Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist

Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34+ bone marrow cells into CD41+ megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production

On extremal graphs with bounded girth

By the extremal number ex(n;t) = ex(n;{C₃,C₄,…,Ct}) we denote the maximum size (number of edges) in a graph of n vertices, n > t, and girth (length of shortest cycle) at least g ≥ t + 1. In 1975, Erdős proposed the problem of determining the extremal numbers ex(n;4) of a graph of n vertices and girth at least 5. In this paper, we consider a generalized version of this problem, for t ≥ 5. In particular, we prove that ex(n;6) for n = 29, 30 and 31 is equal to 45, 47 and 49, respectively

The GJ 504 system revisited. Combining interferometric, radial velocity, and high contrast imaging data

International audienceContext. The G-type star GJ504A is known to host a 3-35 M<SUB>Jup</SUB> companion whose temperature, mass, and projected separation all contribute to making it a test case for planet formation theories and atmospheric models of giant planets and light brown dwarfs. <BR /> Aims: We aim at revisiting the system age, architecture, and companion physical and chemical properties using new complementary interferometric, radial-velocity, and high-contrast imaging data. <BR /> Methods: We used the CHARA interferometer to measure GJ504A's angular diameter and obtained an estimation of its radius in combinationwith the HIPPARCOS parallax. The radius was compared to evolutionary tracks to infer a new independent age range for the system. We collected dual imaging data with IRDIS on VLT/SPHERE to sample the near-infrared (1.02-2.25 mum) spectral energy distribution (SED) of the companion. The SED was compared to five independent grids of atmospheric models (petitCODE,Exo-REM, BT-SETTL, Morley et al., and ATMO) to infer the atmospheric parameters of GJ 504b and evaluate model-to-model systematic errors. In addition, we used a specific model grid exploring the effect of different C/O ratios. Contrast limits from 2011 to 2017 were combined with radial velocity data of the host star through the MESS2 tool to define upper limits on the mass of additional companions in the system from 0.01 to 100 au. We used an MCMC fitting tool to constrain the companion'sorbital parameters based on the measured astrometry, and dedicated formation models to investigate its origin. <BR /> Results: We report a radius of 1.35 ± 0.04 R<SUB>&sun;</SUB> for GJ504A. The radius yields isochronal ages of 21 ± 2 Myr or 4.0 ± 1.8 Gyr for the system and line-of-sight stellar rotation axis inclination of 162.4<SUB>-4.3</SUB><SUP> 3.8</SUP> degrees or 186.6<SUB>-3.8</SUB><SUP> 4.3</SUP> degrees. We re-detect the companion in the Y2, Y3, J3, H2, and K1 dual-band images. The complete 1-4 mum SED shape of GJ504b is best reproduced by T8-T9.5 objects with intermediate ages (<= 1.5Gyr), and/or unusual dusty atmospheres and/or super-solar metallicities. All atmospheric models yield T<SUB>eff</SUB> = 550 ± 50 K for GJ504b and point toward a low surface gravity (3.5-4.0 dex). The accuracy on the metallicity value is limited by model-to-model systematics; it is not degenerate with the C/O ratio. We derive log L/L<SUB>&sun;</SUB> = -6.15 ± 0.15 dex for the companion from the empirical analysis and spectral synthesis. The luminosity and T<SUB>eff</SUB> yield masses of M = 1.3<SUB>-0.3</SUB><SUP> 0.6</SUP> M<SUB>Jup</SUB> and M = 23<SUB>-9</SUB><SUP> 10</SUP> M<SUB>Jup</SUB> for the young and old age ranges, respectively. The semi-major axis (sma) is above 27.8 au and the eccentricity is lower than 0.55. The posterior on GJ 504b's orbital inclination suggests a misalignment with the rotation axis of GJ 504A. We exclude additional objects (90% prob.) more massive than 2.5 and 30 M<SUB>Jup</SUB> with semi-major axes in the range 0.01-80 au for the young and old isochronal ages, respectively. <BR /> Conclusions: The mass and semi-major axis of GJ 504b are marginally compatible with a formation by disk-instability if the system is 4 Gyr old. The companion is in the envelope of the population of planets synthesized with our core-accretion model. Additional deep imaging and spectroscopic data with SPHERE and JWST should help to confirm the possible spin-orbit misalignment and refine the estimates on the companion temperature, luminosity, and atmospheric composition

Staphylococcus capitis isolated from bloodstream infections: a nationwide 3-month survey in 38 neonatal intensive care units

International audienceTo increase the knowledge about S. capitis in the neonatal setting, we conducted a nationwide 3-month survey in 38 neonatal intensive care units (NICUs) covering 56.6% of French NICU beds. We demonstrated 14.2% of S. capitis BSI (S.capBSI) among nosocomial BSIs. S.capBSI incidence rate was 0.59 per 1000 patient-days. A total of 55.0% of the S.capBSIs were late onset catheter-related BSIs. The S. capitis strains infected preterm babies (median gestational age 26 weeks, median birth weight 855 g). They were resistant to methicillin and aminoglycosides and belonged to the NRCS-A clone. Evolution was favorable in all but one case, following vancomycin treatment

Successful Thrombectomy Improves Functional Outcome in Tandem Occlusions with a Large Ischemic Core

International audienceBackground: Emergent stenting in tandem occlusions and mechanical thrombectomy (MT) of acute ischemic stroke related to large vessel occlusion (LVO-AIS) with a large core are tested independently. We aim to assess the impact of reperfusion with MT in patients with LVO-AIS with a large core and a tandem occlusion and to compare the safety of reperfusion between large core with tandem and nontandem occlusions in current practice. Methods: We analyzed data of all consecutive patients included in the prospective Endovascular Treatment in Ischemic Stroke Registry in France between January 2015 and March 2023 who presented with a pretreatment ASPECTS (Alberta Stroke Program Early CT Score) of 0–5 and angiographically proven tandem occlusion. The primary end point was a favorable outcome defined by a modified Rankin Scale (mRS) score of 0–3 at 90 days. Results: Among 262 included patients with a tandem occlusion and ASPECTS 0–5, 203 patients (77.5%) had a successful reperfusion (modified Thrombolysis in Cerebral Infarction grade 2b-3). Reperfused patients had a favorable shift in the overall mRS score distribution (adjusted odds ratio [aOR], 1.57 [1.22–2.03]; P < 0.001), higher rates of mRS score 0–3 (aOR, 7.03 [2.60–19.01]; P < 0.001) and mRS score 0–2 at 90 days (aOR, 3.85 [1.39–10.68]; P = 0.009) compared with nonreperfused. There was a trend between the occurrence of successful reperfusion and a decreased rate of symptomatic intracranial hemorrhage (aOR, 0.5 [0.22–1.13]; P = 0.096). Similar safety outcomes were observed after large core reperfusion in tandem and nontandem occlusions. Conclusions: Successful reperfusion was associated with a higher rate of favorable outcome in large core LVO-AIS with a tandem occlusion, with a safety profile similar to nontandem occlusion