Assessing low laser damage densities of fused silica optics by means of a functional raster scan protocol.

The knowledge of the laser damage resistance of fused silica optics for their use in high-power lasers is of primary importance for the operation and maintenance of these facilities. Among the control procedures developed, one of the most relevant to date is the raster scan procedure [Lamaignère et al., Rev. Sci. Instrum. 78, 103105 (2007)]. This procedure is used to determine the damage density of optical components as a function of fluence. To date, this procedure takes into account all triggered damage sites, regardless of their size and/or morphology. We have added a step to this procedure, which consists in irradiating again all the damage sites with a series of shots to ascertain their ability to grow. This allows us to estimate the densities of growing damage sites, which are most critical for the safe operation of lasers. This pragmatic approach can be considered a functional test procedure. By applying this procedure to large optical areas, we were then able to measure extremely low damage densities (∼10-4 damage cm-2) over a wide range of fluences [0-18 J cm-2], corresponding to fluences to which the optics are irradiated during the operation of high-power lasers. We can then determine the damage law of a given set of optical components. This reference law makes it possible, on the one hand, to predict the lifetime of the optics. On the other hand, any deviation can then be analyzed with regard to this reference law. Thanks to the determination of confidence intervals, this functional procedure can also be used to delimit the reference law by upper and lower bounds.

Inter- and intraobserver consistency in assessing eligibility for bevacizumab (BVZ) in non-small-cell lung cancer (NSCLC) patients with centrally located tumors.

BACKGROUND: Bevacizumab (BVZ) combined with platinum-based therapy is registered for first-line treatment of nonsquamous non-small-cell lung cancer (NSCLC). Patients with centrally located tumors are stated ineligible for BVZ treatment. The goal of this study was to assess the consistency in evaluating eligibility of patients with central tumors for BVZ treatment. MATERIALS AND METHODS: The study group was composed of 150 NSCLC patients with centrally located tumors. Eligibility for BVZ was assessed by chest computed tomography (CT) scan. Eligibility was assessed independently using CT images reviewed on workstations. Inter- and intraobserver variations on 50 randomly extracted patients were estimated through a statistical modeling (multiple correspondence analysis). RESULTS: Discordance in eligibility was found for 82 patients (55%). The interobserver strength of agreement was fair to moderate (average kappa = 0.40). Contrarily, the intraobserver strength of agreement was good to very good (average kappa = 0.74). At multivariate analysis, the risk of discrepancy was essentially related to the assessment of the contact between the tumor and the vessels (odds ratio = 13.3, 95% confidence interval 2.8-62.6, P = 0.001). CONCLUSIONS: The consistency in evaluating eligibility of patients with central tumors for BVZ treatment is weak. The study group indicated more stringent criteria to help physicians in taking the best treatment choice that need however to be prospectively validated.

Surveillance of avian influenza in the Caribbean through the Caribbean Animal Health Network: surveillance tools and epidemiologic studies.

The Caribbean region is considered to be at risk for avian influenza (AI) due to a large backyard poultry system, an important commercial poultry production system, the presence of migratory birds, and disparities in the surveillance systems. The Caribbean Animal Health Network (CaribVET) has developed tools to implement AI surveillance in the region with the goals to have 1) a regionally harmonized surveillance protocol and specific web pages for AI surveillance on www.caribvet.net, and 2) an active and passive surveillance for AI in domestic and wild birds. A diagnostic network for the Caribbean, including technology transfer and AI virus molecular diagnostic capability in Guadeloupe (real-time reverse transcription-polymerase chain reaction for the AI virus matrix gene), was developed. Between 2006 and 2009, 627 samples from four Caribbean countries were tested for three circumstances: importation purposes, following a clinical suspicion of AI, or through an active survey of wild birds (mainly waders) during the southward and northward migration periods in Guadeloupe. None of the samples tested were positive, suggesting a limited role of these species in the AI virus ecology in the Caribbean. Following low pathogenic H5N2 outbreaks in the Dominican Republic in 2007, a questionnaire was developed to collect data for a risk analysis of AI spread in the region through fighting cocks. The infection pathway of the Martinique commercial poultry sector by AI, through introduction of infected cocks, was designed, and recommendations were provided to the Caribbean Veterinary Services to improve cock movement control and biosecurity measures. The CaribVET and its organization allowed interaction between diagnostic and surveillance tools on the one hand and epidemiologic studies on the other, both of them developed in congruence with regional strategies. Together, these CaribVET activities contribute to strengthening surveillance of avian influenza virus (AIV) in the Caribbean region and may allow the development of research studies on both AI risk analysis and on AIV ecology.

[Diffusion-weighted MR imaging of liver pathology: principles and clinical applications]. / Imagerie par résonance magnétique de diffusion (IRMD) en pathologie hépatique: principe et applications cliniques.

Due to ongoing technological advances, the range of clinical applications for diffusion-weighted MR imaging has expanded to now include abdominal pathology. Current applications for liver pathology include two main directions. First, oncologic imaging with detection, characterization and follow-up of lesions. Second, evaluation of diffuse liver diseases, including hepatic fibrosis. The diagnostic impact and role of diffusion-weighted MR imaging remain under investigation, but appear promising. Because of its short acquisition time, sensitivity, and additional information it provides, diffusion-weighted MR imaging should be included in routine liver imaging protocols.

Universality of solar-wind turbulent spectrum from MHD to electron scales.

To investigate the universality of magnetic turbulence in space plasmas, we analyze seven time periods in the free solar wind under different plasma conditions. Three instruments on Cluster spacecraft operating in different frequency ranges give us the possibility to resolve spectra up to 300 Hz. We show that the spectra form a quasiuniversal spectrum following the Kolmogorov's law approximately k(-5/3) at MHD scales, a approximately k(-2.8) power law at ion scales, and an exponential approximately exp[-sqrt[k(rho)e]] at scales k(rho)e approximately [0.1,1], where rho(e) is the electron gyroradius. This is the first observation of an exponential magnetic spectrum in space plasmas that may indicate the onset of dissipation. We distinguish for the first time between the role of different spatial kinetic plasma scales and show that the electron Larmor radius plays the role of a dissipation scale in space plasma turbulence.

[Excellent performances of Wells' score and of the modified Wells' score for the diagnosis of proximal or distal deep venous thrombosis in outpatients or inpatients at Toulouse University Hospital: TVP-PREDICT study]. / Excellentes performances du score de Wells et du score de Wells modifié dans le diagnostic de thrombose veineuse profonde proximale ou distale chez des patients hospitalisés ou ambulatoires au CHU de Toulouse: étude TVP-PREDICT.

AIM OF THE STUDY: In order to validate a standardized strategy for the diagnosis of lower limb deep vein thrombosis (DVT) in the regional university hospital of Toulouse, we decided to study the performances of Wells' score and the modified Wells' score for the diagnosis of proximal and distal DVT. METHOD: Inpatients or outpatients referred to the vascular medicine department from April 2006 to March 2007 with suspected DVT were included prospectively and consecutively. Wells' score was determined for each patient and compared with the duplex ultrasound result. RESULTS: Two hundred and ninety-seven patients were included. The prevalence of DVT was 13.5%. The negative predictive values of Wells' score and the modified Wells' score were 99 and 97% respectively. Similar results were found for proximal or distal thrombosis. The performances of the modified Wells' score were not statistically better than those of the original score. In 48% of patients, the determination of the D-dimers would not have been contributory. In the group with low probability (70% of patients), the incidence of thrombosis was 0.6%. CONCLUSION: Wells' score and Wells' modified score have shown excellent performances. The value of the modified Wells' score is not superior and our preference, for practical reasons, goes to the original score. The widespread use of duplex ultrasound, the large proportion of patients in which D-dimers would not have been contributory and the excellent results of Wells score for patients with a low probability of DVT are encouraging arguments in favor of the development of an alternative strategy for these patients.

[Imaging of incidental cystic lesions of the pancreas]. / Imagerie des lésions kystiques du pancréas de découverte fortuite.

Cystic lesions of the pancreas, with an estimated prevalence of 20%, frequently are incidental findings at imaging on asymptomatic patients. Pseudocysts, typically in a setting of pancreatitis, should first be excluded. Characterization of cystic tumors is more complicated. Still, it is important to differentiate between benign and malignant lesions. Multi-detector row CT and MRI allow characterization of such lesions in over 75% of cases. Indeterminate lesions should undergo endoscopic US with biopsy/aspiration and fluid analysis, especially for mucin producing tumors (rounded with thick enhancing wall). When imaging fails to fully characterize a lesion, follow-up may be proposed for lesions less than 3 cm in size, that are either unilocular with thin nonenhancing wall (simple cyst) or lobulated multilocular with thin nonenhancing wall (serous cystadenoma, isolated side branch IPMTP). Follow-up imaging shows that these tumors usually show very little change over time. Management is based on comparing estimated patient survival without treatment to surgical risks (morbidity, mortality, functional sequelae from the procedure).

Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney.

Erythropoietin (Epo)-producing cells were identified in the murine hypoxic kidney by in situ hybridization. Profound anemia was induced in order to greatly increase Epo production. This resulted in high levels of Epo mRNA in the kidney. 35S-labeled DNA fragments of the murine Epo gene were used as probes for in situ hybridization. Control experiments conducted in parallel included kidneys of nonanemic mice, RNase-treated hypoxic kidney sections, and 35S-labeled non-Epo-related DNA. The Epo probe gave a specific hybridization signal in the hypoxic kidney in the cortex and to a lesser extent in the outer medulla. Glomerular and tubular cells were not labeled. All positive cells were identified as peritubular cells. Using immunofluorescence, we showed that cells with the same topography contained Factor VIII-related antigen. These data demonstrated that peritubular cells, most likely endothelial cells, constitute the major site of Epo production in the murine hypoxic kidney.

Expression of the erythropoietin gene.

Injection of cobalt into rats resulted in erythropoietin (EPO) mRNA accumulation in the kidney. The same response was obtained upon bleeding. No EPO mRNA was detected in the spleen, salivary gland, or thymus following cobalt injection or bleeding. In some animals, but not in others, EPO mRNA was also expressed in the liver in response to cobalt injection. Time course studies showed that message appearance begins sometime between 3 and 6 h after cobalt injection. This correlated very well with the EPO concentration in the circulation; EPO levels in the circulation were the same as those of controls at 3 h but increased to six- to sevenfold that of controls by 6 h after cobalt injection. The mature EPO mRNA in the rat and mouse comigrated with the 18S rRNA, indicating that it is about 1,850 nucleotides in length.

A sequence of the CIS gene promoter interacts preferentially with two associated STAT5A dimers: a distinct biochemical difference between STAT5A and STAT5B.

Two distinct genes encode the closely related signal transducer and activator of transcription proteins STAT5A and STAT5B. The molecular mechanisms of gene regulation by STAT5 and, particularly, the requirement for both STAT5 isoforms are still undetermined. Only a few STAT5 target genes, among them the CIS (cytokine-inducible SH2-containing protein) gene, have been identified. We cloned the human CIS gene and studied the human CIS gene promoter. This promoter contains four STAT binding elements organized in two pairs. By electrophoretic mobility shift assay studies using nuclear extracts of UT7 cells stimulated with erythropoietin, we showed that these four sequences bound to STAT5-containing complexes that exhibited different patterns and affinities: the three upstream STAT binding sequences bound to two distinct STAT5-containing complexes (C0 and C1) and the downstream STAT box bound only to the slower-migrating C1 band. Using nuclear extracts from COS-7 cells transfected with expression vectors for the prolactin receptor, STAT5A, and/or STAT5B, we showed that the C1 complex was composed of a STAT5 tetramer and was dependent on the presence of STAT5A. STAT5B lacked this property and bound with a stronger affinity than did STAT5A to the four STAT sequences as a homodimer (C0 complex). This distinct biochemical difference between STAT5A and STAT5B was confirmed with purified activated STAT5 recombinant proteins. Moreover, we showed that the presence on the same side of the DNA helix of a second STAT sequence increased STAT5 binding and that only half of the palindromic STAT binding sequence was sufficient for the formation of a STAT5 tetramer. Again, STAT5A was essential for this cooperative tetrameric association. This property distinguishes STAT5A from STAT5B and could be essential to explain the transcriptional regulation diversity of STAT5.

MR lymphography of abdominal and retroperitoneal lymphatic vessels.

OBJECTIVE: The abdominal and retroperitoneal lymphatic system is characterized by numerous anatomic variations. Our objective is to review MR lymphographic features of normal anatomy and abnormal conditions. CONCLUSION: MR lymphography is a noninvasive technique that is well suited for the examination of abdominal and retroperitoneal lymphatic vessels.

[Imaging of thoracic pathology in patients with AIDS]. / Imagerie des pathologies thoraciques chez le patient VIH au stade sida.

The imaging features of infectious and non-infectious pathologies in HIV patients with AIDS (less than 200 CD4/mm3) are illustrated. Opportunistic infections, tumors and vascular pathologies have variable appearances based on the degree of immunosuppression and patient compliance with opportunistic infection prophylaxis. Because of advances in retroviral treatments and wider use of anti-infectious prophylaxis, thoracic pathologies in AIDS patients are less frequent but must nonetheless be recognized, and diagnosis should be suggested in patients with unknown serologic status.

[Pineapple juice as a negative oral contrast agent in magnetic resonance cholangiopancreatography]. / Utilisation du jus d'ananas en tant qu'agent de contraste négatif en cholangiopancréatographie par résonance magnétique*

PURPOSE: The quality of magnetic resonance cholangiopancreatography (MRCP) images is frequently degraded by high signal from the gastrointestinal tract on heavily T2W images. The purpose of this study is to evaluate pineapple juice (PJ) as an oral negative contrast agent in MRCP. MATERIALS AND METHODS: Results from MRCP in 50 patients with PJ and 50 patients with paramagnetic contrast (ferumoxsil-Lumirem) were compared. Reviewers were blinded to the type of contrast agent. Exam quality was recorded with regards to signal suppression in the stomach, duodenum and proximal small bowel and with regards to pancreatic duct and biliary ducts visualization. In vitro, the signal characteristics of several commercially available brands of PJ were assessed using T1W, T2W and MRCP sequences. Signal intensity was correlated with the manganese concentration measured using atomic absorption spectrometry. Finally, the reviewers compared the taste of PJ and ferumoxsil. RESULTS: On MRCP sequences, results were similar with regards to signal suppression in the stomach, duodenum and proximal small bowel with PJ and ferumoxsil. Visualization of the pancreatic duct, intrahgepatic bile ducts and CBD was similar with PJ and ferumoxsil. The signal intensity of commercially available brands of PJ on T2W and MRCP sequences correlated well with the measured manganese concentration on spectroscopy. Variations in manganese concentration were observed, with values ranging from 3.65 to 27.24 mg/L. The reviewers noted that PJ tasted "good" or "very good" and that ferumoxsil tasted "bad" or "very bad". CONCLUSION: Ingestion of PJ provides effective signal suppression in the GI tract on MRCP, similar to paramagnetic contrast agents. Because manganese concentration is highly variable in commercially available PJ brands, a brand with high manganese concentration should be selected.

High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells.

Alterations in metabolic activities are cancer hallmarks that offer a wide range of new therapeutic opportunities. Here we decipher the interplay between mTORC1 activity and glucose metabolism in acute myeloid leukemia (AML). We show that mTORC1 signaling that is constantly overactivated in AML cells promotes glycolysis and leads to glucose addiction. The level of mTORC1 activity determines the sensitivity of AML cells to glycolysis inhibition as switch-off mTORC1 activity leads to glucose-independent cell survival that is sustained by an increase in mitochondrial oxidative phosphorylation. Metabolic analysis identified the pentose phosphate pathway (PPP) as an important pro-survival pathway for glucose metabolism in AML cells with high mTORC1 activity and provided a clear rational for targeting glucose-6-phosphate dehydrogenase (G6PD) in AML. Indeed, our analysis of the cancer genome atlas AML database pinpointed G6PD as a new biomarker in AML, as its overexpression correlated with an adverse prognosis in this cohort. Targeting the PPP using the G6PD inhibitor 6-aminonicotinamide induces in vitro and in vivo cytotoxicity against AML cells and synergistically sensitizes leukemic cells to chemotherapy. Our results demonstrate that high mTORC1 activity creates a specific vulnerability to G6PD inhibition that may work as a new AML therapy.

Abnormal erythropoietin (Epo) gene expression in the murine erythroleukemia IW32 cells results from a rearrangement between the G-protein beta2 subunit gene and the Epo gene.

Abnormal production of erythropoietin (Epo) has been described in several human and murine erythroleukemia. The murine IW32 cell line is derived from an F-MuLV-induced erythroleukemia. An autocrine Epo production due to the rearrangement of one Epo allele has been previously described (Beru et al., 1989). However, the exact mechanism leading to the transcriptional activation of the abnormal Epo gene was unknown. In this study, we show that this deregulated expression results from a deletion within chromosome 5. The Epo gene in the abnormal allele is under the control of the G-protein beta2 subunit gene promoter and the expressed mRNA results from the fusion of the non coding exon 1 of the G-protein beta2 subunit gene to a truncated Epo exon 1 gene. This resulting abnormal cDNA allows the expression of a normal Epo protein.

c-kit mRNA expression in human and murine hematopoietic cell lines.

The c-kit proto-oncogene belongs to the tyrosine kinase receptor family. Although its ligand is still unknown, there is increasing evidence to suggest its involvement in hematopoiesis. In order to detect lineage or differentiation related specificity, we have studied c-kit mRNA expression in both human and murine hematopoietic organs and cell lines. We show that c-kit mRNA expression is found at early stages of erythroid and myeloid differentiation. There is however, no evidence of c-kit expression in the lymphoid lineage. Our results suggest a possible role for c-kit as a receptor in the early stages of the erythroid/myeloid differentiation.

Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation.

Spi-1 transcriptional activation and wild-type p53 extinction are two oncogenic alterations involved in the malignant transformation of erythroblasts during the Friend acute erythroleukemia. To dissect the contribution of these alterations in the deregulation of the differentiation and proliferation of erythroblasts, we generated spi-1 transgenic mice. Analysis of these animals revealed that Spi-1 overexpression was directly involved in the block of proerythroblast differentiation. However, the erythroleukemia that develops in these animals evolved in two steps. During the early step (HS1 step), non tumorigenic proerythroblasts remained strictly dependent upon erythropoietin (Epo) for their survival and proliferation. Later on, Epo-independent and tumorigenic proerythroblasts emerged (HS2 step) suggesting that other oncogenes cooperate with Spi-1 to lead to a fully malignant phenotype. By provirus tagging, we demonstrate that the HS1 step was clonal indicating that a cell selection must occur in vivo. Analysis of the nature of p53 in both the in vivo HS1 and HS2 proerythroblasts and in cultured erythroblastic cell lines showed that--p53 was normal in the HS1 primary tissues but was mutated in the HS1 cultured cell lines--p53 was frequently altered in HS2 primary tissues but was found normal in some mice. These data indicate that (i) the blockage of the erythroblast differentiation by Spi-1 occurs independently of p53 alteration (ii) p53 alteration is not necessary to confer Epo independence and tumorigenicity to spi-1 transgenic proerythroblasts.

Role of Gab proteins in phosphatidylinositol 3-kinase activation by thrombopoietin (Tpo).

In this study, we show that upon thrombopoietin (Tpo) stimulation the two adapter proteins Gab1 and Gab2 are strongly tyrosine phosphorylated and associated with Shc, SHP2, PI 3-kinase and Grb2 in mpl-expressing UT7 cells. Although Gab1 and Gab2 seem to mediate overlapping biological signals in many cells, only Gab1 is expressed and phosphorylated in response to Tpo in primary human megakaryocytic progenitors; furthermore, it associates with the same proteins. Although a low level of tyrosine phosphorylated IRS-2 protein is also detected in PI 3-kinase immunoprecipitates, Gab proteins are the essential proteins associated with PI 3-kinase after Tpo stimulation. We demonstrate that, albeit no association is detected between the Tpo receptor mpl and Gab proteins, Y112 located in the C-terminal cytoplasmic domain of mpl is required for Gab1/2 tyrosine phosphorylation. Gab proteins are not tyrosine phosphorylated after Tpo stimulation of UT-7 and Ba/F3 cells expressing a mpl mutant lacking Y112. Moreover, no activation of the PI 3-kinase/Akt pathway is observed in cells expressing this mpl mutant. Finally, we show that this mutant does not allow cell proliferation, thereby confirming that PI 3-kinase activation is required for Tpo-induced cell proliferation.

Effect of 3,4-dihydroxybutyl-1-phosphonate on cardiolipin synthesis in B. subtilis.

Endogenous phosphatidylglycerol is rapidly transformed into cardiolipin when B. subtilis 168 cells were incubated in a buffer without an energy source. Upon addition of 3,4-dihydroxybutyl-1-phosphonate (DHBP), a synthetic glycerol 3-phosphate analogue, this synthesis was completely blocked after a short lag; if the cells were grown in the presence of the analogue, there was no lag. When membrane fractions were incubated with exogenous [32P]phosphatidylglycerol, free DHBP and glycerol 3-phosphate had no effect on [32P]cardiolipin synthesis, but phosphatidyl-DHBP and phosphatidylglycerolphosphate were potent inhibitors. These results are consistent with our hypothesis that phosphatidylglycerolphosphate, the phosphatidylglycerol precursor, might also be a physical inhibitor of cardiolipin synthesis.