Le travail … c’est la santé : la santé au travail … une pratique en question

C’est en 1946 qu’est née cette institution originale qu’est la médecine du travail. Au départ, principalement basée sur une approche essentiellement individuelle, la notion d’aptitude y occupait une place centrale au sein du système de santé. Ce système a connu des évolutions où l’approche individuelle s’est peu à peu couplée à une dimension plus collective, laissant cependant encore un système largement perfectible. Dans ces évolutions, la décision d’aptitude s’est, quant à elle, complexifiée. De nombreux rapports ont d’ailleurs été écrits ces cinq dernières années afin de mettre en débat à la fois la légitimité de pérenniser un tel concept, mais également son efficacité en ce qui a trait à la prévention des pathologies liées au travail. Une loi sera sans doute prévue fin 2009, 2010… Mais qu’en sera-t-il de la pratique, quelle réalité perdurera ? Apte/inapte ? Comment peut-on aider à la compatibilité entre droit à la santé et droit au travail ? En quoi le système français de l’aptitude et de l’inaptitude a pu offrir des garanties pour l’employeur, le salarié, la société ? Tel sera l’objet de cette intervention.It was in 1946 that this new original institution, occupational medicine, was created in France. At the beginning, based mainly on an essentially individual approach, the concept of medical ability held a central place in the health system. This system has changed and the individual approach is now paired with a more collective vision, leaving the system still largely perfectible. Among these evolutions, the medical ability decision has become increasingly complex. Numerous reports have been written in the last five years to debate the legitimacy of maintaining such a concept, as well as its efficiency as far as the prevention of work-related pathologies is concerned. A law will certainly be expected at the end of 2009/beginning of 2010. But, what about practices ? What reality will remain ? Medical ability or disability… How can we help in the compatibility between the right to health and the right to work ? How has this French system, based on medical ability or disability, been able to offer guaranties to employers, workers, society ? That is the purpose of this presentation.Es en 1946 que nace esta institución original que es la medicina del trabajo. Al principio, basada principalmente en un enfoque esencialmente individual, la noción de aptitud, esta institución ocupaba un lugar central en el seno del sistema de salud. Poco a poco, ella evoluciona del enfoque individual y se asocia a una dimensión más colectiva. Dejando sin embargo, todavía un sistema grandemente perfectible. En esa evolución, la decisión de aptitud como tal, se complicó. Un gran número de informes se han escrito en los últimos cinco años con el fin de debatir la legitimidad de perpetuar tal concepto, pero también su eficacia en lo concierne la prevención de las patologías ligadas al trabajo. Una ley será sin duda prevista al final del 2009, 2010… pero ¿que será de la práctica ? ¿Qué realidad perdurará ? ¿Apto/inapto ? ¿Cómo podemos contribuir a la compatibilidad entre el derecho a la salud y el derecho al trabajo ? ¿En qué medida el sistema francés de aptitud e ineptitud pudo ofrecer garantías para el empleador, el asalariado, la sociedad ? Tal será el objetivo de esta intervención

Cell patterning for spatially standardized cell biology

The onus in modern cell biology is on the development of reproducible, develop cell patterning capabilities that are accessible to biologists and to demonstrate new and innovative analytical methods based on the spatial control of cell positioning for widespread cell biology applications as well as fundamental research applications. Plasma stencilling methods for cell patterning were developed which are simple, rapid, inexpensive, reproducible, effective and potentially universal cell line patterning techniques. PDMS micropatterning techniques were also developed to achieve a high resolution patterning capability over large areas and with absolute freedom of design while remaining efficient, cheap, simple and highly reproducible. These features make these methods accessible and desirable to biologists and microengineers alike. As a result from these developments, novel bio-analytical platforms were produced and innovative assays are presented. Cell patterning using these novel techniques was successfully used for the parallel and mass production of 3D spheroids, with high reproducibility and excellent control of the uniformity of spheroid size. A spatially standardized analytical display for high throughput neurotoxicity screening is also presented where cell patterning offers a route to standardize the neurite outgrowth lengths. In addition, a microfluidic system was also used to efficiently pattern and couple single cells by differential resistance pathway principles and validates the concept of using the natural behaviour of cells for mechanical operations within microengineered environments. Taken together, this thesis demonstrates that it is possible to exploit cell micropatterning technologies for the realization of spatially standardized, highly reproducible and quantitative cell biology assays for both fundamental research and commercial applications

A microfluidic array with cellular valving for single cell co-culture

We present a highly parallel microfluidic approach for contacting single cell pairs. The approach combines a differential fluidic resistance trapping method with a novel cellular valving principle for homotypic and heterotypic single cell co-culturing. Differential fluidic resistance was used for sequential single cell arraying, with the adhesion and flattening of viable cells within the microstructured environment acting to produce valves in the open state. Reversal of the flow was used for the sequential single cell arraying of the second cell type. Plasma stencilling, along the linear path of least resistance, was required to confine the cells within the trap regions. Prime flow conditions with minimal shear stress were identified for highly efficient cell arraying (similar to 99%) and long term cell culture. Larger trap dimensions enabled the highest levels of cell pairing (similar to 70%). The single cell co-cultures were in close proximity for the formation of connexon structures and the study of contact modes of communication. The research further highlights the possibility of using the natural behaviour of cells as the working principle behind responsive microfluidic element

Lésions endothéliales liées à un défaut de contrôle du complément (de la génétique du complément au syndrome hémolytique et urémique)

L identification fréquente de mutations des protéines régulatrices du complément suggère que les lésions endothéliales du syndrome hémolytique et urémique atypique (SHUa) résultent d une activation incontrôlée de la voie alterne du complément. Les mutations, en soi, ne constituent cependant que des facteurs de susceptibilité et les mécanismes menant de l anomalie de régulation du complément au développement de lésions de microangiopathie thrombotique rénale restent mal compris. L objectif de ce projet était donc d'étudier certains mécanismes de l activation du complément à la surface des cellules endothéliales dans le SHUa et les conséquences de cette activation pour l endothélium. Dans ce but, ce travail s est initialement concentré sur la mutation C3R139W, dont nous avons réalisé la caractérisation phénotypique et fonctionnelle et qui a constitué un modèle d étude des conséquences d un complément dérégulé sur l endothélium. Cette mutation a été identifiée de façon sporadique chez 4% des patients de la cohorte française de SHUa. Son étude phénotypique a mis en avant une évolution fonctionnelle rénale souvent sévère mais inhomogène ainsi qu une fréquence non négligeable d événements cardio-vasculaires. Sa caractérisation fonctionnelle a révélé une augmentation de son affinité pour le facteur B, à l origine de la formation d une hyper C3 convertase , échappant également en partie aux systèmes de contrôle (diminution de liaison avec la MCP). L étude de ses conséquences endothéliales a montré, à la surface de cellules pré-activées, une augmentation des produits d activation du complément et de l expression membranaire de facteur tissulaire, faisant le lien avec l acquisition d un phénotype endothélial prothrombotique. Nous rapportons également, sous l effet de sérum porteur de cette mutation, une majoration de la perméabilité et du détachement cellulaire, susceptibles de traduire une souffrance endothéliale. Dans la deuxième partie et en vue de préciser les liens entre anomalie du complément et activation des cellules endothéliales, nous nous sommes intéressés au rôle de l hémolyse, dénominateur commun des SHU. Nous avons ainsi montré que l hème libre activait la voie alterne du complément dans le sérum et à la surface des cellules endothéliales et ce, de façon exacerbé, en cas de dysrégulation sous-jacente du complément. Nous avons identifié plusieurs mécanismes d action par lesquels l hème peut activer le complément : il favorise les interactions C3/C3 et ainsi la formation d une hyper C3/C5 convertase, déclenche une mobilisation des corps de Weibel-Palade à l origine de l expression membranaire de P-selectine, qui est capable d activer la voie alterne du complément et induit une diminution de l expression membranaire des régulateurs MCP et DAF. Par ces travaux, nous avons précisé les liens entre activation du complément et acquisition d un phénotype endothélial prothrombotique dans le SHUa. Nous avons notamment identifié l hémolyse comme un acteur potentiel de l amplification des lésions endothéliales complément-dépendantes. Son contrôle pourrait ainsi constituer une nouvelle voie thérapeutique dans le SHU.Pas de résumé en anglaisPARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Spatial patterning of the Notch ligand Dll4 controls endothelial sprouting in vitro

Angiogenesis, the formation of new blood vessels, is a vital process for tissue growth and development. The Notch cell-cell signalling pathway plays an important role in endothelial cell specification during angiogenesis. Dll4 - Notch1 signalling directs endothelial cells into migrating tip or proliferating stalk cells. We used the directing properties of Dll4 to spatially control endothelial cell fate and the direction of endothelial sprouts. We created linear arrays of immobilized Dll4 using micro contact printing. HUVECs were seeded perpendicular to these Dll4 patterns using removable microfluidic channels. The Notch activating properties of surface immobilized Dll4 were confirmed by qPCR. After induction of sprouting, microscopic images of fluorescently labelled endothelial sprouts were analysed to determine the direction and the efficiency of controlled sprouting (Ecs). Directionality analysis of the sprouts showed the Dll4 pattern changes sprout direction from random to unidirectional. This was confirmed by the increase of Ecs from 54.5 +/- 3.1% for the control, to an average of 84.7 +/- 1.86% on the Dll4 patterned surfaces. Our data demonstrates a surface-based method to spatially pattern Dll4 to gain control over endothelial sprout location and direction. This suggests that spatial ligand patterning can be used to provide control over (neo) vascularization

Modeling the influence of Twitter in reducing and increasing the spread of influenza epidemics

In this paper we present compartmentalized neuron arraying (CNA) microfluidic circuits for the preparation of neuronal networks using minimal cellular inputs (10–100-fold less than existing systems). The approach combines the benefits of microfluidics for precision single cell handling with biomaterial patterning for the long term maintenance of neuronal arrangements. A differential flow principle was used for cell metering and loading along linear arrays. An innovative water masking technique was developed for the inclusion of aligned biomaterial patterns within the microfluidic environment. For patterning primary neurons the technique involved the use of meniscus-pinning micropillars to align a water mask for plasma stencilling a poly-amine coating. The approach was extended for patterning the human SH-SY5Y neuroblastoma cell line using a poly(ethylene glycol) (PEG) back-fill and for dopaminergic LUHMES neuronal precursors by the further addition of a fibronectin coating. The patterning efficiency Epatt was >75% during lengthy in chip culture, with ~85% of the outgrowth channels occupied by neurites. Neurons were also cultured in next generation circuits which enable neurite guidance into all outgrowth channels for the formation of extensive inter-compartment networks. Fluidic isolation protocols were developed for the rapid and sustained treatment of the different cellular and sub-cellular compartments. In summary, this research demonstrates widely applicable microfluidic methods for the construction of compartmentalized brain models with single cell precision. These minimalistic ex vivo tissue constructs pave the way for high throughput experimentation to gain deeper insights into pathological processes such as Alzheimer and Parkinson Diseases, as well as neuronal development and function in health

Everolimus Plus Reduced-Exposure CsA versus Mycophenolic Acid Plus Standard-Exposure CsA in Renal-Transplant Recipients

Everolimus allows calcineurin-inhibitor reduction without loss of efficacy and may improve renal-transplant outcomes. In a 24-month, open-label study, 833 de novo renal-transplant recipients were randomized to everolimus 1.5 or 3.0 mg/day (target troughs 3–8 and 6–12 ng/mL, respectively) with reduced-exposure CsA, or mycophenolic acid (MPA) 1.44 g/day plus standard-exposure CsA. Patients received basiliximab ± corticosteroids. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up) and the main safety endpoint was renal function (estimated glomerular filtration rate [eGFR], by Modification of Diet in Renal Disease [MDRD]) at Month 12 (last-observation-carried-forward analyses). Month 12 efficacy failure rates were noninferior in the everolimus 1.5 mg (25.3%) and 3.0 mg (21.9%) versus MPA (24.2%) groups. Mean eGFR at Month 12 was noninferior in the everolimus groups versus the MPA group (54.6 and 51.3 vs 52.2 mL/min/1.73 m 2 in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively; 95% confidence intervals for everolimus 1.5 mg and 3.0 mg vs MPA: −1.7, 6.4 and −5.0, 3.2, respectively). The overall incidence of adverse events was comparable between groups. The use of everolimus with progressive reduction in CsA exposure, up to 60% at 1 year, resulted in similar efficacy and renal function compared with standard-exposure CsA plus MPA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79307/1/j.1600-6143.2010.03129.x.pd

Long-Term Impact of Cyclosporin Reduction with MMF Treatment in Chronic Allograft Dysfunction: REFERENECE Study 3-Year Follow Up

Calcineurin inhibitor (CNI) toxicity contributes to chronic allograft nephropathy (CAN). In the 2-year, randomized, study, we showed that 50% cyclosporin (CsA) reduction in combination with mycophenolate mofetil (MMF) treatment improves kidney function without increasing the risk for graft rejection/loss. To investigate the long-term effect of this regimen, we conducted a follow up study in 70 kidney transplant patients until 5 years after REFERENCE initiation. The improvement of kidney function was confirmed in the MMF group but not in the control group (CsA group). Four graft losses occurred, 2 in each group (graft survival in the MMF group 95.8% and 90.9% in control group). One death occurred in the control group. There was no statistically significant difference in the occurrence of serious adverse events or acute graft rejections. A limitation is the weak proportion of patient still remaining within the control group. On the other hand, REFERENCE focuses on the CsA regimen while opinions about the tacrolimus ones are still debated. In conclusion, CsA reduction in the presence of MMF treatment seems to maintain kidney function and is well tolerated in the long term