A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa

BACKGROUND: In sub-Saharan Africa, the burden of human immunodeficiency virus (HIV)-associated tuberculosis is high. We conducted a trial with a 2-by-2 factorial design to assess the benefits of early antiretroviral therapy (ART), 6-month isoniazid preventive therapy (IPT), or both among HIV-infected adults with high CD4+ cell counts in Ivory Coast. METHODS: We included participants who had HIV type 1 infection and a CD4+ count of less than 800 cells per cubic millimeter and who met no criteria for starting ART according to World Health Organization (WHO) guidelines. Participants were randomly assigned to one of four treatment groups: deferred ART (ART initiation according to WHO criteria), deferred ART plus IPT, early ART (immediate ART initiation), or early ART plus IPT. The primary end point was a composite of diseases included in the case definition of the acquired immunodeficiency syndrome (AIDS), non-AIDS-defining cancer, non-AIDS-defining invasive bacterial disease, or death from any cause at 30 months. We used Cox proportional models to compare outcomes between the deferred-ART and early-ART strategies and between the IPT and no-IPT strategies. RESULTS: A total of 2056 patients (41% with a baseline CD4+ count of ≥500 cells per cubic millimeter) were followed for 4757 patient-years. A total of 204 primary end-point events were observed (3.8 events per 100 person-years; 95% confidence interval [CI], 3.3 to 4.4), including 68 in patients with a baseline CD4+ count of at least 500 cells per cubic millimeter (3.2 events per 100 person-years; 95% CI, 2.4 to 4.0). Tuberculosis and invasive bacterial diseases accounted for 42% and 27% of primary end-point events, respectively. The risk of death or severe HIV-related illness was lower with early ART than with deferred ART (adjusted hazard ratio, 0.56; 95% CI, 0.41 to 0.76; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.56; 95% CI, 0.33 to 0.94) and lower with IPT than with no IPT (adjusted hazard ratio, 0.65; 95% CI, 0.48 to 0.88; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.61; 95% CI, 0.36 to 1.01). The 30-month probability of grade 3 or 4 adverse events did not differ significantly among the strategies. CONCLUSIONS: In this African country, immediate ART and 6 months of IPT independently led to lower rates of severe illness than did deferred ART and no IPT, both overall and among patients with CD4+ counts of at least 500 cells per cubic millimeter. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis; TEMPRANO ANRS 12136 ClinicalTrials.gov number, NCT00495651.)

Overview of the Proton-coupled MCT (SLC16A) Family of Transporters: Characterization, Function and Role in the Transport of the Drug of Abuse γ-Hydroxybutyric Acid

The transport of monocarboxylates, such as lactate and pyruvate, is mediated by the SLC16A family of proton-linked membrane transport proteins known as monocarboxylate transporters (MCTs). Fourteen MCT-related genes have been identified in mammals and of these seven MCTs have been functionally characterized. Despite their sequence homology, only MCT1–4 have been demonstrated to be proton-dependent transporters of monocarboxylic acids. MCT6, MCT8 and MCT10 have been demonstrated to transport diuretics, thyroid hormones and aromatic amino acids, respectively. MCT1–4 vary in their regulation, tissue distribution and substrate/inhibitor specificity with MCT1 being the most extensively characterized isoform. Emerging evidence suggests that in addition to endogenous substrates, MCTs are involved in the transport of pharmaceutical agents, including γ-hydroxybuytrate (GHB), 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), salicylic acid, and bumetanide. MCTs are expressed in a wide range of tissues including the liver, intestine, kidney and brain, and as such they have the potential to impact a number of processes contributing to the disposition of xenobiotic substrates. GHB has been extensively studied as a pharmaceutical substrate of MCTs; the renal clearance of GHB is dose-dependent with saturation of MCT-mediated reabsorption at high doses. Concomitant administration of GHB and l-lactate to rats results in an approximately two-fold increase in GHB renal clearance suggesting that inhibition of MCT1-mediated reabsorption of GHB may be an effective strategy for increasing renal and total GHB elimination in overdose situations. Further studies are required to more clearly define the role of MCTs on drug disposition and the potential for MCT-mediated detoxification strategies in GHB overdose

Post-Training Dephosphorylation of eEF-2 Promotes Protein Synthesis for Memory Consolidation

Memory consolidation, which converts acquired information into long-term storage, is new protein synthesis-dependent. As protein synthesis is a dynamic process that is under the control of multiple translational mechanisms, however, it is still elusive how these mechanisms are recruited in response to learning for memory consolidation. Here we found that eukaryotic elongation factor-2 (eEF-2) was dramatically dephosphorylated within 0.5–2 hr in the hippocampus and amygdala of mice following training in a fear-conditioning test, whereas genome-wide microarrays did not reveal any significant change in the expression level of the mRNAs for translational machineries or their related molecules. Moreover, blockade of NMDA receptors with MK-801 immediately following the training significantly impeded both the post-training eEF-2 dephosphorylation and memory retention. Notably, with an elegant sophisticated transgenic strategy, we demonstrated that hippocampus-specific overexpression of eEF-2 kinase, a kinase that specifically phosphorylates and hence inactivates eEF-2, significantly inhibited protein synthesis in the hippocampus, and this effects was more robust during an “ongoing” protein synthesis process. As a result, late phase long-term potentiation (L-LTP) in the hippocampus and long-term hippocampus-dependent memory in the mice were significantly impaired, whereas short-term memory and long-term hippocampus-independent memory remained intact. These results reveal a novel translational underpinning for protein synthesis pertinent to memory consolidation in the mammalian brain

Production, commercialisation et consommation de pots en pierre ollaire, aspects d’une vaisselle originale à travers l’exemple du Saint-Mont

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Compared abilities of filled and unfilled natural rubbers to crystallize in a large strain rate domain

cited By 5International audienceStrain induced crystallization (SIC) in filled and unfilled natural rubbers is investigated through insitu wide angle X-rays scattering (WAXS) experiments at various strain rates. The values of local stretching ratio at SIC onset (λc,local) are found similar between filled and unfilled rubbers stretched at slow strain rate (10-3s-1) and in a large temperature range [21°C, 80°C]. This is consistent with the fact that the calculated 'local' network densities of the first chains involved in SIC are very close in all samples. Conversely, λm,local for tests carried out in a large temperature range [21°C, 80°C] is found higher in filled samples compared to unfilled one due to a lower crystallites size. In order to investigate SIC in filled and unfilled rubbers submitted to conditions of solicitations met in pneumatic tires, insitu WAXS experiments are performed during high strain rates cycles (10-100s-1) thanks to a recent homemade machine. By increasing the frequency, strong self-heating related to filler-rubber interaction causes a dramatic fall of the crystallinity index (CI) in filled rubber. © 2015 Elsevier Ltd

A comparison of the abilities of natural rubber (NR) and synthetic polyisoprene cis-1,4 rubber (IR) to crystallize under strain at high strain rates

cited By 4International audienceStrain induced crystallization (SIC) of a natural rubber (NR) and a synthetic rubber (IR) with a high amount of cis-1,4 units (98.6%) is studied, thanks to in situ wide angle X-ray (WAXS) experiments at room temperature performed in a large range of strain rates. During stretching at a low strain rate (4.2 × 10-3 s-1), SIC in IR occurs at a larger stretching ratio than in NR. As a result, the crystallinity index at a given stretching ratio is lower in IR than in NR, in spite of the similar crosslink densities of the chains involved in the crystallization in both materials. This lower ability for crystallization in IR is attributed to the presence of branching along its backbone and its lower stereoregularity. Conversely, dynamic experiments performed at high strain rates (101/102 s-1) show for both materials a similar ability to crystallize. This unexpected result is confirmed by monotonic tensile tests performed in a large range of strain rates. The reason is thermodynamic: the chain extension plays a predominant role compared to the role of the microstructure defects when the strain rate is high, i.e. when the kinetics of the crystallite nucleation forces the crystallization to occur at a large stretching ratio. A thermodynamic model enables qualitative reproduction of the experimental results. © 2016 the Owner Societies

Strain-induced crystallization of natural rubber and cross-link densities heterogeneities

cited By 30International audienceStrain-induced crystallization (SIC) of natural rubber (NR) is characterized during a cyclic deformation at room temperature and low strain rate (∼10-3 s-1) using in situ wide angle X-rays scattering (WAXS) measurements. The crystallinity index (CI) and average size of the crystallites in the three main directions are measured during loading and unloading. A scenario describing SIC is then proposed, assuming that SIC corresponds to the successive appearance of crystallite populations whose nucleation and growth depend on the local network density. From this scenario, a methodology, coupling experimental observations and thermodynamic description is developed to determine the distribution of the network chain density associated with the size of a corresponding crystallite population. Finally, complex cyclic tests are performed. They suggest the existence of a memory effect in the chains involved in crystallization, which eases the nucleation process of the crystallites. © 2014 American Chemical Society