK) et pharmacogénétiques (PG) influençant l'exposition aux médicaments antirétroviraux (ARVs) nous offrant ainsi une base rationnelle pour l'optimisation du traitement antiviral et pour l'ajustement posologique des médicaments chez les patients VIH-positifs. Une thérapie antirétrovirale adaptée au patient est susceptible d'augmenter la probabilité d'efficacité et de tolérance à ce traitement, permettant ainsi une meilleure compliance à long terme, et réduisant le risque d'émergence de résistance et d'échec thérapeutique.A cet effet, des méthodes de quantification des concentrations plasmatiques totales, libres et cellulaires des ARVs ainsi que de certains de leurs métabolites ont été développées et validées en utilisant la chromatographie liquide coupée à la spectrométrie de masse en tandem. Ces méthodes ont été appliquées pour la surveillance des taux d'ARVs dans diverses populations de patients HIV-positifs. Une étude clinique a été initiée dans le cadre de l'étude VIH Suisse de cohorte mère-enfant afin de déterminer si la grossesse influence la cinétique des ARVs. Les concentrations totales et libres du lopînavir, de l'atazanavir et de la névirapine ont été déterminées chez les femmes enceintes suivies pendant leur grossesse, et celles-ci ont été trouvées non influencées de manière cliniquement significative par la grossesse. Un ajustement posologique de ces ARVs n'est donc pas nécessaire chez les femmes enceintes. Lors d'une petite étude chez des patients HIV- positifs expérimentés, la corrélation entre l'exposition cellulaire et plasmatique des nouveaux ARVs, notamment le raltégravir, a été déterminée. Une bonne corrélation a été obtenue entre taux plasmatiques et cellulaires de raltégravir, suggérant que la surveillance des taux totaux est un substitut satisfaisant. Cependant, une importante variabilité inter¬patient a été observée dans les ratios d'accumulation cellulaire du raltégravir, ce qui devrait encourager des investigations supplémentaires chez les patients en échec sous ce traitement. L'efficacité du suivi thérapeutique des médicaments (TDM) pour l'adaptation des taux d'efavirenz chez des patients avec des concentrations au-dessus de la cible thérapeutique recommandée a été évaluée lors d'une étude prospective. L'adaptation des doses d'efavirenz basée sur le TDM s'est montrée efficace et sûre, soutenant l'utilisation du TDM chez les patients avec concentrations hors cible thérapeutique. L'impact des polymorphismes génétiques des cytochromes P450 (CYP) 2B6, 2A6 et 3A4/5 sur la pharmacocinétique de l'efavirenz et de ces métabolites a été étudié : un modèle de PK de population intégrant les covariats génétiques et démographiques a été construit. Les variations génétiques fonctionnelles dans les voies de métabolisation principales (CYP2B6) et accessoires {CYP2A6et 3A4/S) de l'efavirenz ont un impact sur sa disposition, et peuvent mener à des expositions extrêmes au médicament. Un? ajustement des doses guidé par le TDM est donc recommandé chez ces patients, en accord avec les polymorphismes génétiques.Ainsi, nous avons démonté qu'en utilisant une approche globale tenant compte à la fois des facteurs PK et PG influençant l'exposition aux ARVs chez les patients infectés, il est possible, si nécessaire, d'individualiser la thérapie antirétrovirale dans des situations diverses. L'optimisation du traitement antirétroviral contribue vraisemblablement à une meilleure efficacité thérapeutique à iong terme tout en réduisant la survenue d'effets indésirables.Résumé grand publicOptimisation de la thérapie antirétrovirale: approches pharmacocinétiques et pharmacogénétiquesLes progrès effectués dans le traitement de l'infection par le virus de llmmunodéficienoe humaine acquise (VIH) ont permis de transformer une affection mortelle en une maladie chronique traitable avec des médicaments de plus en plus efficaces. Malgré ce succès, un certain nombre de patients ne répondent pas de façon optimale à leur traitement etyou souffrent d'effets indésirables médicamenteux entraînant de fréquentes modifications dans leur thérapie. Il a été possible de mettre en évidence que l'efficacité d'un traitement antirétroviral est dans la plupart des cas corrélée aux concentrations de médicaments mesurées dans le sang des patients. Cependant, le virus se réplique dans la cellule, et seule la fraction des médicaments non liée aux protéines du plasma sanguin peut entrer dans la cellule et exercer l'activité antirétrovirale au niveau cellulaire. Il existe par ailleurs une importante variabilité des concentrations sanguines de médicament chez des patients prenant pourtant la même dose de médicament. Cette variabilité peut être due à des facteurs démographiques et/ou génétiques susceptibles d'influencer la réponse au traitement antirétroviral.Cette thèse a eu pour objectif de mieux comprendre les facteurs pharmacologiques et génétiques influençant l'efficacité et ta toxicité des médicaments antirétroviraux, dans le but d'individualiser la thérapie antivirale et d'améliorer le suivi des patients HIV-positifs.A cet effet, des méthodes de dosage très sensibles ont été développées pour permettre la quantification des médicaments antirétroviraux dans le sang et les cellules. Ces méthodes analytiques ont été appliquées dans le cadre de diverses études cliniques réalisées avec des patients. Une des études cliniques a recherché s'il y avait un impact des changements physiologiques liés à la grossesse sur les concentrations des médicaments antirétroviraux. Nous avons ainsi pu démontrer que la grossesse n'influençait pas de façon cliniquement significative le devenir des médicaments antirétroviraux chez les femmes enceintes HIV- positives. La posologie de médicaments ne devrait donc pas être modifiée dans cette population de patientes. Par ailleurs, d'autres études ont portés sur les variations génétiques des patients influençant l'activité enzymatique des protéines impliquées dans le métabolisme des médicaments antirétroviraux. Nous avons également étudié l'utilité d'une surveillance des concentrations de médicament (suivi thérapeutique) dans le sang des patients pour l'individualisation des traitements antiviraux. Il a été possible de mettre en évidence des relations significatives entre l'exposition aux médicaments antirétroviraux et l'existence chez les patients de certaines variations génétiques. Nos analyses ont également permis d'étudier les relations entre les concentrations dans le sang des patients et les taux mesurés dans les cellules où le virus HIV se réplique. De plus, la mesure des taux sanguins de médicaments antirétroviraux et leur interprétation a permis d'ajuster la posologie de médicaments chez les patients de façon efficace et sûre.Ainsi, la complémentarité des connaissances pharmacologiques, génétiques et virales s'inscrit dans l'optique d'une stratégie globale de prise en charge du patient et vise à l'individualisation de la thérapie antirétrovirale en fonction des caractéristiques propres de chaque individu. Cette approche contribue ainsi à l'optimisation du traitement antirétroviral dans la perspective d'un succès du traitement à long terme tout en réduisant la probabilité des effets indésirables rencontrés. - The improvement in antirétroviral therapy has transformed HIV infection from an inevitably fatal condition to a chronic, manageable disease. However, treatment failure and drug toxicity are frequent. Inadequate response to treatment is clearly multifactorial and, therefore, dosage individualisation based on demographic factors, genetic markers and measurement of total, free and/or cellular drug level may increase both drug efficacy and tolerability. Drug tolerability is certainly a major issue for a treatment that must be taken indefinitely.The global objective of this thesis aimed at increasing our current understanding of pharmacokinetic (PK) and pharmacogenetic (PG) factors influencing the exposition to antirétroviral drugs (ARVs) in HIV-positive patients. In turn, this should provide us with a rational basis for antiviral treatment optimisation and drug dosage adjustment in HIV- positive patients. Patient's tailored antirétroviral regimen is likely to enhance treatment effectiveness and tolerability, enabling a better compliance over time, and hence reducing the probability of emergence of viral resistance and treatment failure.To that endeavour, analytical methods for the measurement of total plasma, free and cellular concentrations of ARVs and some of their metabolites have been developed and validated using liquid chromatography coupled with tandem mass spectrometry. These assays have been applied for the monitoring of ARVs levels in various populations of HIV- positive patients. A clinical study has been initiated within the frame of the Mother and Child Swiss HIV Cohort Study to determine whether pregnancy influences the exposition to ARVs. Free and total plasma concentrations of lopinavir, atazanavir and nevirapine have been determined in pregnant women followed during the course of pregnancy, and were found not influenced to a clinically significant extent by pregnancy. Dosage adjustment for these drugs is therefore not required in pregnant women. In a study in treatment- experienced HIV-positive patients, the correlation between cellular and total plasma exposure to new antirétroviral drugs, notably the HIV integrase inhibitor raltegravir, has been determined. A good correlation was obtained between total and cellular levels of raltegravir, suggesting that monitoring of total levels are a satisfactory. However, significant inter-patient variability was observed in raltegravir cell accumulation which should prompt further investigations in patients failing under an integrase inhibitor-based regimen. The effectiveness of therapeutic drug monitoring (TDM) to guide efavirenz dose reduction in patients having concentrations above the recommended therapeutic range was evaluated in a prospective study. TDM-guided dosage adjustment of efavirenz was found feasible and safe, supporting the use of TDM in patients with efavirenz concentrations above therapeutic target. The impact of genetic polymorphisms of cytochromes P450 (CYP) 2B6, 2A6 and 3A4/5 on the PK of efavirenz and its metabolites was studied: a population PK model was built integrating both genetic and demographic covariates. Functional genetic variations in main (CYP2B6) and accessory (2A6, 3A4/5) metabolic pathways of efavirenz have an impact on efavirenz disposition, and may lead to extreme drug exposures. Dosage adjustment guided by TDM is thus required in those patients, according to the pharmacogenetic polymorphism.Thus, we have demonstrated, using a comprehensive approach taking into account both PK and PG factors influencing ARVs exposure in HIV-infected patients, the feasibility of individualising antirétroviral therapy in various situations. Antiviral treatment optimisation is likely to increase long-term treatment success while reducing the occurrence of adverse drug reactions.

Rapid diagnostic tests for non-malarial febrile illness in the tropics.

The recent roll-out of rapid diagnostic tests (RDTs) for malaria has highlighted the decreasing proportion of malaria-attributable illness in endemic areas. Unfortunately, once malaria is excluded, there are few accessible diagnostic tools to guide the management of severe febrile illnesses in low resource settings. This review summarizes the current state of RDT development for several key infections, including dengue fever, enteric fever, leptospirosis, brucellosis, visceral leishmaniasis and human African trypanosomiasis, and highlights many remaining gaps. Most RDTs for non-malarial tropical infections currently rely on the detection of host antibodies against a single infectious agent. The sensitivity and specificity of host-antibody detection tests are both inherently limited. Moreover, prolonged antibody responses to many infections preclude the use of most serological RDTs for monitoring response to treatment and/or for diagnosing relapse. Considering these limitations, there is a pressing need for sensitive pathogen-detection-based RDTs, as have been successfully developed for malaria and dengue. Ultimately, integration of RDTs into a validated syndromic approach to tropical fevers is urgently needed. Related research priorities are to define the evolving epidemiology of fever in the tropics, and to determine how combinations of RDTs could be best used to improve the management of severe and treatable infections requiring specific therapy.

Plasma Level of Mmp-9 as Predictive Factor for Response and Progression Free Survival in Patients Treated with Bevacizumab (Bev) and Pegylated Liposomal Doxorubicin (Pld): Sakk 24/06

Background: There is currently no identified marker predicting benefit from Bev in patients with breast cancer (pts). We monitored prospectively 6 angiogenesis-related factors in the blood of advanced stage pts treated with a combination of Bev and PLD in a phase II trial of the Swiss Group for Clinical Cancer Research, SAKK.Methods: Pts received PLD (20 mg/m2) and Bev (10 mg/kg) every 2 weeks for a maximum of 12 administrations, followed by Bev monotherapy until progression or severe toxicity. Blood samples were collected at baseline, during treatment and at treatment discontinuation. Enzyme-linked immunosorbent assays (Quantikine, R&DSystems and Reliatech) were used to measure vascular endothelial growth factor (VEGF), placental growth factor (PlGF), matrix metalloproteinase 9 (MMP-9) and soluble VEGF receptors -1, -2 and -3. The natural log-transformed (ln) data for each factor was analyzed by analysis of variance (ANOVA) model to investigate differences between the mean values of the subgroups of interest (where a = 0.05), based on the best tumor response by RECIST.Results: 132 samples were collected in 41 pts. The mean of baseline ln MMP-9 levels was significantly lower in pts with tumor progression than those with tumor response (p=0.0202, log fold change=0.8786) or disease control (p=0.0035, log fold change=0.8427). Higher MMP-9 level was a significant predictor of superior progression free survival (PFS): p=0.0417, hazard ratio=0.574, 95% CI=0.336-0.979. In a multivariate cox proportional hazards model, containing performance status, disease free interval, number of tumor sites, visceral involvement and prior adjuvant chemotherapy, using stepwise regression baseline MMP-9 was still a statistically 117P Table 1. SOLTI-0701* AC01B07* NU07B1* SOR+CAP N=20 PL+CAP N=33 SOR+ GEM/CAP N=23 PL+ GEM/CAP N=27 SOR+PAC N=48 PL+PAC N=46 Baseline characteristics Age, median (range), y 49 (32-72) 53 (30-78 54 (32-69) 57 (31-82) 50 (27-80) 52 (23-74) AJCC stage, n (%) IIIB/IIIC 3 (15) 6 (18) 0 (0) 3 (11) 8 (17) 9 (20) IV 17 (85) 27 (82) 23 (100) 24 (89) 40 (83) 37 (80) Metastatic site, n (%) Non-visceral 3 (15) 6 (18) 7 (30) 6 (22) 9 (19) 17 (37) Visceral 17 (85) 27 (82) 16 (70) 21 (78) 39 (81) 29 (63) Prior metastatic chemo, n (%) 8 (40) 15 (45) 21 (91) 25 (93) - - Efficacy PFS, median, mo 4.3 2.5 3.1 2.6 5.6 5.5 HR (95% CI)_ 0.60 (0.31, 1.14) 0.57 (0.30, 1.09) 0.86 (0.50, 1.45) 1-sided P value_ 0.055 0.044 0.281 Overall survival, median, mo 17.5 16.1 Pending 14.7 18.2 HR (95% CI)_ 0.98 (0.50, 1.89) 1.11 (0.64, 1.94) 1-sided P value_ 0.476 0.352 Safety N=20 N=33 N=22 N=27 N=46 N=46 Tx-emergent Grade 3/4, n (%) 15 (75) 16 (48) 20 (91) 17 (63) 36 (78) 16 (35) Grade 3§ hand-foot skin reaction/ syndrome 8 (40) 5 (15) 8 (36) 0 (0) 14 (30) 2 (4) *Efficacy results based on intent-to-treat population and safety results based on safety population (pts who received study drug[s]); _Cox regression within each subgroup; _log-rank test within each subgroup; §maximum toxicity grade for hand-foot skin reaction/syndrome; AJCC, American Joint Committee on Cancer mittedabstractsª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com Downloaded from annonc.oxfordjournals.org at Bibliotheque Cantonale et Universitaire on June 6, 2011 significant factor (p=0.0266). The results of the other measured factors were presented elsewhere.Conclusions: Higher levels of MMP-9 could predict tumor response and superior PFSin pts treated with a combination of Bev and PLD. These exploratory results justify further investigations of MMP-9 in pts treated with Bev combinations in order to assess its role as a prognostic and predictive factor.Disclosure: K. Zaman: Participation in advisory board of Roche; partial sponsoring ofthe study by Roche (the main sponsor was the Swiss Federation against Cancer (Oncosuisse)). B. Thu¨rlimann: stock of Roche; Research grants from Roche. R. vonMoos: Participant of Advisory Board and Speaker honoraria

First Report of a Newborn Rat Ventilation Model for Bronchopulmonary Dysplasia Permitting Evaluation of Long-Term Outcome

Background: Bronchopulmonary dysplasia (BPD) remains the leading cause of chronic pulmonary morbidity among preterm neonates. However, the exact pathophysiology is still unknown. Here we present the first results from a new model inteAbstracts, 25th International Workshop on Surfactant Replacement 400 Neonatology 2010;97:395-400 grating the most common risk factors for BPD (lung immaturity, inflammation, mechanical ventilation (MV), oxygen), which allows long-term outcome evaluation due to a non-traumatic intubation procedure. Objectives: To test the feasibility of a new rat model by investigating effects of MV, inflammation and oxygen applied to immature lungs after a ventilation-free interval. Methods: On day 4, 5, or 6 newborn rats were given an intraperitoneal injection of lipopolysaccharides to induce a systemic inflammation. 24 h later they were anesthetized, endotracheally intubated and ventilated for 8 h with 60% oxygen. After weaning of anesthesia and MV the newborn rats were extubated and returned to their mothers. Two days later they were killed and outcome measurements were performed (histology, quantitative RT-PCR) and compared to animals investigated directly after MV. Results: Directly after MV, histological signs of ventilator-induced lung injury were found. After 48 h, the first signs of early BPD were seen with delayed alveolar formation. Expression of inflammatory genes was only transiently increased. After 48 h genes involved in alveolarization, such as matrix metalloproteinase-9 and tropoelastin, showed a significant change of their expression. Conclusion: For the first time we can evaluate in a newborn rat model the effects of MV after a ventilation-free interval. This allows discrimination between immediate response genes and delayed changes of expression of more structural genes involved in alveolarization.

T cell responses to repeat and non-repeat regions of the circumsporozoite protein detected in volunteers immunized with Plasmodium falciparum sporozoites

The design of malarial vaccine based on the circumsporozoite (CS) protein, a majuor surface antigen of the sporozoite stage of the malaria parasite, requires the identification of T and B cell epitopes for inclusion in recombinant or synthetic vaccine candidates. We have investigated the specificity and function of a series of T cell clones, derived from volunteers immunized with Plasmodium falciparum sporozoites in an effort to identify relevant epitopes in the immune response to the pre-erythrocytic stages of the parasite. CD4+ T cell clones were obtained wich specifically recognized a repetitive epitope located in the 5'repeat region of the CS protein. This epitope, when conjugated to the 3'repeat region in a synthetic MAPs construct, induced high titers of antisporozoite antibodies in C57B1 mice. A second T cell epitope, which mapped to aa 326-345 of the carboxy terminal, was recognized by lytic, as well as non-lytic, CD4+ T cells derived from the sporozoite-immunized volunteers. The demonstration of CD4+ CTL in the volunteers, and the recent studies inthe rodent model (Renia et al., 1991; Tsuji et al., 1990), suggested that CS-specific CD4+ T cells, in addition to their indirect role as helper cells in the induction of antibody and CD8 + effector cells, may also play a direct role in protection against sporozoite challenge by targeting EEF within the liver.

Differentially expressed gene profile in the 6-hydroxy-dopamine-induced cell culture model of Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons of the substantia nigra pars compacta with unknown aetiology. 6-Hydroxydopamine (6-OHDA) treatment of neuronal cells is an established in vivo model for mimicking the effect of oxidative stress found in PD brains. We examined the effects of 6-OHDA treatment on human neuroblastoma cells (SH-SY5Y) and primary mesencephalic cultures. Using a reverse arbitrarily primed polymerase chain reaction (RAP-PCR) approach we generated reproducible genetic fingerprints of differential expression levels in cell cultures treated with 6-OHDA. Of the resulting sequences, 23 showed considerable homology to known human coding sequences. The results of the RAP-PCR were validated by reverse transcription PCR, real-time PCR and, for selected genes, by Western blot analysis and immunofluorescence. In four cases, [tomoregulin-1 (TMEFF-1), collapsin response mediator protein 1 (CRMP-1), neurexin-1, and phosphoribosylaminoimidazole synthetase (GART)], a down-regulation of mRNA and protein levels was detected. Further studies will be necessary on the physiological role of the identified proteins and their impact on pathways leading to neurodegeneration in PD.

Online estimation of respiratory mechanics in non-invasive pressure support ventilation: a bench model study.

An online algorithm for determining respiratory mechanics in patients using non-invasive ventilation (NIV) in pressure support mode was developed and embedded in a ventilator system. Based on multiple linear regression (MLR) of respiratory data, the algorithm was tested on a patient bench model under conditions with and without leak and simulating a variety of mechanics. Bland-Altman analysis indicates reliable measures of compliance across the clinical range of interest (± 11-18% limits of agreement). Resistance measures showed large quantitative errors (30-50%), however, it was still possible to qualitatively distinguish between normal and obstructive resistances. This outcome provides clinically significant information for ventilator titration and patient management.

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.

An epidemiological and clinical approach to adolescent suicide. A comparison between suicidal and non-suicidal clinical groups in a health foundation center for French students.

Suicidal behaviour among young people represents a major public health problem. This study seeks to compare the major sociological, clinical, schooling and family features of suicidal and non-suicidal subgroups of adolescents hospitalised in the Health Foundation Center for French Students of neufmoutiers en Brie (France). All these adolescents suffered from the severe mental disorders. The adolescents from the suicidal subgroup presented significantly fewer psychoses and more mood disorders than those of the non-suicidal subgroup. Half of the patients from the suicidal subgroup presented some features of personality disorders, mostly borderline personality disorders. Nevertheless, their global functioning was more frequently improved between admission and discharge than was the case for the non-suicidal group.

Potassium restores vasorelaxation of resistance arterioles in non-hypertensive DOCA/salt fed mice.

BACKGROUND: Potassium-enriched diets exert renal and cardiovascular protective effects, but the underlying mechanisms are largely unknown. METHODS: Using the dorsal skinfold chamber model for intravital microscopy, we examined endothelium-dependent vasorelaxation of precapillary resistance arterioles in response to acetylcholine or the NO donor SNAP in awake mice. Experiments were performed in uni-nephrectomized one renin gene (Ren-1c) C57BL/6 mice (control group) and in mice having received a continuous administration of deoxycorticosterone acetate and a dietary supplementation of 1% sodium chloride for 8weeks (DOCA/salt group). An additional group of DOCA/salt treated animals received a dietary supplement of 0.4% KCl for 3weeks prior to the experiments (DOCA/salt + potassium group). RESULTS: DOCA/salt treatment for 8weeks resulted in hypokalemia, but blood pressure remained unchanged. In DOCA/salt mice, relaxation of resistance arterioles was blunted in response to acetylcholine, and to a lesser extent to SNAP, suggesting endothelial dysfunction. Endothelium-dependent vasorelaxation was restored by the potassium-enriched diet. CONCLUSION: This study is the first to demonstrate a protective effect of potassium on endothelium-dependent vasorelaxation in the absence of confounding anti-hypertensive effects, as observed in most animal models and the clinical situation. We propose that the known cardio- and nephro-protective effects of potassium might - at least in part - be mediated by the salutary effects on endothelium-dependent arteriolar relaxation.

Time-Course In Vivo Trafficking Pattern and Effector Function of Donor-Specific Regulatory T Cells in Response to an Allograft.

Background: Experimental data have suggested that adoptive transfer of CD4+CD25+Foxp3+ regulatory T cells (Tregs), capable of controlling immune responses to specifi c auto- or alloantigens, could be used as a therapeutic strategy to promote specifi c tolerance in T-cell mediated diseases and in organ transplantation (Tx). However, before advocating the application of immunotherapy with Tregs in Tx, we need to improve our understanding of their in vivo homeostasis, traffi cking pattern and effector function in response to alloantigens. Methods : Donor-antigen specifi c murine Tregs were generated and characterized in vitro following our described protocols. Using an adoptive transfer and skin allotransplantation model, we have analyzed the in vivo expansion and homing of fl uorescent-labeled effector T cells (Teff) and Tregs, at different time-points after Tx, using fl ow-cytometry as well as fl uorescence microscopy techniques. Results: Tregs expressed CD62L, CCR7 and CD103 allowing their homing into lymphoid and non-lymphoid tissues (gut, skin) after intravenous injection. While hyporesponsive to TCR stimulation in vitro, transferred Tregs survived, migrated to secondary lymphoid organs and preferentially expanded within the allograft draining lymph nodes. Furthermore, Foxp3+ cells could be detected inside the allograft as early as day 3-5 after Tx. At a much later time-point (day 60 after Tx), graft-infi ltrating Foxp3+ cells were also detectable in tolerant recipients. When transferred alone, CD4+CD25- Teff cells expanded within secondary lymphoid organs and infi ltrated the allograft by day 3-5 after Tx. The co-transfer of Tregs limited the expansion of alloreactive Teff cells as well as their recruitment into the allograft. The promotion of graft survival observed in the presence of Tregs was in part mediated by the inhibition of the production of effector cytokines by CD4+CD25- T cells. Conclusion: Taken together, our results suggest that the suppression of allograft rejection and the induction of Tx tolerance are in part dependant on the alloantigendriven homing and expansion of Tregs. Thus, the appropriate localization of Tregs may be critical for their suppressive function in vivo.