Reversing Gut Damage in HIV Infection: Using Non-Human Primate Models to Instruct Clinical Research

International audienceAntiretroviral therapy (ART) has led to dramatic improvements in the lives of HIV-infected persons. However, residual immune activation, which persists despite ART, is associated with increased risk of non-AIDS morbidities. Accumulating evidence shows that disruption of the gut mucosal epithelium during SIV/HIV infections allows translocation of microbial products into the circulation, triggering immune activation. This disruption is due to immune, structural and microbial alterations. In this review, we highlighted the key findings of gut mucosa studies of SIV-infected macaques and HIV-infected humans that have revealed virus-induced changes of intestinal CD4, CD8 T cells, innate lymphoid cells, myeloid cells, and of the local cytokine/chemokine network in addition to epithelial injuries. We review the interplay between the host immune response and the intestinal microbiota, which also impacts disease progression. Collectively, these studies have instructed clinical research on early ART initiation, modifiers of microbiota composition, and recombinant cytokines for restoring gut barrier integrity

Seismic stratigraphic framework and depositional history for Cretaceous and Cenozoic contourite depositional systems of the Mozambique Channel, SW Indian Ocean

International audienceThis study describes previously unrecognized contourite depositional systems (CDSs) in the Mozambique Channel which constrain palaeoceanographic models for this area. The stratigraphic stacking patterns record nine seismic units (SU1 to SU9) separated by eight major discontinuities (a to h, oldest to youngest). Key seismic markers in CDS evolutionary history occur during Aptian-Albian (~122 Ma), late Cenomanian (94 Ma), early (38.2–36.2 Ma) and late (25–23 Ma) Oligocene, and early-middle Miocene (~17–15 Ma) epochs. These record onset (~122 to 94 Ma), growth (94 to 25–23 Ma), maintenance (25–23 to 17–15 Ma), and burial (17–15 Ma to the actual time) stages for CDSs. CDSs first develop during the onset stage which coincides with the opening and deepening of the African-Southern Ocean gateway (at 122 and 100 Ma, respectively). The growth stage, beginning in the late Cenomanian (94 Ma), correlates with the opening and deepening of the Equatorial Atlantic gateway. During the growth stage, two major shifts in sedimentary stacking pattern occur which coincide with palaeoceanographic changes during the early (38.2–36.2 Ma) and late (25–23 Ma) Oligocene. These in turn coincide with the onset and local enhancement of Antarctic water masses. CDS growth continued until the early-middle Miocene during the maintenance stage (~17–15 Ma). Most CDS growth ceased at the end of the maintenance stage. Circulation of the North Atlantic water mass into the Southern Hemisphere led to a deepening of Antarctic water masses in the area

The Urine-to-Plasma Urea Concentration Ratio is associated with eGFR and eGFR decline over time in a population cohort.

BACKGROUND Evaluation of renal function and of factors associated with its decline are important public health issues. Besides markers of glomerular function (e.g., GFR), those of tubular functions are rarely evaluated. Urea, the most abundant urinary solute, is markedly concentrated in urine when compared to plasma. We explored the urine-to-plasma ratio of urea concentrateions (U/P-urea-ratio) as a marker of tubular functions. METHODS We evaluated the relationship of the U/P-urea-ratio with eGFR at baseline in 1043 participants (48±17y) from the SKIPOGH population-based cohort, using mixed regression. In 898 participants, we assessed the relation between U/P-urea-ratio and renal function decline between two study waves 3 years apart. We studied U/P ratios for osmolarity, Na, K, uric acid for comparison. RESULTS In a transversal study at baseline, eGFR was positively associated with U/P-urea-ratio (βscaled = 0.08, 95%CI[0.04;0.13]) but not with the U/P ratio of osmolarity. Considering separately participants with renal function > or ≤ 90 ml/minx1.73m2, this association was observed only in those with reduced renal function. In the longitudinal study, eGFR declined at a mean rate of 1.2 ml/min per year. A significant association was observed between baseline U/P-urea-ratio and eGFR decline (βscaled = 0.08, 95%CI[0.01;0.15]). A lower baseline U/P-urea-ratio was associated with a greater eGFR decline. CONCLUSION This study provides evidence that the U/P-urea-ratio is an early marker of kidney function decline in the general adult population. Urea is easy to measure with well-standardized techniques and at low cost. Thus, the U/P-urea-ratio could become an easily available tubular marker for evaluating renal function decline

LILAC pilot study : effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy

Background: Chronic inflammation and residual HIV transcription persist in people living with HIV (PLWH) receiving antiretroviral therapy (ART), thus increasing the risk of developing non-AIDS co-morbidities. The mechanistic target of rapamycin (mTOR) is a key regulator of cellular metabolism and HIV transcription, and therefore represents an interesting novel therapeutic target. Methods: The LILAC pilot clinical trial, performed on non-diabetic ART-treated PLWH with CD4+ /CD8+ T-cell ratios <0.8, evaluated the effects of metformin (12 weeks oral administration; 500-850 mg twice daily), an indirect mTOR inhibitor, on the dynamics of immunological/virological markers and changes in mTOR activation/phosphorylation in blood collected at Baseline, Week 12, and 12 weeks after metformin discontinuation (Week 24) and sigmoid colon biopsies (SCB) collected at Baseline and Week 12. Findings: CD4+ T-cell counts, CD4+ /CD8+ T-cell ratios, plasma markers of inflammation/gut damage, as well as levels of cell-associated integrated HIV-DNA and HIV-RNA, and transcriptionally-inducible HIV reservoirs, underwent minor variations in the blood in response to metformin. The highest levels of mTOR activation/ phosphorylation were observed in SCB at Baseline. Consistently, metformin significantly decreased CD4+ Tcell infiltration in the colon, as well as mTOR activation/phosphorylation, especially in CD4+ T-cells expressing the Th17 marker CCR6. Also, metformin decreased the HIV-RNA/HIV-DNA ratios, a surrogate marker of viral transcription, in colon-infiltrating CD4+ T-cells of 8/13 participants

PhenoExplorer: An Interactive Web-based Platform for Exploring (Epi)Genome-Wide Associations Using a Swiss Population-based Study

The recent advent of high-throughput sequencing technologies has allowed exploring the contribution of thousands of genomic, epigenomic, transcriptomic, or proteomic variants to complex phenotypic traits. Here, we sought to conduct large-scale (Epi)Genome-Wide Association Studies (GWAS/EWAS) to investigate the associations between genomic (Single Nucleotide Polymorphism; SNP) and epigenomic (Cytosine-Phospho-Guanine; CpG) markers, with multiple phenotypic traits in a population-based context. We used data from SKIPOGH, a family- and population-based cohort conducted in the cities of Lausanne, Geneva, and Bern (N=1100). We used 7,577,572 SNPs, 420,444 CpGs, and 825 phenotypes, including anthropometric, clinical, blood, urine, metabolite, and metal measures. GWAS analyses assessed the associations between SNPs and metabolites and metals (N=279), using regression models adjusted for age, sex, recruitment center, and familial structure, whereas EWAS analyses explored the relations between CpGs and 825 phenotypes, additionally adjusting for the seasonality of blood sampling and technical nuisance. Following the implementation of GWAS and EWAS analyses, we developed a web-based platform, PhenoExplorer, aimed at providing an open access to the obtained results. Of the 279 phenotypes included in GWAS, 103 displayed significant associations with 2804 SNPs (2091 unique SNPs) at Bonferroni threshold, whereas 109 of the 825 phenotypes included in EWAS analyses were associated with 4893 CpGs (2578 unique CpGs). All of the obtained GWAS and EWAS results were eventually made available using the in-house built web-based PhenoExplorer platform, with the purpose of providing an open-access to the tested associations. In conclusion, we provide a comprehensive outline of GWAS and EWAS associations performed in a Swiss population-based study. Further, we set up a web-based PhenoExplorer platform with the purpose of contributing to the overall understanding of the role of molecular variants in regulating complex phenotypes

Residual vascular risk in diabetes – will the SPPARM alpha concept hold the key?

No abstract available

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARM) paradigm : conceptual framework and therapeutic potential: A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARM) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARM agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARM agonist safely reduces residual cardiovascular risk.Peer reviewe

Transformations agricoles et agroalimentaires

À l’heure des robots et du numérique, la terre (habitat, agriculture, paysage, planète) et la nourriture (du corps et de l’âme) sont parmi les préoccupations majeures dans les espaces médiatiques et politiques. Le pétrole et l’abondance qui l’a accompagné nous avaient fait oublier qu’elles sont au fondement des sociétés humaines. La « crise alimentaire » de 2008, qui a secoué plusieurs continents, a rappelé aux gouvernements l’enjeu de la sécurité alimentaire. Après des décennies d’excédents, de baisse du prix des produits agricoles de base, la question de la valeur de la terre et de l’agriculture est de retour. La question de la santé et celle des droits humains prennent une place élargie tant dans les politiques publiques et dans la production de normes alimentaires. Des mouvements sociaux transnationaux s’emparent de la question de l’avenir de l’agriculture et de l’alimentation, et de celle de la « bonne vie ». Pour contribuer à cette réflexion sur l’avenir de la terre et de la nourriture, cet ouvrage étudie la socialisation de l’agriculture, c’est-à-dire sa prise en charge tant par les politiques agricoles (essentiellement nationales) que par l’organisation des marchés dans un cadre national et international. Il le fait en prenant un large recul et mobilise trois temporalités. La première est celle de la planète. La seconde, celle des régimes métaboliques, façons dont l’humanité à différents stades de développement, mobilise matériaux et énergie. La troisième est celle du capitalisme, avec la succession de systèmes hégémoniques (ce qui n’exclue pas de multiples polarités). Cet ouvrage réunit des recherches récentes d’économistes, de sociologues, d’historiens et d’agronomes, de différents pays, recherches qui ont en commun de concerner la place de l’agriculture dans l’évolution des capitalismes

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways