Echocardiographic Evidence for Valvular Toxicity of Benfluorex: A Double-Blind Randomised Trial in Patients with Type 2 Diabetes Mellitus

OBJECTIVES: REGULATE trial was designed to compare the efficacy and safety of benfluorex versus pioglitazone in type 2 diabetes mellitus (DM) patients. METHODS: Double-blind, parallel-group, international, randomised, non-inferiority trial. More than half of the 196 participating centres were primary care centres. Patients eligible had type 2 DM uncontrolled on sulfonylurea. 846 were randomised. They received study treatment for 1 year. 423 patients were allocated to benfluorex (150 to 450 mg/day) and 423 were allocated to pioglitazone (30 to 45 mg/day). Primary efficacy criterion was HbA(1c). Safety assessment included blinded echocardiographic evaluation of cardiac and valvular status. RESULTS: At baseline, patients were 59.1 ± 10.5 years old with HbA1c 8.3 ± 0.8%, and DM duration 7.1 ± 6.0 years. During the study, mean HbA1c significantly decreased in both groups (benfluorex: from 8.30 ± 0.80 to 7.77 ± 1.31 versus pioglitazone: from 8.30 ± 0.80 to 7.45 ± 1.30%). The last HbA1c value was significantly lower with pioglitazone than with benfluorex (p<0.001) and non-inferiority of benfluorex was not confirmed (p = 0.19). Among the 615 patients with assessable paired echocardiography (310 benfluorex, 305 pioglitazone), 314 (51%) had at least one morphological valvular abnormality and 515 (84%) at least one functional valvular abnormality at baseline. Emergent morphological abnormalities occurred in 8 patients with benfluorex versus 4 with pioglitazone (OR 1.99), 95% CI (0.59 to 6.69). Emergent regurgitation (new or increased by one grade or more) occurred more frequently with benfluorex (82 patients, 27%) than with pioglitazone (33 patients, 11%) (OR 2.97), 95% CI (1.91 to 4.63) and were mainly rated grade 1; grade 2 (mild) was detected in 2 patients with benfluorex and 3 with pioglitazone. There was no moderate or severe regurgitation. CONCLUSION: After 1 year of exposure, our results show a 2.97 fold increase in the incidence of valvular regurgitation with benfluorex and provide evidence for the valvular toxicity of this drug

Sex-Specific Genetic Structure and Social Organization in Central Asia: Insights from a Multi-Locus Study

In the last two decades, mitochondrial DNA (mtDNA) and the non-recombining portion of the Y chromosome (NRY) have been extensively used in order to measure the maternally and paternally inherited genetic structure of human populations, and to infer sex-specific demography and history. Most studies converge towards the notion that among populations, women are genetically less structured than men. This has been mainly explained by a higher migration rate of women, due to patrilocality, a tendency for men to stay in their birthplace while women move to their husband's house. Yet, since population differentiation depends upon the product of the effective number of individuals within each deme and the migration rate among demes, differences in male and female effective numbers and sex-biased dispersal have confounding effects on the comparison of genetic structure as measured by uniparentally inherited markers. In this study, we develop a new multi-locus approach to analyze jointly autosomal and X-linked markers in order to aid the understanding of sex-specific contributions to population differentiation. We show that in patrilineal herder groups of Central Asia, in contrast to bilineal agriculturalists, the effective number of women is higher than that of men. We interpret this result, which could not be obtained by the analysis of mtDNA and NRY alone, as the consequence of the social organization of patrilineal populations, in which genetically related men (but not women) tend to cluster together. This study suggests that differences in sex-specific migration rates may not be the only cause of contrasting male and female differentiation in humans, and that differences in effective numbers do matter

In the heartland of Eurasia: the multilocus genetic landscape of Central Asian populations

Located in the Eurasian heartland, Central Asia has played a major role in both the early spread of modern humans out of Africa and the more recent settlements of differentiated populations across Eurasia. A detailed knowledge of the peopling in this vast region would therefore greatly improve our understanding of range expansions, colonizations and recurrent migrations, including the impact of the historical expansion of eastern nomadic groups that occurred in Central Asia. However, despite its presumable importance, little is known about the level and the distribution of genetic variation in this region. We genotyped 26 Indo-Iranian- and Turkic-speaking populations, belonging to six different ethnic groups, at 27 autosomal microsatellite loci. The analysis of genetic variation reveals that Central Asian diversity is mainly shaped by linguistic affiliation, with Turkic-speaking populations forming a cluster more closely related to East-Asian populations and Indo-Iranian speakers forming a cluster closer to Western Eurasians. The scattered position of Uzbeks across Turkic- and Indo-Iranian-speaking populations may reflect their origins from the union of different tribes. We propose that the complex genetic landscape of Central Asian populations results from the movements of eastern, Turkic-speaking groups during historical times, into a long-lasting group of settled populations, which may be represented nowadays by Tajiks and Turkmen. Contrary to what is generally thought, our results suggest that the recurrent expansions of eastern nomadic groups did not result in the complete replacement of local populations, but rather into partial admixture

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&lt;SUB&gt;Jup&lt;/SUB&gt; 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. &lt;BR /&gt; 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. &lt;BR /&gt; 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. &lt;BR /&gt; Results: We report a radius of 1.35 &plusmn; 0.04 R&lt;SUB&gt;&amp;sun;&lt;/SUB&gt; for GJ504A. The radius yields isochronal ages of 21 &plusmn; 2 Myr or 4.0 &plusmn; 1.8 Gyr for the system and line-of-sight stellar rotation axis inclination of 162.4&lt;SUB&gt;-4.3&lt;/SUB&gt;&lt;SUP&gt; 3.8&lt;/SUP&gt; degrees or 186.6&lt;SUB&gt;-3.8&lt;/SUB&gt;&lt;SUP&gt; 4.3&lt;/SUP&gt; 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 (&lt;= 1.5Gyr), and/or unusual dusty atmospheres and/or super-solar metallicities. All atmospheric models yield T&lt;SUB&gt;eff&lt;/SUB&gt; = 550 &plusmn; 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&lt;SUB&gt;&amp;sun;&lt;/SUB&gt; = -6.15 &plusmn; 0.15 dex for the companion from the empirical analysis and spectral synthesis. The luminosity and T&lt;SUB&gt;eff&lt;/SUB&gt; yield masses of M = 1.3&lt;SUB&gt;-0.3&lt;/SUB&gt;&lt;SUP&gt; 0.6&lt;/SUP&gt; M&lt;SUB&gt;Jup&lt;/SUB&gt; and M = 23&lt;SUB&gt;-9&lt;/SUB&gt;&lt;SUP&gt; 10&lt;/SUP&gt; M&lt;SUB&gt;Jup&lt;/SUB&gt; 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&lt;SUB&gt;Jup&lt;/SUB&gt; with semi-major axes in the range 0.01-80 au for the young and old isochronal ages, respectively. &lt;BR /&gt; 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