Abraham visionnaire apocalyptique. Lectures midrashiques de Genèse 15

(Résumé de l'ouvrage) Les trois grandes religions monothéistes se partagent un même ancêtre: Abraham. Pour les juifs, il est le Juste; les chrétiens voient en lui le Père des croyants et les musulmans le nomment Ami de Dieu. Il n'y a donc pas un discours sur Abraham, mais une multitude de lectures des textes fondamentaux et superbes qui racontent le destin d'Abraham dans la Bible. Dans ce livre, on propose quelques relectures du personnage et de son accueil dans l'histoire. Les auteurs permettent ainsi de redonner à la figure emblématique d'Abraham une jeunesse oh! combien nécessaire.

Assessing the Glaucoma Quality of Life-15 (GCL-15) Questionnaire, Goldmann Tonometry and Moorfields Motion Displacement Test in Glaucoma Case Finding

Purpose: To compare the performance Glaucoma Quality of Life-15 (GQL-15) Questionnaire, intraocular pressure measurement (IOP Goldmann tonometry) and a measure of visual field loss using Moorfields Motion Displacement Test (MDT) in detecting glaucomatous eyes from a self referred population. Methods: The GQL-15 has been suggested to correlate with visual disability and psychophysical measures of visual function in glaucoma patients. The Moorfields MDT is a multi location perimetry test with 32 white line stimuli presented on a grey background on a standard laptop computer. Each stimulus is displaced between computer frames to give the illusion of "apparent motion". Participants (N=312, 90% older than 45 years; 20.5% family history of glaucoma) self referred to an advertised World Glaucoma Day (March 2009) Jules Gonin Eye Hospital, Lausanne Switzerland. Participants underwent a clinical exam (IOP, slit lamp, angle and disc examination by a general ophthalmologist), 90% completed a GQL-15 questionnaire and over 50% completed a MDT test in both eyes. Those who were classified as abnormal on one or more of the following (IOP >21 mmHg/ GQL-15 score >20/ MDT score >2/ clinical exam) underwent a follow up clinical examination by a glaucoma specialist including imaging and threshold perimetry. After the second examination subjects were classified as "healthy"(H), "glaucoma suspect" (GS) (ocular hypertension and/or suspicious disc, angle closure with SD) or "glaucomatous" (G). Results: One hundred and ten subjects completed all 4 initial examinations; of these 69 were referred to complete the 2nd examination and were classified as; 8 G, 24 GS, and 37 H. MDT detected 7/8 G, and 7/24 GS, with false referral rate of 3.8%. IOP detected 2/8 G and 8/24 GS, with false referral rate of 8.9%. GQL-15 detected 4/8 G, 16/24 GS with a false referral rate of 42%. Conclusions: In this sample of participants attending a self referral glaucoma detection event, the MDT performed significantly better than the GQL-15 and IOP in discriminating glaucomatous patients from healthy subjects. Further studies are required to assess the potential of the MDT as a glaucoma screening tool.

Airway epithelial IL-15 transforms monocytes into dendritic cells.

IL-15 has recently been shown to induce the differentiation of functional dendritic cells (DCs) from human peripheral blood monocytes. Since DCs lay in close proximity to epithelial cells in the airway mucosa, we investigated whether airway epithelial cells release IL-15 in response to inflammatory stimuli and thereby induce differentiation and maturation of DCs. Alveolar (A549) and bronchial (BEAS-2B) epithelial cells produced IL-15 spontaneously and in a time- and dose-dependent manner after stimulation with IL-1beta, IFN-gamma, or TNF-alpha. Airway epithelial cell supernatants induced an increase of IL-15Ralpha gene expression in ex vivo monocytes, and stimulated DCs enhanced their IL-15Ralpha gene expression up to 300-fold. Airway epithelial cell-conditioned media induced the differentiation of ex vivo monocytes into partially mature DCs (HLA-DR+, DC-SIGN+, CD14+, CD80-, CD83+, CD86+, CCR3+, CCR6(+), CCR7-). Based on their phenotypic (CD123+, BDCA2+, BDCA4+, BDCA1(-), CD1a-) and functional properties (limited maturation upon stimulation with LPS and limited capacity to induce T cell proliferation), these DCs resembled plasmacytoid DCs. The effects of airway epithelial cell supernatants were largely blocked by a neutralizing monoclonal antibody to IL-15. Thus, our results demonstrate that airway epithelial cell-conditioned media have the capacity to differentiate monocytes into functional DCs, a process substantially mediated by epithelial-derived IL-15.

Glutamine synthesis rate in the hyperammonaemic rat brain using simultaneous localized in vivo H-1 and N-15 MRS

Objectives: Glutamine synthetase is a critical step in the glutamate-glutamine cycle, the major mechanism of glutamate neurotransmission and is implicated in the mechanism of ammonia toxicity. 15N MRS is an alternative approach to 13C MRS in studying glutamate- glutamine metabolism. 15N MRS studies allow to measure an apparent glutamine synthesis rate (Vsyn) which reflects a combination of the glutamate- glutamine cycle activity (Vnt) and net glutamine accumulation. The net glutamine synthesis (Vsyn-Vnt) can be directly measured from 1H NMR. Therefore, the aim of this study was to perform in vivo localized 1H MRS interleaved with 15N MRS to directly measure the net glutamine synthesis rate and the apparent glutamine synthesis rate under 15N labeled ammonia infusion in the rat brain, respectively. Methods: 1H and 15N MRS data were acquired interleaved on a 9.4T system (Varian/Magnex Scientific) using 5 rats. 15NH4Cl solution was infused continuously into the femoral vein for up to 10 h (4.5 mmol/h/kg).1 The plasma ammonia concentration was increased to 0.95±0.08 mmol/L (Analox GM7 analyzer). 1H spectra were acquired and quantified as described previously.2 15N unlocalized and localized spectra were acquired using the sequence;3 and quantified using AMARES and an external reference method.4 The metabolic model used to analyze the total Gln and 5-15N labeled Gln time courses is shown on Figure 1A. Results: Glutamine concentration increased from 2.5±0.3 to 15±3.3 mmol/kg whereas the total glutamate concentrations remained unchanged (Figure 1B). The linear fit of the time-evolution of the total Gln from the 1H spectra gave the net synthesis flux (Vsyn-Vnt), which was 0.021± 0.006 mmol/min per g (Figure 1D). The 5-15N Gln peak (_271 ppm) was visible in the first and all subsequent scans, whereas the 2-15N Gln/Glu peak (_342 ppm) appeared after B1.5 h (Figure 1C). From the in vivo 5-15N Gln time course, Vsyn = 0.29±0.1 mmol/min per g and a plasma NH3 fractional enrichment of 71%±6% were calculated. Vnt was 0.26±0.1 mmol/min/g, obtained assuming a negligible Gln efflux.5 Vsyn and Vnt were within the range of 13C NMR measurements.6 Conclusion: The combination of 1H and 15N NMR allowed for the first time a direct and localized measurement of Vnt and apparent glutamine synthesis rate. Vnt is approximately one order of magnitude faster than the net glutamine accumulation.

Stimulation of thermogenesis in men after combined glucose-long-chain triglyceride infusion.

The effect of combined long-chain triglyceride infusion (Intralipid 20%) with graded doses of insulin/glucose on energy expenditure was examined in 17 healthy young male volunteers by using the euglycemic insulin clamp technique in combination with indirect calorimetry. Intralipid was infused for 90 min at a constant rate of 0.23 g/min; plasma free fatty acids increased from base-line values of 380 +/- 8 mumol/l to steady state levels of 650 +/- 12 mumol/l. After 90 min the Intralipid was continued and insulin was infused at three rates (0.5, 2, and 4 mU/kg . min) to achieve steady state hyperinsulinemic plateaus of 63 +/- 4, 167 +/- 10, and 410 +/- 15 microU/ml. Plasma glucose concentration was maintained constant at basal euglycemic levels (insulin clamp technique) by infusing glucose at 0.24, 0.48, and 0.59 g/min, respectively. Glucose storage during the insulin clamp (ie, glucose uptake minus glucose oxidation) was 0.13, 0.33, and 0.40 g/min for each group and exogenous lipid storage was 0.17, 0.18, and 0.19 g/min, respectively. The net increment in energy expenditure was 0.15, 0.24, and 0.26 kcal/min, respectively, which represents 8.5% of the energy content of the total amount of glucose and lipid stored. The experimentally determined value (approximately 9%) for the cost of storing both glucose and lipid was found to be significantly greater than predicted by stoichiometric calculations. However, the experimental value for the combined infusion was less than that observed for glucose storage alone (12%). This finding provides support for the use of combined glucose/fat infusions in parenteral nutrition as it is used more economically than when glucose is infused alone.

Cardiovascular risk estimation and eligibility for statins in primary prevention comparing different strategies

Recommendations for statin use for primary prevention of coronary heart disease (CHD) are based on estimation of the 10-year CHD risk. It is unclear which risk algorithm and guidelines should be used in European populations. Using data from a population-based study in Switzerland, we first assessed 10-year CHD risk and eligibility for statins in 5,683 women and men 35 to 75 years of age without cardiovascular disease by comparing recommendations by the European Society of Cardiology without and with extrapolation of risk to age 60 years, the International Atherosclerosis Society, and the US Adult Treatment Panel III. The proportions of participants classified as high-risk for CHD were 12.5% (15.4% with extrapolation), 3.0%, and 5.8%, respectively. Proportions of participants eligible for statins were 9.2% (11.6% with extrapolation), 13.7%, and 16.7%, respectively. Assuming full compliance to each guideline, expected relative decreases in CHD deaths in Switzerland over a 10-year period would be 16.4% (17.5% with extrapolation), 18.7%, and 19.3%, respectively; the corresponding numbers needed to treat to prevent 1 CHD death would be 285 (340 with extrapolation), 380, and 440, respectively. In conclusion, the proportion of subjects classified as high risk for CHD varied over a fivefold range across recommendations. Following the International Atherosclerosis Society and the Adult Treatment Panel III recommendations might prevent more CHD deaths at the cost of higher numbers needed to treat compared with European Society of Cardiology guidelines.

Lessons Learned from 15 Years of KIMS and 5 Years of ACROSTUDY.

Background: Pharmacoepidemiological surveys provide a valuable contribution to the continued monitoring of drug-related effects in patients with rare disorders. One of the earliest examples of this type of survey is KIGS (Pfizer International Growth Study Database), which has monitored the safety and effectiveness of growth hormone (GH) therapy in GH-deficient children since its inception in 1987. Following closely in the footsteps of KIGS is KIMS (Pfizer International Metabolic Database). As of 2009, KIMS has been collecting data on the long-term safety and clinical outcomes of GH replacement in GH-deficient adults for 15 years. Approximately 5 years ago, the ACROSTUDY database was established to monitor the long-term safety and effectiveness of pegvisomant in patients with acromegaly. Conclusions: By collecting data on the treatment of relatively rare conditions in routine clinical practice, pharmacoepidemiological surveys such as KIMS and ACROSTUDY provide valuable information on the safety and effectiveness of treatment with GH replacement and pegvisomant in the real world.

European Cardiovascular Magnetic Resonance (EuroCMR) registry--multi national results from 57 centers in 15 countries.

BACKGROUND: The EuroCMR registry sought to evaluate indications, image quality, safety and impact on patient management of clinical routine CMR in a multi-national European setting. Furthermore, interim analysis of the specific protocols should underscore the prognostic potential of CMR. METHODS: Multi-center registry with consecutive enrolment of patients in 57 centers in 15 countries. More than 27000 consecutive patients were enrolled. RESULTS: The most important indications were risk stratification in suspected CAD/Ischemia (34.2%), workup of myocarditis/cardiomyopathies (32.2%), as well as assessment of viability (14.6%). Image quality was diagnostic in more than 98% of cases. Severe complications occurred in 0.026%, always associated with stress testing. No patient died during or due to CMR. In 61.8% CMR findings impacted on patient management. Importantly, in nearly 8.7% the final diagnosis based on CMR was different to the diagnosis before CMR, leading to a complete change in management. Interim analysis of suspected CAD and risk stratification in HCM specific protocols revealed a low rate of adverse events for suspected CAD patients with normal stress CMR (1.0% per year), and for HCM patients without LGE (2.7% per year). CONCLUSION: The most important indications in Europe are risk stratification in suspected CAD/Ischemia, work-up of myocarditis and cardiomyopathies, as well as assessment of viability. CMR imaging is a safe procedure, has diagnostic image quality in more than 98% of cases, and its results have strong impact on patient management. Interim analyses of the specific protocols underscore the prognostic value of clinical routine CMR in CAD and HCM.

c-Myc controls the development of CD8alphaalpha TCRalphabeta intestinal intraepithelial lymphocytes from thymic precursors by regulating IL-15-dependent survival.

The murine gut epithelium contains a large population of thymus-derived intraepithelial lymphocytes (IELs), including both conventional CD4(+) and CD8alphabeta(+) T cells (expressing T-cell receptor alphabeta [TCRalphabeta]) and unconventional CD8alphaalpha(+) T cells (expressing either TCRalphabeta or TCRgammadelta). Whereas conventional IELs are widely accepted to arise from recirculation of activated CD4(+) and CD8alphabeta(+) T cells from the secondary lymphoid organs to the gut, the origin and developmental pathway of unconventional CD8alphaalpha IELs remain controversial. We show here that CD4-Cre-mediated inactivation of c-Myc, a broadly expressed transcription factor with a wide range of biologic activities, selectively impairs the development of CD8alphaalpha TCRalphabeta IELs. In the absence of c-Myc, CD4(-) CD8(-) TCRalphabeta(+) thymic precursors of CD8alphaalpha TCRalphabeta IELs are present but fail to develop on adoptive transfer in immunoincompetent hosts. Residual c-Myc-deficient CD8alphaalpha TCRalphabeta IEL display reduced proliferation and increased apoptosis, which correlate with significantly decreased expression of interleukin-15 receptor subunits and lower levels of the antiapoptotic protein Bcl-2. Transgenic overexpression of human BCL-2 resulted in a pronounced rescue of CD8alphaalpha TCRalphabeta IEL in c-Myc-deficient mice. Taken together, our data support a model in which c-Myc controls the development of CD8alphaalpha TCRalphabeta IELs from thymic precursors by regulating interleukin-15 receptor expression and consequently Bcl-2-dependent survival.