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A comprehensive comparison of the dominant sources of radiation-induced blur for radiographic imaging system performance is made. End-point energies of 6, 10, 15, and 20 MeV bremsstrahlung photon radiation produced at the Los Alamos National Laboratory Microtron facility were used to examine the performance of large-panel cerium-doped lutetium yttrium silicon oxide (LYSO:Ce) scintillators 3, 5 and 10 mm thick. The system resolution was measured and compared between the various end-point energies and scintillator thicknesses. Contrary to expectations, it is found that there was only a minor dependence of system resolution on scintillator thickness or beam end-point energy. This indicates that increased scintillator thickness does not have a dramatic effect on system performance. The data are then compared to Geant4 simulations to assess contributions to the system performance through the examination of modulation transfer functions. It was determined that the low-frequency response of the system is dominated by the radiation-induced signal, while the higher-frequency response of the system is dominated by the optical imaging of the scintillation emission.

High-energy X-ray radiographic image restoration is performed using a simulated radiation point spread function and an experimentally derived optical point spread function. It is shown that a robust method for removal of thick monolithic scintillator blur can be determined through independent examination of the blur components. We show that the scintillator blur for a 20 MeV end-point X-ray beam and 20 mm thick LYSO scintillator contributes significantly to the system blur. It is also shown that the optical scatter in the monolithic crystal degrades the low-frequency response of the system. The use of a simulated point spread function for image restoration using deconvolution provides a simple method for image restoration, thereby enhancing feature identification and areal density reconstruction.

The single tyrosyl-tRNA synthetase (TyrRS) gene in trypanosomatid genomes codes for a protein that is twice the length of TyrRS from virtually all other organisms. Each half of the double-length TyrRS contains a catalytic domain and an anticodon-binding domain; however, the two halves retain only 17% sequence identity to each other. The structural and functional consequences of this duplication and divergence are unclear. TyrRS normally forms a homodimer in which the active site of one monomer pairs with the anticodon-binding domain from the other. However, crystal structures of Leishmania major TyrRS show that, instead, the two halves of a single molecule form a pseudo-dimer resembling the canonical TyrRS dimer. Curiously, the C-terminal copy of the catalytic domain has lost the catalytically important HIGH and KMSKS motifs characteristic of class I aminoacyl-tRNA synthetases. Thus, the pseudo-dimer contains only one functional active site (contributed by the N-terminal half) and only one functional anticodon recognition site (contributed by the C-terminal half). Despite biochemical evidence for negative cooperativity between the two active sites of the usual TyrRS homodimer, previous structures have captured a crystallographically-imposed symmetric state. As the L. major TyrRS pseudo-dimer is inherently asymmetric, conformational variations observed near the active site may be relevant to understanding how the state of a single active site is communicated across the dimer interface. Furthermore, substantial differences between trypanosomal TyrRS and human homologs are promising for the design of inhibitors that selectively target the parasite enzyme.

The great power of protein crystallography to reveal biological structure is often limited by the tremen26 dous effort required to produce suitable crystals. A hybrid crystal growth predictive model is presented 27 that combines both experimental and sequence-derived data from target proteins, including novel vari28 ables derived from physico-chemical characterization such as R30, the ratio between a protein’s DSF 29 intensity at 30 C and at Tm. This hybrid model is shown to be more powerful than sequence-based pre30 diction alone – and more likely to be useful for prioritizing and directing the efforts of structural genom31 ics and individual structural biology laboratories. 32

This study sought to determine whether the quality of enzyme preparations can be determined from their melting curves, which may easily be obtained using a fluorescent probe and a standard reverse transcription-polymerase chain reaction (RT-PCR) machine. Thermal melt data on 31 recombinant enzymes from Plasmodium parasites were acquired by incrementally heating them to 90 degrees C and measuring unfolding with a fluorescent dye. Activity assays specific to each enzyme were also performed. Four of the enzymes were denatured to varying degrees with heat and sodium dodecyl sulfate (SDS) prior to the thermal melt and activity assays. In general, melting curve quality was correlated with enzyme activity; enzymes with high-quality curves were found almost uniformly to be active, whereas those with lower quality curves were more varied in their catalytic performance. Inspection of melting curves of bovine xanthine oxidase and Entamoeba histolytica cysteine protease 1 allowed active stocks to be distinguished from inactive stocks, implying that a relationship between melting curve quality and activity persists over a wide range of experimental conditions and species. Our data suggest that melting curves can help to distinguish properly folded proteins from denatured ones and, therefore, may be useful in selecting stocks for further study and in optimizing purification procedures for specific proteins.

Fundamento El perfil farmacologico del propofol ha facilitado su uso en la sedacion prolongada de pacientes con enfermedad pulmonar en cuidados intensivos. Los efectos del propofol sobre el corazon y la circulacion sistemica han sido estudiados con detalle. Sin embargo, sus efectos sobre la circulacion pulmonar son menos conocidos. En este estudio analizamos los efectos del propofol sobre la vasoconstriccion pulmonar hipoxica (VPH). Metodos Se midieron los cambios de la vasoconstriccion pulmonar por hipoxia y angiotensina II antes y tras administrar propofol e intralipid en 42 preparaciones de pulmones aislados de ratas. Propofol e intralipid se aportaron entre dos pares de respuestas a hipoxia (grupos B, C, D y E) y angiotensina (F). Resultados El grupo A fue el control. El grupo B fue tratado con 2 μg/ml de propofol; las respuestas a la hipoxia fueron de 10,41 (5,70) mmHg antes de propofol y 11,17 (5,17) mmHg tras propofol (p = 0,096). En el grupo C la concentracion de propofol fue de 8 μg/ml y las respuestas fueron de 7,39 (2,37) y 8,75 (2,60) (p = 0,063). En el grupo D, la preparacion fue pretratada con azul de metileno (140 μμol/l) y propofol 8 μg/ml, siendo las respuestas de 15,20 (2,28) y 15,60 (3,50) (p = 0,739). En el grupo E, se aportaron 20 μl de intralipid al 20% entre la segunda y tercera respuestas a la hipoxia. La respuesta previa a intralipid fue de 9,82 (3,96) mmHg y de 10,84 (3,68) mmHg las posteriores (p = 0,163). En el grupo F, se estudiaron 2 respuestas a angiotensina II antes y tras propofol 8 μg/ml. Las respuestas fueron de 7,55 (1,87) y 7,94 (2,40) mmHg (p = 0,41), respectivamente. Conclusiones El propofol a las concentraciones estudiadas no modifica la VPH en el pulmon aislado de rata.

Three species of Cheirolophus endemic to the Canary Islands were studied and yielded eight sesquiterpane lactones: acetylaguerin A (a new natural product), aguerin A, 11βH-11,13-dihydrodeacylageurin A, 11αH-11,13-dihydrodeacylaguerin A (not previously described), 11βH-11,13-dihydroaguerin A (new as a natural product); deacylaguerin A, cynaropicrin and aguerin B.

Resume Introduction L’eculizumab est un medicament orphelin onereux, le plus cher au monde en 2013. Malgre la rarete des indications de son Autorisation de mise sur le marche (AMM), en 2013 l’eculizumab atteignait un des postes de depenses les plus eleves de la liste de produits onereux finances en sus des groupes homogenes de malades (GHM). Objectifs (1) Decrire l’evolution de l’utilisation hors indications de l’AMM de l’eculizumab (Soliris ® ) globalement et pour transplantation sur la periode 2009–2013 dans les etablissements publics et prives non lucratifs (ex-DGF) et (2) evaluer l’impact des publications de la litterature medicale (articles originaux ou non et abstracts presentes en congres) dans la meme periode sur la tendance temporelle d’utilisation hospitaliere dans les memes etablissements de l’eculizumab (Soliris ® ) dans la transplantation et rejet d’organes. Methodes Il s’agit d’une etude ecologique temporelle sur des donnees agregees de consommation hospitaliere d’eculizumab dans la base de donnees du Programme de medicalisation des systemes d’information (PMSI). Premierement, le nombre de sejours hospitaliers trimestriels avec dispensation d’eculizumab a ete confronte a notre estimation de la consommation maximale pouvant rentrer dans le cadre de l’AMM (globalement, puis pour transplantation). Deuxiemement, les publications en faveur de l’efficacite de l’eculizumab en transplantation ont ete recueillies par le biais d’une revue systematique de la litterature. Leur impact sur les tendances temporelles d’utilisation du medicament en transplantation a ete evalue par le biais d’une regression binomiale negative avec ajustement sur les tendances temporelles et sur les variations saisonnieres. Resultats La consommation de l’eculizumab pour toutes les indications a depasse la consommation maximale pouvant rentrer dans le cadre de l’AMM a partir de la fin de l’annee 2011 et elle continue a augmenter depuis. Par ailleurs, l’utilisation de l’eculizumab pour transplantation et rejet d’organes (i.e. hors AMM) a montre visuellement une cinetique semblable a celle de la consommation pour toutes les indications, avec une rupture de niveau observee vers la fin du deuxieme trimestre 2012. En outre, le niveau de preuve des donnees d’efficacite clinique de l’eculizumab en transplantation et rejet d’organes hors AMM etait tres faible pendant la periode d’etude, les publications retrouvees ( n = 61) etant seulement des series, des rapports de cas ou bien des revues non systematiques basees dessus. Enfin, apres ajustement sur les tendances a long terme, la rupture de niveau et les variations saisonnieres, nous n’avons pas trouve d’association statistiquement significative entre la parution trimestrielle de publications en faveur de l’utilisation de l’eculizumab et les variations a court terme de la consommation du medicament pour cette indication. Neanmoins, il est difficile de separer l’effet des publications de l’extension de l’AMM du medicament vers la fin 2011. Conclusion L’eculizumab est tres probablement utilise hors indications de l’AMM en France et cette utilisation (dont transplantation et rejet d’organes) semblent augmenter. Un tres faible niveau de preuve supporte l’utilisation hors AMM de l’eculizumab en transplantation et rejet d’organes. L’impact des publications sur l’augmentation observee de l’utilisation du medicament pour cette indication n’a pas pu etre separe de celle de l’extension de son AMM vers la fin 2011.

L’echec d’une insulinotherapie intensifiee par multi-injections (MI) pose la question non resolue de la place de l’insulinotherapie par pompe, OPT2MISE est le premier essai multicentrique, randomise et controle evaluant l’efficacite de la pompe apres echec d’un schema basal-bolus optimise. Au total, 495 patients DT2 ont ete inclus dans une phase de titration des doses d’insuline de 8 semaines (dose totale ≥ 0,7 et ≤ 1,8 U/kg/j) et les patients avec une HbA 1c ≥ 8 % et ≤ 12 % randomises dans le groupe pompe (P) ou MI pendant 6 mois. L’HbA 1c et un enregistrement continu de la glycemie (CGM) ont ete effectues avant et 6 mois post-randomisation. Un total de 331 patients ont ete inclus (M/F 55/45 %, âge 56,0 ± 9,6 ans, IMC 33,4 ± 7,3, duree du diabete 15,1 ± 8,0 ans, HbA 1c 9,0 ± 0,8 %. A 6 mois, on observe une reduction de l’HbA 1c sous P vs MI (–1,1 ± 1,2 % vs –0,4 ± 1,1 %, p 1c p p p p = 0,215). Aucune hypoglycemie severe ni acidocetose n’est survenue sous pompe. En conclusion, OPT2MISE demontre l’efficacite et la securite de la pompe a insuline chez les patients DT2 en echec d’insulinotherapie intensifiee et valide son utilisation au cours du diabete de type 2.