EXAFS Debye-Waller factors issued from Car-Parrinello molecular dynamics: application to the fit of oxaliplatin and derivatives.

One of the main pitfalls in EXAFS fitting is correlation among parameters, which can lead to unreliable fits. The use of theoretical Debye-Waller factors (DWs) is a promising way to reduce the number of fitted parameters. When working with molecular dynamics, it is not only possible to evaluate DWs from the statistical distributions issued from the trajectory but also to estimate the distribution anharmonicity, and to compute simulated average EXAFS spectra that can be fitted as experimental ones, in order to assess the ability of EXAFS fitting to recover information on DWs, as well as other structural and spectroscopical parameters. The case studied is oxaliplatin, a third generation anticancer drug. The structural information and the simulated average spectra were derived from a Car-Parrinello molecular dynamics (CP-MD) trajectory of a compound closely related to oxaliplatin. We present the DWs issued from this simulation and their use, by taking their theoretical absolute values (no DW fitted) or their ratios (one DW fitted). In this second approach, the fit of oxaliplatin experimental spectra leads to DWs values very close to the theoretical ones. This shows that the CP-MD trajectory provides a good representation of the distance distributions for oxaliplatin. Transferability of oxaliplatin DWs, for all relevant single and multiple scattering paths, to closely related compounds is proven for the case of bis(oxalato)platinum(II) and bis(ethylene diamine)platinum(II).

Unveiling the Ir single atoms as selective active species for the partial hydrogenation of butadiene by operando XAS.

Single-atom catalysts represent an intense topic of research due to their interesting catalytic properties for a wide range of reactions. Clarifying the nature of the active sites of single-atom catalysts under realistic working conditions is of paramount importance for the design of performant materials. We have prepared an Ir single-atom catalyst supported on a nitrogen-rich carbon substrate that has proven to exhibit substantial activity toward the hydrogenation of butadiene with nearly 100% selectivity to butenes even at full conversion. We evidence here, by quantitative operando X-ray absorption spectroscopy, that the initial Ir single atoms are coordinated with four light atoms i.e., Ir-X4 (X = C/N/O) with an oxidation state of +3.2. During pre-treatment under hydrogen flow at 250 °C, the Ir atom loses one neighbour (possibly oxygen) and partially reduces to an oxidation state of around +2.0. We clearly demonstrate that Ir-X3 (X = C/N/O) is an active species with very good stability under reactive conditions. Moreover, Ir single atoms remain isolated under a reducing atmosphere at a temperature as high as 400 °C.

[Prolongation of anti vitamin K treatment for 18 months versus placebo after 6 months treatment of a first episode of ideopathic pulmonary embolism: a mutlicentre, randomised double blind trail. The PADIS-EP Trial]. / Prolongation d'un traitement par antivitamine K pendant dix-huit mois versus placebo au décours d'un premier épisode d'embolie pulmonaire idiopathique traité six mois: un essai randomisé multicentrique en double aveugle. Essai "PADIS-EP".

BACKGROUND: After stopping a 3 to 6 months course of oral anticoagulation for a first episode of idiopathic venous thromboembolism (VTE), the risk of recurrent VTE is high (10% per year). In this setting, international guidelines recommend at least 6 months treatment. However, this recommendation is not satisfactory for the following reasons: (1) no randomized trial has compared 6 months to extended duration (2 years) anticoagulation; and (2), even though the frequency of recurrent VTE is similar after pulmonary embolism (PE) and deep vein thrombosis (DVT), the fatality rate of recurrent VTE after PE is higher than that after DVT. METHODS: A French multicentre double blind randomized trial. The main objective is to demonstrate, after a first episode of symptomatic idiopathic PE treated for 6 months using a vitamin K antagonist, that extended anticoagulation for 18 months (INR between 2 and 3) is associated with an increased benefit / risk ratio (recurrent VTE and severe anticoagulant-related bleeding) compared to placebo. The double blind evaluation is ensured using by active warfarin and placebo, and blinded INR. The protocol was approved by the ethics board of the Brest Hospital on the 7th of March 2006. For an alpha risk of 5% and a beta risk of 20%, the estimated sample size is 374 patients. EXPECTED RESULTS: This study has the potential to: (1) demonstrate that the benefit / risk ratio of extended anticoagulation for 18 months is higher than that observed with placebo in patients with a first episode of idiopathic PE initially treated for 6 months, during and after the treatment period; and (2) to validate or invalidate the contribution of isotope lung scans, lower limb Doppler ultrasound and D-Dimer at 6 months of treatment as predictors of recurrent VTE (medico-economic analysis included).

Long-term prognosis in patients with alcoholic cardiomyopathy and severe heart failure after total abstinence.

We prospectively evaluated the long-term prognosis of 14 patients with alcoholic cardiomyopathy and severe end-stage congestive heart failure after total abstinence. Improvement was very significant after 6 months of follow-up in most patients, and continued thereafter.

Intermittent left coronary occlusion caused by native aortic valve thrombosis in a patient with protein S deficiency.

A 77-year-old woman presented with chest pain and cardiogenic shock. Transesophageal echocardiography showed a mobile mass occluding intermittently the left coronary ostium. The mass was surgically resected, and histologic examination revealed an organized thrombus. Coagulation study demonstrated a protein S deficiency. This is the first case of aortic thrombosis associated with protein S deficiency, and it is the first time that transesophageal echocardiography provided definite evidence that a mass can cause intermittent left ostium coronary obstruction.

[Endocoronary ultrasonography and quantitative coronary angiography. Correlations before and after transluminal coronary angioplasty]. / Echographie endocoronaire et coronarographie quantitative. Corrélations avant et après angioplastie transluminale coronaire.

A comparative study of the results of quantitative coronary angiography and endocoronary ultrasonography was performed in 37 patients undergoing percutaneous transluminal coronary angioplasty to determine the correlations between the two methods. The analyses were made before and after angioplasty at the site of stenosis and on a reference segment. A complete study before and after angioplasty using both techniques was only possible in 24 cases. The quantitative ultrasonographic analysis consisted of measurement of two orthogonal diameters, total surface area of the vessel, the endoluminal surface area and surface area of plaque. Transluminal coronary angioplasty acts mainly by forcing the plaque outwards. Ultrasonography showed a decrease in plaque area, from 10.5 +/- 6 mm2 to 9.8 +/- 5.5 mm2 and the total surface area of the vessel increased from 12.8 +/- 0.7 to 15.3 +/- 6.9 mm2 (p < 0.05). This accounted for the gain in main surface area of the stenosed lumen, from 2.28 +/- 1.28 to 5.9 +/- 2.65 mm2 (p < 0.001). The correlations between quantitative coronary angiography and ultrasonography at the site of stenosis were only significant after angioplasty both the vessel diameter (r = 0.67; p < 0.0002) and endoluminal surface area (r = 0.63; p < 0.0001). A correlation was not observed before angioplasty because of the complexity of the plaque and its excentric location. At the reference site, the correlations between ultrasonography and angiography before and after angioplasty were significant but not very close (Spearman coefficient 0.53 and 0.82 respectively, p < 0.001). Therefore, correlations between quantitative data obtained by coronary angiography and ultrasonography are modest in patients undergoing transluminal coronary angioplasty. The ultrasonographic information is more qualitative, enabling a better understanding of the mechanism of the therapeutic procedure and allowing optimal choice of the appropriate tool.

[Myocardial infarction caused by acute left main coronary artery occlusion. Apropos of 4 cases and review of the literature]. / Infarctus du myocarde par occlusion aiguë du tronc commun gauche. A propos de 4 cas et revue de la littérature.

Between 1979 and 1996, 4 acute occlusions of the left main coronary artery (LMC) were treated by primary transluminal coronary angioplasty. They were 4 men with a mean age of 43 +/- 5 years, admitted to hospital less than 8 hours after the clinical onset of symptoms of anterior myocardial infarction in Killip class 4 with complete right bundle branch block on the initial electrocardiogramme. All cases had a previous history of unstable angina over 2 to 15 days. Angioplasty was undertaken immediately in view of the haemodynamic instability. The coronary circulation was of a dominant right coronary type in the 4 cases: significant stenoses were discovered after recanalisation, on the left anterior descending artery (LAD) in 2 cases and the circumflex or marginal arteries in 3 cases. The right coronary artery was atheromatous in all cases but without significant stenosis. Angioplasty was completed by implantation of a stent in 3 cases (LAD : 1 case, LMC : 2 cases). The outcome was rapidly fatal in 3 cases. Only one patient survived 6 months in functional class 3. These results show that myocardial infarction due to occlusion of the left main coronary artery is a very severe condition which justifies rapid recanalisation. Primary angioplasty with stent implantation in an immediate therapeutic option which enables the patient to survive the acute stage, though only in a limited number of cases.

CRYSTALFF--from crystallography to EXAFS multiple-scattering calculations with FEFF.

CRYSTALFF is an alternative utility to ATOMS containing most of the features of this standard program for converting crystallographic data to FEFF input. In addition, it offers an interface with molecular modelling programs via the PDB format and new coordination sphere analysis options.

Lysozyme crystal growth, as observed by small angle X-ray scattering, proceeds without crystallization intermediates.

A combination of small angle X-ray scattering and gel techniques was used to follow the kinetics of protein crystal growth as a function of time. Hen egg white lysozyme, at different protein concentrations, was used as a model system. A new sample holder was designed, in which supersaturation is induced in the presence of salt by decreasing the temperature. It had been shown previously that a decrease in temperature and/or an increase in crystallizing agent induces an increase in the attractive interactions present in the lysozyme solutions, the lysozyme remaining monomeric. In the present paper we show that similar behaviour is observed in NaCl when agarose gels are used. During crystal growth, special attention was paid to determine whether oligomers were formed as the protein in solution was incorporated in the newly formed crystals. From these first series of experiments, we did not find any indication of oligomer formation between monomer in solution and crystal. The results obtained are in agreement with the hypothesis that lysozyme crystals in NaCl grow by addition of monomeric particles.

Main structural and functional features of the basic cytosolic bovine 21 kDa protein delineated through hydrophobic cluster analysis and molecular modelling.

A 21 kDa protein purified from bovine brain cytosol was previously described as a hydrophobic ligand binding protein; however, its accurate biological function remained still uncertain. In order to get further information about its potential biological role, an extended prediction of its secondary and three dimensional structures was undertaken. We describe here a process which permitted us to discover a structural homology between the 21 kDa protein and the N-domain of yeast phosphoglycerate kinase (PGK). This process is based on comparing the 21 kDa protein with all the proteins presenting a slight homology, by using the Hydrophobic Cluster Analysis (HCA) method. According to the observed similarity between the N-domain of yeast PGK and the 21 kDa protein, we built a model which was shown to possess a potential binding site for nucleotides. Moreover, the model obtained presents three-dimensional (3D) structure similarity with adenylate kinase. These results suggest two main hypotheses: (i) the 21 kDa protein may belong to the kinase family; (ii) the binding of a nucleotide could imply a modification of the 3D structure of the 21 kDa protein that can promote the transfer of hydrophobic ligands to the plasma membrane. Meanwhile, verification of these hypotheses has been in part performed experimentally: the 21 kDa protein binds MgATP as well as, to a lesser extent, phosphoglycerate.

Photoaffinity reagents for use with pepsin and other carboxyl proteases.

Two compounds have been designed to serve as photoaffinity reagents for use with carboxyl proteases. 1,2-Epoxy-3-(4'-azido-2'-nitrophenoxy)propane has been synthesized and shown to react with porcine pepsin in the same fashion as the traditional inhibitor 1,2-epoxy-3-(p-nitrophenoxy)propane, while p-azidophenacyl bromide is similar to other phenacyl bromides in its reaction with pepsin. In combination with p-azido-alpha-diazoacetophenone, previously shown to resemble alpha-diazo carbonyl reagents in its reaction with pepsin, photoaffinity analogs are now available for all three of the widely-used carboxyl protease inhibitors.

Carboplatin and oxaliplatin decomposition in chloride medium, monitored by XAS.

The stability of carboplatin and oxaliplatin aqueous solutions has been studied under different chloride ions concentration and pH conditions. For both compounds, we demonstrate the chloration of the platinum first coordination shell.

Synthesis, crystal structure, EXAFS, and magnetic properties of catena [mu-tris(1,2-bis(tetrazol-1-yl)propane-N1,N1')iron(II)] bis(perchlorate). First crystal structure of an iron(II) spin-crossover chain compound.

[Fe(btzp)3](ClO4)2 (btzp = 1,2-bis(tetrazol-1-yl)propane) represents the first structurally characterized Fe(II) linear chain compound exhibiting thermal spin crossover. It shows a very gradual spin transition (T1/2 = 130 K) which has been followed by magnetic susceptibility measurements and 57Fe Mössbauer spectroscopy. The structure has been solved at 200 and 100 K by single-crystal X-ray analysis. It crystallizes in the trigonal space group P3c1 with Z = 2 Fe(II) units at both temperatures. The molecular structure consists of chains running along the c axis in which the Fe(II) ions are linked by three N4,N4' coordinating bis(tetrazole) ligands. The main difference between the two forms appears to be in the Fe-N bond lengths, which are 2.164(4) A at 200 K and 2.038(4) A at 100 K. The Fe-Fe separations are 7.422(1) A at 200 K and 7.273(1) A at 100 K. The EXAFS results are consistent with the crystal structure. In both spin states, the FeN6 octahedron is almost regular within the EXAFS resolution. The Fe-N distance is found as 2.16(2) A at 300 K and 2.00(2) A at 40 K. The absence of the "7 A peak" in the EXAFS spectra of [Fe(btzp)3](ClO4)2, in contrast with what has been observed for the [Fe(4-R-1,2,4-triazole)3]-(anion)2 chain compounds, confirms that this peak can be used as the signature of a metal alignment only when it involves a strongly enhanced multiple scattering M-M-M path, with M-M spacing less than 4 A. Irradiation with green light at 5 K has led to the population of the metastable high-spin state for the iron(II) ion. The nature of the spin-crossover behavior has been discussed on the basis of the structural features.