Validation de la mesure de la durée de l'onde P dans une étude de population

Introduction et objectifs : ce travail de master s'inscrit dans le cadre d'une étude cardiologique menée par le Dr. Monney en collaboration avec le Dr. Pruvot. Cette étude analyse par échocardiographie les déterminants morphologiques de la fonction ventriculaire de la cohorte SKIPOGH (Swiss Kidney Project of Genes in Hypertension). L'objectif du travail de master est d'analyser différents types de mesure de la durée de l'onde P (P-wave duration : PWD). Dans un premier temps, il s'agit de mesurer manuellement la PWD de 411 électrocardiogrammes (ECG) provenant du collectif lausannois de la cohorte SKIPOGH. Ensuite, il s'agit de comparer la PWD manuelle (=PWD mesurée) avec la PWD automatique (=PWD calculée), i.e. la valeur de PWD fournie par l'appareil d'enregistrement des ECG. Le but est d'évaluer quel type de mesure de la PWD (automatique vs mesurée) est la plus exacte, i.e. laquelle correspond au plus près à la valeur réelle de la PWD. L'idée est de disposer d'une valeur de PWD la plus juste possible pour l'exploiter par la suite dans l'étude cardiologique susmentionnée. Méthode : pour la PWD manuelle, les 411 ECG ont été « copiés-collés » depuis leur format de stockage PDF (Adobe Reader) vers un fichier PowerPoint. Chaque ECG a été analysé avec un grossissement de 400 fois (valeur maximale dans PowerPoint). La PWD a été mesurée dans la dérivation DII (ou dans une autre dérivation en cas d'onde P difficilement visible). Pour la PWD automatique, il y a 2 types de valeurs : 1) notée sur l'ECG (format PDF) et 2) enregistrée dans un fichier Excel. On a ainsi 3 types de valeurs : la PWD_pdf, la PWD_xls et la PWD_m (mesurée manuellement dans PowerPoint). Les PWD ont été comparées à l'aide du programme statistique StatView®. Résultats : 1) la PWD_m (119±16 ms) s'est révélée significativement plus élevée que la PWD_pdf (105±18 ms) et que la PWD_xls (105±18 ms) ; 2) la différence moyenne entre les deux PWD calculées et la PWD_m était semblable (14ms, p<0.001) ; 3) la PWD_pdf et la PWD_xls montraient une corrélation forte et statistiquement significative avec la PWD_m (R=0.61 et R=0.58 respectivement, p<0.001). Discussion : les résultats ont montré une valeur moyenne de PWD_m significativement plus élevée que les valeurs moyennes de PWD automatiques, ce qui suggère soit une « surestimation » de la PWD par la mesure manuelle, soit une « sous-estimation » de la PWD par la mesure automatique. Pour certains ECG, la mesure automatique est clairement fausse avec une sous-estimation de la PWD. Pour ces ECG, la faible amplitude de l'onde P conjointement à des fluctuations de la ligne de base contribue sans doute à la sous-estimation de la PWD. Pour d'autres ECG, la mesure automatique est erronée avec une surestimation de la PWD consécutive à du bruit (déflections rapides de faible amplitude) s'ajoutant à la partie terminale de l'onde P et majorant artificiellement la PWD. Conclusion: l'ensemble des analyses effectuées sur les 411 ECG n'a pas permis d'établir la supériorité en termes de précision de l'une ou l'autre des méthodes de mesure de la PWD. La mesure manuelle donne des valeurs plus longues d'une quinzaine de ms en moyenne par rapport aux mesures automatiques. Certaines mesures automatiques se sont révélées erronées en raison d'une surestimation ou d'une sous-estimation de la PWD liées à la qualité du tracé. Malgré ces différences, la corrélation entre mesures manuelle et automatiques s'est révélée bonne. Ce travail de master valide ainsi les mesures automatiques de la PWD et permet leur emploi dans l'étude menée par le Dr. Monney. En effet, les valeurs de PWD_xls donnent l'avantage de pouvoir étendre les analyses à l'ensemble des sujets de l'étude SKIPOGH (sujets lausannois, genevois et bernois) et d'augmenter ainsi la puissance statistique des analyses ultérieures

Smooth free involution of HCP3H{\Bbb C}P^3 and Smith conjecture for imbeddings of S3S^3 in S6S^6

This paper establishes an equivalence between existence of free involutions on $H{\Bbb C}P^3$ and existence of involutions on $S^6$ with fixed point set an imbedded $S^3$, then a family of counterexamples of the Smith conjecture for imbeddings of $S^3$ in $S^6$ are given by known result on $H{\Bbb C}P^3$. In addition, this paper also shows that every smooth homotopy complex projective 3-space admits no orientation preserving smooth free involution, which answers an open problem [Pe]. Moreover, the study of existence problem for smooth orientation preserving involutions on $H{\Bbb C}P^3$ is completed.Comment: 10 pages, final versio

Genital Chlamydia trachomatis: understanding the roles of innate and adaptive immunity in vaccine research.

Chlamydia trachomatis is the leading cause of bacterial sexually transmitted disease worldwide, and despite significant advances in chlamydial research, a prophylactic vaccine has yet to be developed. This Gram-negative obligate intracellular bacterium, which often causes asymptomatic infection, may cause pelvic inflammatory disease (PID), ectopic pregnancies, scarring of the fallopian tubes, miscarriage, and infertility when left untreated. In the genital tract, Chlamydia trachomatis infects primarily epithelial cells and requires Th1 immunity for optimal clearance. This review first focuses on the immune cells important in a chlamydial infection. Second, we summarize the research and challenges associated with developing a chlamydial vaccine that elicits a protective Th1-mediated immune response without inducing adverse immunopathologies

A classification of smooth embeddings of 3-manifolds in 6-space

We work in the smooth category. If there are knotted embeddings S^n\to R^m, which often happens for 2m<3n+4, then no concrete complete description of embeddings of n-manifolds into R^m up to isotopy was known, except for disjoint unions of spheres. Let N be a closed connected orientable 3-manifold. Our main result is the following description of the set Emb^6(N) of embeddings N\to R^6 up to isotopy. The Whitney invariant W : Emb^6(N) \to H_1(N;Z) is surjective. For each u \in H_1(N;Z) the Kreck invariant \eta_u : W^{-1}u \to Z_{d(u)} is bijective, where d(u) is the divisibility of the projection of u to the free part of H_1(N;Z). The group Emb^6(S^3) is isomorphic to Z (Haefliger). This group acts on Emb^6(N) by embedded connected sum. It was proved that the orbit space of this action maps under W bijectively to H_1(N;Z) (by Vrabec and Haefliger's smoothing theory). The new part of our classification result is determination of the orbits of the action. E. g. for N=RP^3 the action is free, while for N=S^1\times S^2 we construct explicitly an embedding f : N \to R^6 such that for each knot l:S^3\to R^6 the embedding f#l is isotopic to f. Our proof uses new approaches involving the Kreck modified surgery theory or the Boechat-Haefliger formula for smoothing obstruction.Comment: 32 pages, a link to http://www.springerlink.com added, to appear in Math. Zei

Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion.

Endothelial connexin40 (Cx40) contributes to regulate the structure and function of vessels. We have examined whether the protein also modulates the altered growth of vessels in tumor models established in control mice (WT), mice lacking Cx40 (Cx40-/-), and mice expressing the protein solely in endothelial cells (Tie2-Cx40). Tumoral angiogenesis and growth were reduced, whereas vessel perfusion, smooth muscle cell (SMC) coverage and animal survival were increased in Cx40-/- but not Tie2-Cx40 mice, revealing a critical involvement of endothelial Cx40 in transformed tissues independently of the hypertensive status of Cx40-/- mice. As a result, Cx40-/- mice bearing tumors survived significantly longer than corresponding controls, including after a cytotoxic administration. Comparable observations were made in WT mice injected with a peptide targeting Cx40, supporting the Cx40 involvement. This involvement was further confirmed in the absence of Cx40 or by peptide-inhibition of this connexin in aorta-sprouting, matrigel plug and SMC migration assays, and associated with a decreased expression of the phosphorylated form of endothelial nitric oxide synthase. The data identify Cx40 as a potential novel target in cancer treatment

REST represses a subset of the pancreatic endocrine differentiation program.

To contribute to devise successful beta-cell differentiation strategies for the cure of Type 1 diabetes we sought to uncover barriers that restrict endocrine fate acquisition by studying the role of the transcriptional repressor REST in the developing pancreas. Rest expression is prevented in neurons and in endocrine cells, which is necessary for their normal function. During development, REST represses a subset of genes in the neuronal differentiation program and Rest is down-regulated as neurons differentiate. Here, we investigate the role of REST in the differentiation of pancreatic endocrine cells, which are molecularly close to neurons. We show that Rest is widely expressed in pancreas progenitors and that it is down-regulated in differentiated endocrine cells. Sustained expression of REST in Pdx1(+) progenitors impairs the differentiation of endocrine-committed Neurog3(+) progenitors, decreases beta and alpha cell mass by E18.5, and triggers diabetes in adulthood. Conditional inactivation of Rest in Pdx1(+) progenitors is not sufficient to trigger endocrine differentiation but up-regulates a subset of differentiation genes. Our results show that the transcriptional repressor REST is active in pancreas progenitors where it gates the activation of part of the beta cell differentiation program

Tumor-Microenvironment Characterization of the MB49 Non-Muscle-Invasive Bladder-Cancer Orthotopic Model towards New Therapeutic Strategies.

Bacillus Calmette-Guérin (BCG) instillations for the treatment of non-muscle-invasive bladder cancer patients can result in significant side effects and treatment failure. Immune checkpoint blockade and/or decreasing tumor-infiltrating myeloid suppressor cells may be alternative or complementary treatments. Here, we have characterized immune cell infiltration and chemoattractant molecules in mouse orthotopic MB49 bladder tumors. Our data show a 100-fold increase in CD45 &lt;sup&gt;+&lt;/sup&gt; immune cells from day 5 to day 9 tumors including T cells and mainly myeloid cells. Both monocytic myeloid-derived suppressor-cells (M-MDSC) and polymorphonuclear (PMN)-MDSC were strongly increased in day 9 tumors, with PMN-MDSC representing ca. 70% of the myeloid cells in day 12 tumors, while tumor associated macrophages (TAM) were only modestly increased. The kinetic of PD-L1 tumor expression correlated with published data from patients with PD-L1 expressing bladder tumors and with efficacy of anti-PD-1 treatment, further validating the orthotopic MB49 bladder-tumor model as suitable for designing novel therapeutic strategies. Comparison of chemoattractants expression during MB49 bladder tumors grow highlighted CCL8 and CCL12 (CCR2-ligands), CCL9 and CCL6 (CCR-1-ligands), CXCL2 and CXCL5 (CXCR2-ligands), CXCL12 (CXCR4-ligand) and antagonist of C5/C5a as potential targets to decrease myeloid suppressive cells. Data obtained with a single CCR2 inhibitor however showed that the complex chemokine crosstalk would require targeting multiple chemokines for anti-tumor efficacy

Intravesical Ty21a vaccine promotes dendritic cells and T cell-mediated tumor regression in the MB49 bladder cancer model

Preclinical data shows that intravesical instillation of Ty21a/Vivotif\uae, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus-Calmette-Gu\ue9rin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). Here we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor-regression towards the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 106 to 108 colony-forming units. By immunohistochemistry and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but effective, doses of Ty21a. Flow cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C+CD103+ dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4+ and CD8+ T cells, but not NK cells nor neutrophils, were required for effective Ty21a bladder tumor responses. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms of intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients

Cohomological tautness for Riemannian foliations

In this paper we present some new results on the tautness of Riemannian foliations in their historical context. The first part of the paper gives a short history of the problem. For a closed manifold, the tautness of a Riemannian foliation can be characterized cohomologically. We extend this cohomological characterization to a class of foliations which includes the foliated strata of any singular Riemannian foliation of a closed manifold

Immunogenic Human Papillomavirus Pseudovirus-Mediated Suicide-Gene Therapy for Bladder Cancer.

Bladder cancer is the second most common urological malignancy in the world. In 70% of cases it is initially diagnosed as non-muscle-invasive bladder cancer (NMIBC) and it is amenable to local treatments, with intravesical (IVES) Bacillus-Calmette-Guerin (BCG) immunotherapy being routinely used after transurethral resection of the lesion. However, this treatment is associated with significant side-effects and treatment failures, highlighting the necessity of novel strategies. One potent approach is the suicide-gene mediated therapy/prodrug combination, provided tumor-specificity can be ensured and anti-tumor immune responses induced. Using the mouse syngeneic orthotopic MB49-bladder tumor model, here we show that IVES human papillomavirus non-replicative pseudovirions (PsV) can pseudoinfect tumors with a ten-fold higher efficacy than normal bladders. In addition, PsV carrying the suicide-gene herpes-simplex virus thymidine kinase (PsV-TK) combined to Ganciclovir (GCV) led to immunogenic cell-death of tumor cells in vitro and to MB49-specific CD8 T-cells in vivo. This was associated with reduction in bladder-tumor growth and increased mice survival. Altogether, our data show that IVES PsV-TK/GCV may be a promising alternative or combinatory treatment for NMIBC