$$ (3)One can envision the EXAFS phenomena by the help of a schematic of the outgoing and backscattered waves as shown in Fig. 2b. As the energy of the photoelectron changes, so does the wavelength of the photoelectron. At a particular energy E 1, the outgoing and the backscattered waves are in phase and constructively interfere, thus increasing the probability of X-ray absorption or, in other words, increase the absorption coefficient. At a different energy E 2, the outgoing and selleck screening library backscattered waves are out-of-phase

and destructively interfere, decreasing the absorption coefficient. This modulation of the absorption coefficient by the backscattered wave from neighboring atoms is essentially the basic phenomenon of EXAFS. And, Fourier transform (FT) of the modulation provides distance information describing the vector(s) between Selleckchem Torin 1 the absorbing atom and atoms to which it is bound—typically within a range limit of 4–5 Å. A quantitative EXAFS modulation χ(k) can be expressed as follows: $$ \chi (k) = \sum\limits_\textj \fracN_\textj \leftkR_\textaj^2 \sin [2kR_\textaj + a_\textaj (k)] , $$ (4)where N

j is the number of equivalent backscattering atoms j at a distance R aj from the absorbing atom, f j(π, k) is the backscattering

amplitude which is a function of the atomic number of the backscattering element j, and α aj(k) includes the phase shift from the central atom absorber as well as the backscattering element j. The phase shift occurs due to the presence of atomic potentials that the photoelectron else experiences as it traverses the potential of the absorber atom, the potential of the backscattering atom, and then back through the potential of the absorber atom. In real systems, there is an inherent static disorder due to a distribution of distances R aj, and dynamic disorder due to thermal vibrations of the absorbing and scattering atoms. Equation 4 is modified to include this disorder term or the Debye–Waller factor \( \texte^ – 2\sigma_\textaj^2 k^2 , \) where \( \sigma_\textaj \) is the root-mean-square deviation to give the following equation: $$ \chi (k) = \sum\limits_j \fracN_\textj \leftkR_\textaj^2 \,\texte^ – 2\sigma_\textaj^2 k^2 \sin [2kR_\textaj + a_\textaj (k)] .

5°C [25]. Heat stroke is defined as a condition in which body temperature is elevated to a level that causes damage to body tissues, giving rise to a characteristic clinical and pathological syndrome that affects multiple organs [29]. Distinguishing features of heat stroke are marked core body temperature

elevations greater than 40.5°C, failing sweating mechanisms, often complete cessation of sweating, and moderate to severe mental status impairment. It is a medical emergency in which total thermoregulatory failure will not reverse without external cooling measures and the mortality rates may exceed 10% [25]. 3.2 Exercise-dependent dehydration-induced ischemia Blood flow to central tissues (gut and liver) is reduced during exercise by

almost 80%, at 70% of VO2max [7]. Such decreased splanchnic blood flow and oxygen supply may induce changes in nutrient absorption, motility Small molecule library purchase and the mucosal integrity of the GI tract, resulting in GI complaints [30]. GI distress has been reported to be common among 30%-50% of endurance athletes, especially during marathons, triathlons and other endurance events. The symptoms seem to occur more often during competition in a warm environment [30] in the presence of systemic dehydration and lower plasma volume [8]. Long-lasting high-dose creatine supplementation (80 g/day during four months) is reported to lead to acute renal failure when associated with exhausting strength exercises and related lower plasma volume [31]. However, few or no adverse effects are observed when INCB024360 taking the recommended dose of creatine (10 g/day) [32, 33]. 3.2.1 Exercise-induced gastric emptying delay Gastric emptying (GE) is thought to be negatively affected as exercise intensities reach over 70% VO2max [34]. The presence of dehydration in strenuous exercise in cyclists was shown to induce significantly increased nausea, epigastric cramps and delay in gastric emptying. Gastric emptying

(GE) was significantly associated with increase in exercise-induced nausea. Exercise by itself led to next significant increase in plasma vasopressin and rectal temperature and significant decrease in plasma volume, irrespective of the dehydration state, but vasopressin concentration was significantly higher in dehydrated athletes. By adding dehydration to strenuous cycling, there was a delayed gastric emptying, but no differences in orocecal transit time, intestinal permeability or glucose uptake [30]. In an endurance running experiment, GI complaints were reported only with the dehydration exercise combination without any GI disturbances being reported by athletes in either exercise or dehydration test alone. Dehydration-exercise resulted in slower GE than in other two treatments with the effects of dehydration and exercise being additives in delayed GE.

Finally, plasmid DNA of positive clones was extracted and sequenced on ABI 377 DNA sequencer. Analysis of β-galactosidase

gene The open reading frame search from DNA sequences was carried out using ORF-finder (NCBI) (http://​www.​ncbi.​nlm.​nih.​gov/​), and database homology search was performed with BLAST program provided by NCBI. Furthermore, the multiple amino acid sequence alignment of Gal308 and known homologous β-galactosidases and the analysis of conserved selleck compound amino acid residues and active site residues of Gal308 were performed by using ClustalW2 program (http://​www.​ebi.​ac.​uk/​Tools/​msa/​clustalw2/​). Expression and purification of recombinant protein The PCR primers for gal308 amplification were listed as follows: gal308-f, 5′-CGCGGATCCATGGCCTTTCCAAACGAGCATGGAG, in which the BamHI site was shown in italics; gal308-r, 5′-CCCAAGCTTTCCCTCGTGTTCTTCATAGAC, in which the HindIII site was shown in italics. PCR reaction

conditions were: 98°C, 10 sec (denaturation); 68°C, 3 min (annealing and extension); repeated for 30 cycles. The PCR product was digested with BamHI/HindIII and subcloned to BamHI/HindIII-treated expression vector pET-32a (+) with a six-histidine tag for purification. The recombinant vector was transformed into E. coli BL21 (DE3), and then the cells were JNK inhibitor plated on LB agar containing 100 μg/ml ampicillin. The transformant was grown in a 100-ml flask containing 10 ml LB medium supplemented with 100 μg/ml ampicillin at 37°C until the optical density at 600 nm reached to 1.0, and then IPTG was added to final concentration of 1.2 mM, and the culture was incubated at 30°C for 8 h with shaking at 200 rpm. Cells were then collected

by centrifugation (6,000 g Y-27632 molecular weight for 20 min at 4°C) and stored at -20°C for later purification. All purification steps were performed according to the instruction of His Bind Purification Kit (Novagen). In brief, the cells were suspended in binding buffer (0.5 M NaCl, 5 mM imidazole, 20 mM Tris–HCl, pH 7.9) followed by sonication on ice. The supernatant was collected by centrifugation at 14,000 g for 20 min at 4°C, and then they were loaded onto a Ni-NTA His · Bind column (Novagen) pre-equilibrated with binding buffer. The column was washed with binding buffer and washing buffer (0.5 M NaCl, 60 mM imidazole, 20 mM Tris–HCl, pH 7.9). Finally, the bound protein was eluted with eluting buffer (1 M imidazole, 0.5 M NaCl, 20 mM Tris–HCl, pH 7.9). Next, the purified enzyme in elution buffer was collected and further removed imidazole by dialysis before the characterization of the enzyme. The dialysis was performed three times, and each dialysis lasted for two hours in dialysis buffer (100 mM NaCl, 3 mM dithiothreitol, 20 mM Tris–HCl, pH 7.9). Determination of molecular mass The molecular mass of the denatured protein was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Proteins were stained with Coomassie brilliant blue G-250.

Furthermore, it shows that concomitant use of antidepressants and dopaminergic drugs further increased the risk of hip/femur fractures (ORadj = 3.51, 95% CI = 2.10–5.87). Y-27632 Concomitant current use of dopaminergic drugs and anticholinergics or antipsychotics or benzodiazepines

did not significantly alter the overall risk of hip/femur fractures. Table 3 Current use of dopaminergic drugs and risk of hip/femur fracture by substance and concomitant use of anticholinergics, antidepressants, antipsychotics or benzodiazepines   Cases (n = 6,763) Controls (n = 26,341) Crude OR [95% CI] ORadj a [95% CI] Among current users of a dopaminergic drug          By substance          Dopamine agonist alone 5 (0.1) 7 (0.0) 2.86 [0.91−9.00] 1.86 [0.56−6.19]  Levodopa alone 117 (1.7) 188 (0.7) 2.46 [1.95−3.11] 1.71 [1.32−2.21]  Combination of dopamine agonist and levodopa 34 (0.5) 42 (0.2) 3.28 [2.09−5.16] 1.98 [1.20−3.26]  By concomitant useb          Anticholinergicsc          Yes 16 (0.2) 28 (0.1) 2.27 [1.23−4.20] 1.59 [0.83−3.05] (a)  No 140 (2.1) 209 (0.8) 2.67 [2.14−3.32] 1.89 [1.49−2.41] (a)  Antidepressants          Yes 31 (0.5) 30 (0.1) 4.16 [2.52−6.88] 3.51 [2.10−5.87]d (b)  No 125 (1.8) 207 (0.8) 2.40 [1.91−3.00] 1.70 [1.31−2.20] (b)  Antipsychotics          Yes 17 (0.3) 29 (0.1) 2.29 [1.25−4.20] 1.43 [0.74−2.77]  No 139

(2.1) 208 (0.8) 2.67 [2.14−3.32] 1.80 [1.40−2.30]  Benzodiazepines          Yes 23 (0.3) 32 (0.1) 2.88 [1.68−4.92] 1.87 [1.07−3.28]  No 133 (2.0) 205 (0.8) 2.58 [2.06−3.22] 1.74 [1.35−2.24] this website aAdjusted for the same confounders as under Table 2 ((a) except for anticholinergics, Bacterial neuraminidase (b) except for antidepressants) bConcomitant current use (1−30 days before the index date) cAnticholinergics include biperiden,

dexetimide, orphenadrine, procyclidine and trihexyphenidyl d p = 0.011 for concomitant versus no concomitant use of antidepressants Figure 1 shows that hip/femur fracture risk was increased immediately after initiation of dopaminergic drug therapy and that it remained more than twofold increased during more than 6 years of continuous use. There were no significant differences between current users of a dopaminergic drug with a duration ≤1 year (ORadj = 1.87, 95% CI = 1.29–2.73) and current users who had been taking the dopaminergic drug >1 year (ORadj = 1.69, 95% CI = 1.28–2.25). Figure 2 shows that after discontinuation of dopaminergic treatment, the increased risk of hip/femur fractures rapidly decreased and that it was no longer increased after 1 year of discontinuation. Fig. 1 The risk of hip/femur fracture with continuous duration of dopaminergic drug use among current users. Datapoints and spline regression line represent adjusted OR (adjusted for the same confounders as under Table 2) Fig. 2 The risk of hip/femur fracture and time since last dispensing for a dopaminergic drug.

The sensitivity for detection of resistance mechanisms largely depends on the composition of the antibiotic drug panel used in the automated microdilution systems, which cannot be changed or modified by the user [2, 7]. The disk diffusion method readily permits detection of inducible phenotypes and most combinations of resistance mechanisms including PF-01367338 research buy ESBL and AmpC co-production. The antibiotic panel composition is flexible and enables the clinical laboratory to readily adjust the composition of panels to its needs [8, 9]. Disadvantages of the disk diffusion method are its labour cost due to manual measurements and manual data documentation, and the investigator dependence

and variation of results [10]. During the past decade several systems have been developed to automate disk diffusion readings. Systems like Sirscan (i2a, Montpellier, France), OSIRIS and ADAGIO (both BIO-RAD, Marne KU-57788 supplier La Coquotte, France),

Oxoid Aura (Oxoid Ltd., Basingstoke, UK), or BIOMIC (Giles Scientific Inc., Santa Barbara, California, USA) are able to automatically read inhibition zone diameters and incorporate expert systems for AST interpretation. These systems allow fully automated (Sirscan) or semi-automated reading (ADAGIO, Aura, BIOMIC), documentation and data interpretation using expert systems. The few studies available investigating the performance of automated zone reading systems indicate a high agreement with standard manual calliper (correlation coefficients ranging from 0.91 to 0.96) resulting in only few susceptibility categorisation errors [10–15]. However, some systems are no longer available (OSIRIS, Oxoid Aura), or have reported practical problems for routine use (BIOMIC) [16]. No studies are available investigating, if and to which extent fully automated zone reading is able to facilitate standardisation of inhibition zone diameter measurements.

High reproducibility and low variation of results become even more important in the light of the new CLSI and EUCAST AST guidelines that contain smaller intermediate susceptibility categories or, in case of EUCAST, second have even partially abandoned the use of the intermediate category. Directly adjacent susceptible and resistant categories lead to a higher frequency of major and very major errors (i.e. susceptible to resistant, resistant to susceptible) simply due to technical reasons, i.e. variation of individual measurements [17–19]. This study aimed at comparing the fully automated Sirscan with standard calliper measurements assessing: i) The agreement of inhibition zone diameter results (comparability), ii) The frequency of discrepancies in susceptibility categorisation (accuracy), and iii) Variation of repeat diameter measurements (reproducibility and precision). Methods Clinical isolates One hundred clinical bacterial isolates were selected as a representative sample of organisms routinely isolated in the clinical microbiological laboratory.

The majority of injuries (41%) were due to high energy blasts from artillery shells and mortars, rocket propelled grenades, high explosive bombs and anti personnel mines. Cuts and stabs accounted for 26% while 17% were due to gunshot wounds. These included high velocity rifles & machine guns; low velocity shot guns and improvised trap guns. Other causes included road traffic accidents (RTA), industrial accidents and iatrogenic trauma following arterial catheterisation. Civilian trauma accounted

Selleckchem Hydroxychloroquine for 54% of injuries while 46% were related to the military conflict. Table 1 Vessels injured by cause of injury   Blast injuries Cuts/stabs Gunshots RTAs Industrial accidents Iatrogenic Total (%) Axillary artery 01   01       02 (2.5%) Brachial artery 11 01 01 01 03 01 18 (22%) Radial artery   12         12 (15%) Ulnar artery   07         07 (8.5%) Femoral artery 06 01 02 01   02 12 (15%) Popliteal artery 08   05 04     17 (21%) Tibial arteries 02   03       05 (06%) Femoral vein 01   01       02 (2.5%) Popliteal vein 03     01     04 (05%) Axillary vein 01   01       02 (2.5%)   33(41%) 21(26%) 14(17%) 07(9%) 03(3.5%) 03(3.5%) 81 (100% Vessels injured and type of presentation All named extremity vessels presented with injuries and were repaired (table Palbociclib mw 1). The brachial artery was the most commonly

injured vessel (22%) followed by popliteal (21%), femoral (15%) and radial (15%) arteries. Indications for referral were acute ischaemia in 36(44%), bleeding in 35 (43%) and traumatic pseudo-aneurysms

in 10(13%). In patients presenting with bleeding, the commonest vessels injured were the radial and ulna arteries (Table 2). Table 2 Presentations and method of management Vessel injured Direct repair Vein graft PTFE graft bypass Endo-vascular stenting Primary amputation N% 1. Injuries presenting with bleeding             Radial/Ulnar arteries 19         19 (54%) Brachial artery 01 04       05 (14%) Femoral artery 01 01       02 (06%) Axillary artery   02       02 (06%) Major limb veins Cediranib (AZD2171) 04 03       07 (20%) Total           35(100%) 2. Injuries presenting with acute ischaemia             Popliteal artery 03 09     05 17 (47%) Brachial artery 02 07     01 10(28%) Femoral artery 01 02 01     04(11%) Crural arteries   05       05(14%) Total           36(100%) 3. Injuries presenting as psuedoaneurysms             Femoral artery 02 03   01   06 (60%) Brachial artery 01 02       03 (30%) Popliteal artery   01       01 (10%) Total           10(100%) Total 35 39 01 01 06 81 N.B Some patients had multiple repairs. Delays in intervention, methods of repair and limb salvage For injuries presenting with bleeding, median time to revascularization was 5.5 hours (range 2-16) and all limbs were salvaged. In injuries presenting with acute ischaemia, popliteal injuries were the most common (Table 2) and 80% of such limbs were revascularized more than 6 hours after injury.

In contrast, when NPG with a pore size of 100 nm served

as a support, the lipase-NPG biocomposites adsorbed for 60, 72, and 84 h all exhibited significant decreases on catalytic activities during the recycle process (Figure 3B). This may be due to the leaching of lipase from NPG with larger pore size, resulting in the loss of lipase activity upon the reuse process [7]. Based on the above results, it is clear that the pore size of NPG and adsorption time played key roles in achieving high stability and reusability for the lipase-NPG biocomposites. The lipase-NPG biocomposites with a pore size of 35 nm adsorbed for 72 h exhibited excellent reusability and had no decrease on catalytic activity after ten recycles. In comparison, there was 60% of its initial catalytic activity after the fifth cycle by lipase encapsulated SCH772984 clinical trial in the porous organic–inorganic system [21], and there was 20% of its initial catalytic activity after 7 cycles click here by lipase immobilized on alginate [22]. The lipase immobilized on surface-modified nanosized magnetite particles showed a significant loss in activity after the first use [23]. Therefore, the lipase-NPG biocomposites with a pore size of 35 nm adsorbed for 72 h was further

discussed in the subsequent experiments due to high lipase loading and excellent catalytic performance. Figure 3 Reusability of lipase-NPG biocomposites with pore sizes of (A) 35 nm and (B) 100 nm. Effect of buffer pH and temperature on lipase-NPG biocomposite An enzyme in a solution may have a different optimal pH from that of the same enzyme immobilized on a solid matrix [24]. The catalytic activities of free lipase and the lipase-NPG biocomposites with a pore size of 35 nm were assayed at varying pH (7.0 to 9.0) at 40°C. The lipase-NPG biocomposite and free lipase had similar pH activity profiles with

the same Glycogen branching enzyme optimum activity at pH 8.4 (Figure 4A). Compared with free lipase, the lipase-NPG biocomposite maintained higher catalytic activity at a broader pH range, which could possibly offer a broader range of applications. Figure 4 Effect of buffer pH and temperature. The effects of (A) pH and (B) temperature on the catalytic activities of free lipase and the lipase-NPG biocomposite with a pore size of 35 nm adsorbed for 72 h. The effects of reaction temperature on the catalytic activity of free lipase and the lipase-NPG biocomposite with a pore size of 35 nm were also investigated by varying temperatures from 30°C to 80°C. Figure 4B shows that the maximum catalytic activity of the lipase-NPG biocomposite was observed at 60°C, whereas free lipase exhibited the highest activity at 50°C.

999. The product of SPy0317 was universally observed in all cellular fractions,

and was relatively highly expressed under shaking culture conditions. It is speculated that SPy0317 is secreted via the Sec pathway and is involved in transport of substances, especially under shaking culture conditions, which mimics mechanical or oxygenic stress. Other interesting examples were SPy1260 and SPy1262, which were identified with relatively high numbers of MS/MS spectra, despite both of them being assigned no GO terms. They should merit further biochemical and biological investigation. A high degree of protein variation was observed in the supernatant compared to the insoluble and soluble fractions of the cell (Figure 2). Our previous reports suggested that stressors, such as addition of antibiotics [39, 44], influenced buy Pifithrin-�� the expressions of extracellular proteins. These results suggest that GAS cells change their expression patterns of extracellular proteins

when adapting to environmental stresses. In contrast to extracellular proteins, core proteins were easily identified in cell-body fractions under the different culture conditions. It is hypothesized that the protein components that we observed were a consequence of growth during the stationary phase of the cultures. For example, a previous report indicated that the effect of different culture atmospheres modulated surface structures. Bisno et al. reported that the expression level of the M protein of the cell wall-associated fraction was greater in 5% CO2 R788 culture conditions [45]. Our results also confirmed this hypothesis (Additional file 4). Interestingly, the highest amounts of M protein in the supernatant were observed under shaking culture conditions. We speculate that the M protein is detached from the cell wall because of the mechanical effects of shaking, although this should be investigated further. Conclusions The proteome of S. pyogenes SF370 was characterized by shotgun LC-MS/MS with a non-biased, six-frame translation of open

reading frames of the actual genome sequence. In this study, nine proteins were discovered as novel ORFs in SF370, with the validation of their corresponding mRNAs. Furthermore, functional 3-oxoacyl-(acyl-carrier-protein) reductase annotation was obtained for 126 hypothetical proteins (22.2% out of all hypothetical proteins). To elucidate the dynamic responses of GAS cells to the environment requires more extensive analysis, which can compare proteomic profiles for different culture conditions, such as atmospheric compositions, culture media, growth phases, temperature, mechanical stress, and the addition of antibiotics. Although effort has been made to illustrate the proteomic profiles of S. pyogenes, several proteins may be inadequately evaluated because of unrecognized CDSs in genomes, or the absence of well-characterized annotations, such as for HyPs and CHyPs.

The simulation result shows that light is mainly guided inside the shells of the top layer nanofilm, and strong light absorption based on the WGM resonances is observed. Furthermore, we measure the UV-visible

(UV-vis) absorption spectra of the ZnO/ZnS, ZnS/ZnO, and ZnO nanofilms in Figure 4a. One can see that the absorbance is more prominent in the ZnO/ZnS bilayer nanofilm, but it is about one third of the simulated absorption spectrum of the ZnO/ZnS bilayer nanofilm (see Figure 4b). This could mainly be caused by the scattering due to the imperfect arrays (or defects) in our samples (see Figure 1c), which weaken the light absorption based Dabrafenib on the WGM resonances to some extent. The big challenge is how to use this interfacial self-assembly strategy to grow high-quality multilayer nanofilms with uniform coverage ratios and smooth surfaces suitable for use in these optoelectronic devices. Even so, we could make a conclusion that the use of wavelength-scale resonant hollow spheres in our bilayer nanofilms supports whispering gallery modes to enhance light absorption and then photocurrent. Figure 2 Electric field (| E |) distribution and absorption power distribution. (a) Electric field (|E|) distribution based on full-wave simulation of electromagnetic waves coupled with the ZnO hollow-sphere nanofilm at 370 nm. (b)

DNA Damage inhibitor Power distribution of the ZnO hollow-sphere nanofilm at 370 nm. (c) Electric field (|E|) distribution based on full-wave simulation of electromagnetic waves coupled with the ZnO hollow-sphere nanofilm at 350 nm. (d) Power distribution of the ZnO hollow-sphere nanofilm at 350 nm. Figure 3 Electric field (| E |) distribution. (a) Electric field (|E|) distribution based on full-wave simulation of electromagnetic waves coupled with the ZnO/ZnS hollow-sphere

nanofilm at 370 nm. (b) Electric field (|E|) distribution based on full-wave simulation of electromagnetic waves coupled with the ZnS/ZnO hollow-sphere nanofilm at 370 nm. Figure Guanylate cyclase 2C 4 UV-vis absorption spectra. (a) UV-vis absorption spectra of the ZnO, ZnO/ZnS, and ZnS/ZnO nanofilms. (b) Absorption spectra simulated from the ZnO, ZnO/ZnS, and ZnS/ZnO nanofilm structures. It is very important to effectively separate the photogenerated carriers within the optoelectronic devices. The ZnO/ZnS and ZnS/ZnO bilayer nanofilms made of ZnO and ZnS hollow nanospheres can be regarded as heterostructured assemblies. The position of the valence band (VB) energy level of ZnS is about 0.6 eV higher than that of ZnO, and a type II heterostructure with a staggered alignment at the heterojunction is formed in our bilayer nanofilms [20]. The presence of an internal electric field due to the band bending at the heterostructure interface facilitates the separation of photogenerated carriers (see Figure 5). By the effective absorption of photons with energy greater than the bandgap, electron-hole pairs are photogenerated in semiconductor nanostructures.

Non-hip fracture costs were also restricted to acute hospitalization cost but care typically extend beyond this (e.g., drugs, doctors, home care). Taking indirect costs such as productivity losses and other care costs into account would improve the cost-effectiveness of strontium ranelate as sensitivity analysis showed that cost-effectiveness improved with higher fracture costs. Conservative assumption was also used for the costs of vertebral fractures as they were calculated from a relationship between fractures in 1995 [36], and treatment of vertebral fractures has become more expensive in recent years due to an increasing

number of surgical GSK3 inhibitor click here procedures [63]. Finally, the generalizability of our results to other settings may be uncertain since the incidence of the disease, the availability of health resources, clinical practice patterns and relative prices may substantially differ between countries

and could impact on the cost-effectiveness [64]. Cost-effectiveness analysis should ideally be performed in each specific country with local data. However, it is likely that strontium ranelate will also confer cost-effective benefits, compared with no treatment, in countries with similar characteristics than those retained in this analysis. In conclusion, under the assumption of the same relative risk reduction of fractures in men as for women, this cost-effectiveness analysis suggests that strontium ranelate

has the potential to be a cost-effective strategy compared with no treatment next for men with osteoporosis from a healthcare payer perspective. Acknowledgments This work was supported by an unrestricted educational grant from Servier, which had no role in the design or conduct of the study, in the collection, analysis, or interpretation of the data. Conflicts of interest Mickaël Hiligsmann: research grant, lecture fees and/or consulting fees from Amgen, Pfizer, Novartis, Servier and SMB. Olivier Bruyère: consulting fees, lecture fees and reimbursement for attending meetings from Servier, GlaxoSmithKline, MSD, Theramex, Galapagos, Rottarpham. Jean-Yves Reginster: consulting fees or paid advisory boards, Servier, Novartis, Negma, Ely Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merkle, Nycomed, NPS, Theramex; lecture fees when speaking from Merck Sharp and Dohme, Eli Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed, Novo-Nordisk; grant support from Bristol Myers Squibb, Merck Sharp & Dhome, Rottapharm, Teva, Eli Lilly, Novartis, Roche, GlaxoSmithKline, Amgen, and Servier. Wafa Ben Sedrine has no conflict of interests.