Unconventional surface plasmon resonance signals reveal quantitative inhibition of transcriptional repressor EthR by synthetic ligands

International audienceEthR is a mycobacterial repressor that limits the bioactivation of ethionamide, a commonly used anti-tuberculosis second-line drug. Several efforts have been deployed to identify EthR inhibitors abolishing the DNA-binding activity of the repressor. This led to the demonstration that stimulating the bioactivation of ETH through EthR inhibition could be an alternative way to fight Mycobacterium tuberculosis. We propose a new SPR methodology to study the affinity between inhibitors and EthR. Interestingly, the binding between inhibitors and immobilized EthR produced a dose dependent negative SPR signal. We demonstrated that this signal reveals the affinity of the small molecules for the repressor. The affinity constants (KD) correlated with their capacity to inhibit the binding of EthR to DNA. We hypothesize that conformational changes of EthR during ligand interaction could be responsible for this SPR signal. Practically, this unconventional result open perspectives to the development of SPR assay that would at the same time tough on the structural changes of the target upon binding with an inhibitor and on the binding constant of this interaction

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

LA LAVANDE ET SON HUILE ESSENTIELLE

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Time of Bariatric Surgery and Hospitalization for SARS-CoV-2: a Nationwide Study

International audienc

Bariatric Surgery Should Be Proposed in Certain Septuagenarian Patients with Obesity

International audienceBariatric surgery (BS) is rarely performed on patients aged 70 and over, due to the fear of adverse effects, particularly related to sarcopenia. We examined the outcome of obese patients who underwent BS after the age of 69 in the French population. Operated subjects were matched with non-operated obese patients (n = 1307 in each group after matching). We showed that BS was associated with a reduction in mortality and no increase in the risks of rehospitalization or fracture events

Change in Birth Rate Before and After Bariatric Surgery in France

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Systematic brain natriuretic peptide (BNP) measurement for cardiac screening in patients with severe obesity: the OLECOEUR study.

Introduction Heart failure (HF) diagnosis is difficult in patients with obesity due to cardiovascular and pulmonary comorbidities associated with physical deconditioning that all lead to dyspnea. Methods The OLECOEUR study screens prospectively for HF using systematic brain natriuretic peptide (BNP) measurement in ambulatory patients with obesity from one Nutrition department (Paris, France). Clinical, biological and echocardiogram data were extracted from electronic medical records. Results We included 1506 patients middle aged (mean age: 47.2 ± 14.6 years old) with severe obesity (mean BMI: 40.4 ± 6.6 kg/m²). Patients with BNP ≥ 35 pg/ml presented left heart remodeling including thicker interventricular septum (10.4 ± 2.0 vs. 9.6 ± 1.8 mm; P=0.0008), higher left ventricle mass (89.9 ± 24.3 vs. 77.2 ± 20.0 g/m2; P=0.0009) and significant modifications of both left and right atria in line with a higher proportion of prior atrial fibrillation. Markers of right heart remodeling on echocardiography were also significantly higher (pulmonary artery systolic pressure: 33.3 ± 17.3 vs. 24.5 ± 6.3 mmHg; P=0.0002). Conclusion The OLECOEUR study shows left and right subclinical heart remodeling in patients with obesity screened for HF with systematic dosage of BNP with usual cut-off at 35 pg/ml

Response to the letter by Onishi and al. regarding “Clinical diagnosis, outcomes and treatment of thiamine deficiency in a tertiary hospital”

International audienceLetter to the Editor Response to the letter by Onishi and al. regarding "Clinical diagnosis, outcomes and treatment of thiamine deficiency in a tertiary hospital" We have read with interest the letter addressed by Onishi and al. about our recent article entitled "Clinical diagnosis, outcomes and treatment of thiamine deficiency in a tertiary hospital". While we agree with the authors' remarks about the diagnosis of thiamine deficiency, we would like to provide some clarifications about the interpretation of our study