Change in Visual Acuity of Patients With Fuchs Endothelial Corneal Dystrophy Over 1 Year.

PURPOSE: To determine whether the clinical and paraclinical course of Fuchs endothelial corneal dystrophy (FECD) over 1 year is related to the extent of triplet repetition in the transcription factor 4 (TCF4) gene. METHODS: A prospective study with a 1-year follow-up was conducted. A total of 104 patients (160 eyes) with FECD and an equivalent number of age- and sex-matched control subjects without FECD were included. At inclusion, the corneas were graded using the modified Krachmer grade (KG) and patients were genotyped for the number of trinucleotide repeats (TNRs) in the TCF4 gene by the short tandem repeat assay. Visual acuity, Scheimpflug tomographic features, and the Visual Function and Corneal Health Status using a visual disability instrument were measured on 2 visits at 1-year intervals. RESULTS: KGs ranged from 1 to 6, and 46% of eyes had grades 1 to 4. 71% of the patients harbored TNR expansion (>40) versus 13% in control subjects (P < 0.001). Severity at inclusion was higher in the presence of TNR expansion when considering eyes independently (mean grade ±SD, 4.08 ± 1.42) without TNR expansion and 4.66 ± 1.27 with TNR expansion (P = 0.024). In 1 year, the ETDRS score significantly decreased by -2.97 (95% confidence interval -4.69 to -1.26, P = 0.001) and the ETDRS score with glare by -4.25 (95% confidence interval -6.22 to -2.27, P < 10-5). There was no relationship between the rate of decline and TNR expansion or KG. Central corneal thickness and Visual Function and Corneal Health Status scores did not significantly vary. CONCLUSIONS: It is possible to measure a subtle progression of FECD over a period as short as 1 year. We did not find a relationship between the presence of TNR expansion and the speed of deterioration over 1 year. This work should facilitate the design of future clinical trials on FECD.Trial Registration-URL: ClinicalTrials.gov. Identifier: French Fuchs Follow-up Study (F3S): NCT03974230.

Corneal Toxicity in Patients Treated by BELANTAMAB MAFODOTIN: How to Improve and Facilitate Patients Follow-Up Using Refractive Shift?

Purpose: Multiple myeloma (MM) is the second most common neoplastic blood disease worldwide. Belantamab mafodotin is a new antibody conjugate anti-B-cell maturation antigen effective against refractory myelomas. It induces intracorneal microcysts leading to refractive fluctuations. The aim of this study is to assess the value of monitoring refractive fluctuations based on the location of microcystic-like epithelial changes (MECs) to facilitate patient follow-up. Methods: This observational and multicentric study was conducted using data collected from several French centers contacted through secure email through a standardized data collection table. Results: The fluctuation of objective refraction in spherical equivalent confirms a significant myopic shift from peripheral to central forms. A decrease in the best-corrected visual acuity (BCVA), an increase in keratometry, and an increase in central epithelial pachymetry have also been observed when MECs migrate toward the center. Conclusion: The myopization found in our study in patients with central and paracentral MECs is consistent with current literature. Fluctuations in BCVA, keratometry, and epithelial pachymetry are also consistent. This study is the first real-world study and highlights heterogeneity in follow-up, emphasizing the need to establish multidisciplinary follow-up strategies. The analysis of refractive fluctuations appears to be a reproducible and noninvasive screening method that could facilitate patient follow-up without the need for consultation focused on corneal diseases.

Soft-Tissue Vibrations and Fatigue During Prolonged Running: Does an Individualized Midsole Hardness Play a Role?

Footwear has the potential to reduce soft-tissue vibrations (STV) but responses are highly subject-specific. Recent evidence shows that compressive garments minimizing STV have a beneficial effect on neuromuscular (NM) fatigue. The aim was to determine whether an individualized midsole hardness can minimize STV and NM fatigue during a half marathon. Twenty experienced runners were recruited for three visits: a familiarization session including the identification of midsole minimizing and maximizing STV amplitude (MIN and MAX, respectively), and two half marathon sessions at 95% of speed at the second ventilatory threshold. STV of the gastrocnemius medialis (GM) muscle, running kinetics, foot strike pattern, rating perceived exhaustion (RPE), and midsole liking were recorded every 3 km. NM fatigue was assessed on plantar flexors (PF) before (PRE) and after (POST) the half marathon. At POST, PF central and peripheral alterations and changes in contact time, step frequency, STV median frequency, and impact force frequency as well as foot strike pattern were found in both MIN and MAX. No significant differences in damping, STV main frequency, flight time, duty factor, and loading rate were observed between conditions whatever the time period. During the half marathon, STV amplitude of GM significantly increased over time for the MAX condition (+13.3%) only. Differences between MIN and MAX were identified for RPE and midsole liking. It could be hypothesized that, while significant, the effect of midsole hardness on STV is too low to substantially affect NM fatigue.

Trust and COVID-19 vaccine hesitancy in the Dominican Republic: a national cross-sectional household survey, June-October 2021.

OBJECTIVE: This study investigates the role of trust in shaping COVID-19 vaccine acceptance in the Dominican Republic (DR) during the COVID-19 pandemic. DESIGN: Cross-sectional household survey. SETTING: Randomly selected households across 134 clusters in the DR, from 30 June 2021 to 12 October 2021. PARTICIPANTS: 5999 participants ≥16 years of age were enrolled. OUTCOME MEASURES: COVID-19 vaccine hesitancy (CVH) data were collected from participants ≥16 years of age and analysed as both an ordinal and binary variable. RESULTS: Overall, CVH was low (5.2% (95% CI 4.6% to 5.8%)), but more common among younger individuals, women and individuals of Mestizo ethnicity. Higher trust in local government, national government, scientists and local doctors (considered official sources) was associated with lower odds of CVH (OR 0.89 (95% CI 0.72 to 0.88), 0.89 (95% CI 0.81 to 0.98), 0.87 (95% CI 0.80 to 0.94) and 0.70 (95% CI 0.62 to 0.80), respectively). Higher trust in religious leaders, social media and traditional media (considered unofficial sources) was associated with higher odds of CVH, with respective ORs of 1.32 (95% CI 1.18 to 1.47), 1.30 (95% CI 1.19 to 1.41) and 1.08 (95% CI 0.97 to 1.22). CONCLUSION: We report findings on CVH from a national household survey in the DR and identify overall low rates of CVH but marked heterogeneity by age, gender and ethnicity. Trust in unofficial versus official sources of information is associated with increased CVH. These findings highlight and quantify the importance of trust as a key parameter when considering public health communication strategies.

Absence of sympathetic innervation hampers the generation of tertiary lymphoid structures upon acute lung inflammation.

Tertiary lymphoid structures (TLS) are lymphoid organs present in inflammatory non-lymphoid tissues. Studies have linked TLS to favorable outcomes for patients with cancers or infectious diseases, but the mechanisms underlying their formation are not fully understood. In particular, secondary lymphoid organs innervation raises the question of sympathetic nerve fibers involvement in TLS organogenesis. We established a model of pulmonary inflammation based on 5 daily intranasal instillations of lipopolysaccharide (LPS) in immunocompetent mice. In this setting, lung lymphoid aggregates formed transiently, evolving toward mature TLS and disappearing when inflammation resolved. Sympathetic nerve fibers were then depleted using 6-hydroxydopamine. TLS quantification by immunohistochemistry showed a decrease in LPS-induced TLS number and surface in denervated mouse lungs. Although a reduction in alveolar space was observed, it did not impair overall pulmonary content of transcripts encoding TNF-α, IL-1ß and IFN-γ inflammation molecules whose expression was induced by LPS instillations. Immunofluorescence analysis of immune infiltrates in lungs of LPS-treated mice showed a drop in the proportion of CD23+ naive cells among CD19+ B220+ B cells in denervated mice whereas the proportion of other cell subsets remained unchanged. These data support the existence of neuroimmune crosstalk impacting lung TLS neogenesis and local naive B cell pool.

Fitness-to-drive recommendations in post-stroke patients: a retrospective study.

BACKGROUND: Stroke sequelae can have an impact on daily life activities such as driving. French legislation stipulates that post-stroke patients should undergo a multi-professional fitness-to-drive assessment before being allowed to drive again. This retrospective study aims to explore the determinants of multi-professional fitness-to-drive recommendations. METHODS: Sixty-six post-stroke patients assessed for fitness to drive in the Kerpape Center, France in 2019 were included. Favorable or unfavorable driving recommendations were attributed to patients following a joint decision by a multi-professional team. Individual characteristics obtained from medical records were compared. RESULTS: Findings showed that 64% of stroke patients received a favorable fitness-to-drive recommendation. Across all demographic, clinical, and driving characteristics, the time interval between stroke and assessment was significantly longer for patients designated as unfit to drive than for those designated as fit to drive (P = .004). Furthermore, the proportion of instrumental sequelae was higher in patients designated as unfit to drive than in those designated as fit to drive (P = .022). Stepwise logistic regression showed that the presence of instrumental sequelae, mainly aphasia, was the best predictor of fitness-to-drive recommendations. CONCLUSIONS: The post-stroke time interval and the presence of instrumental sequelae explained the difference between patients recommended as fit-to-drive and unfit-to-drive. Furthermore, aphasia was found be the best predictor of a fitness-to-drive recommendation. It is possible that aphasia impacts the understanding of instructions during on-road testing. These findings emphasize the need for a standardized multi-professional fitness-to-drive assessment, since the determinants of fitness-to-drive recommendation differ between studies.

Intestinal absorption of sphingosine: new insights on generated ceramide species using stable isotope tracing in vitro.

Dietary sphingomyelin (SM) has been reported to favorably modulate postprandial lipemia. Mechanisms underlying these beneficial effects on cardiovascular risk markers are not fully elucidated. Rodent studies showed that tritiated SM was hydrolyzed in the intestinal lumen into ceramides (Cer) and further to sphingosine (SPH) and fatty acids (FA) that were absorbed by the intestine. Our objective was to investigate the uptake and metabolism of SPH and/or tricosanoic acid (C23:0), the main FA of milk SM, as well as lipid secretion in Caco-2/TC7 cells cultured on semipermeable inserts. Mixed micelles (MM) consisting of different digested lipids and taurocholate were prepared without or with SPH, SPH and C23:0 (SPH+C23:0), or C23:0. Triglycerides (TG) were quantified in the basolateral medium, and sphingolipids were analyzed by tandem mass spectrometry. TG secretion increased 11-fold in all MM-incubated cells compared with lipid-free medium. Apical supply of SPH-enriched MM led to increased concentrations of total Cer in cells, and coaddition of C23:0 in SPH-enriched MM led to a preferential increase of C23:0 Cer and C23:0 SM. Complementary experiments using deuterated SPH demonstrated that SPH-d9 was partly converted to sphingosine-1-phosphate-d9, Cer-d9, and SM-d9 within cells incubated with SPH-enriched MM. A few Cer-d9 (2% of added SPH-d9) was recovered in the basolateral medium of (MM+SPH)-incubated cells, especially C23:0 Cer-d9 in (MM+SPH+C23:0)-enriched cells. In conclusion, present results indicate that MM enriched with (SPH+C23:0), such as found in postprandial micelles formed after milk SM ingestion, directly impacts sphingolipid endogenous metabolism in enterocytes, resulting in the secretion of TG-rich particles enriched with C23:0 Cer.

Disrupted BMP-9 Signaling Impairs Pulmonary Vascular Integrity in Hepatopulmonary Syndrome.

RATIONALE: Hepatopulmonary syndrome (HPS) is a severe complication of liver diseases characterized by abnormal dilatation of pulmonary vessels, resulting in impaired oxygenation. Recent research highlights the pivotal role of liver-produced bone morphogenetic protein (BMP)-9 in maintaining pulmonary vascular integrity. OBJECTIVES: This study aimed to investigate the involvement of BMP-9 in human and experimental HPS. METHODS: Circulating BMP-9 levels were measured in 63 healthy controls and 203 cirrhotic patients, with or without HPS. Two animal models of portal hypertension were employed: common bile duct ligation (CBDL) with cirrhosis and long-term partial portal vein ligation (PPVL) without cirrhosis. Additionally, the therapeutic effect of low-dose BMP activator FK506 was investigated, and the pulmonary vascular phenotype of BMP-9 knockout rats was analyzed. MEASUREMENTS AND MAIN RESULTS: Patients with HPS related to compensated cirrhosis demonstrated lower levels of circulating BMP-9 compared to patients without HPS. Severe cirrhosis patients exhibited consistently low levels of BMP-9. In animal models, HPS characteristics, including intrapulmonary vascular dilations (IPVDs) and alveolo-arterial gradient enlargement, were observed. HPS development in both rat models correlated with reduced intrahepatic BMP-9 expression, decreased circulating BMP-9 level and activity, and impaired pulmonary BMP-9 endothelial pathway. Daily treatment with FK506 for 2-weeks restored BMP pathway in the lungs, alleviating IPVDs, and improving gas exchange impairment. Furthermore, BMP-9 knockout rats displayed a pulmonary HPS phenotype, supporting its role in disease progression. CONCLUSION: The study findings suggest that portal hypertension-induced loss of BMP-9 signaling contributes to HPS development.

Whole milk dairy foods and cardiometabolic health: dairy fat and beyond.

Bovine dairy milk is a nutrient-rich matrix, but consumption of full-fat dairy food varieties has been claimed historically to be associated with poorer cardiometabolic health, a notion often attributed to the saturated fat content. However, continued investigation that includes observational studies and randomized controlled trials (RCTs) provide evidence that favorably supports full-fat dairy foods and their bioactive components on cardiometabolic health. This review addresses this controversy by examining the evidence surrounding full-fat dairy foods and their implications for human health. Dairy foods are heterogeneous, not just in their fat content but also in other compositional aspects within and between fermented (e.g., yogurt, cheese) and nonfermented products (e.g., milk) that could differentially influence cardiometabolic health. Drawing from complementary lines of evidence from epidemiological studies and RCTs, this review describes the health effects of dairy foods regarding their fat content, as well as their polar lipids that are concentrated in the milk fat globule fraction. Observational studies have limitedly supported the consumption of full-fat dairy to protect against cardiometabolic disorders. However, this framework has been disputed by RCTs indicating that dairy foods, regardless of their fat content or fermentation, are not detrimental to cardiometabolic health and may instead alleviate certain cardiometabolic risk factors. As dietary recommendations evolve, which currently indicate to avoid full-fat dairy foods, it is essential to consider the totality of evidence, especially from RCTs, while also recognizing that investigation is needed to evaluate the complexity of dairy foods within diverse dietary patterns and their impacts on cardiometabolic health.

Postmortem concentrations for total blood carbon monoxide (TBCO) as a novel biomarker for carbon monoxide (CO) poisonings.

Total blood carbon monoxide (TBCO) showed promising results in improving accuracy of CO determinations in blood and presenting better stability to different storage conditions. Therefore, it was proposed as an alternative biomarker to carboxyhemoglobin (COHb) for CO poisoning diagnosis. However, given that current interpretation reference values exist for COHb only, it is difficult to implement TBCO analysis in routine. Therefore, we aimed at determining TBCO reference values for postmortem CO poisoning cases. A previously validated method for TBCO analysis via gas chromatography-mass spectrometry was applied to cardiac, peripheral, cranial and spleen blood samples collected from 92 autopsies. Autopsy cases included 21 non-CO-related and 71 CO-related cases with varying postmortem intervals (PMIs). Statistical analyses were performed using statistical software R Studio. When comparing lower to higher PMIs for non-CO-related cases, no significant differences were found, which suggests that CO formation or degradation at low PMIs does not occur. Spleen blood showed potential as an alternative matrix to CO determinations in cases with sample availability issues but needs to be evaluated for CO-positive cases. Results for cardiac blood in CO-related autopsies showed a positive correlation between COHb and TBCO values (R = 0.78). This value is lower than what is found in the literature, suggesting that even though COHb and TBCO are correlated, a potential underestimation of the true CO exposure might occur if only COHb values are taken into consideration. Samples were divided into CO exposure groups based on COHb concentrations, and with the data obtained, classification into the following TBCO concentration groups is proposed: no significant CO exposure case <6 µmol/mL, medium CO exposure case 6-20 µmol/mL and high CO exposure case >20 µmol/mL. Even if a higher number of samples in each group would enable to increase the confidence, these results are very promising and highlight the importance of TBCO measurement.

Advancing Endocrine Disruptors via In Vitro Evaluation: Recognizing the Significance of the Organization for Economic Co-Operation and Development and United States Environmental Protection Agency Guidelines, Embracing New Assessment Methods, and the Urgent Need for a Comprehensive Battery of Tests.

Efforts are being made globally to improve the evaluation and understanding of endocrine-disrupting chemicals. Recognition of their impact on human health and the environment has stimulated attention and research in this field. Various stakeholders, including scientists, regulatory agencies, policymakers, and industry representatives, are collaborating to develop robust methodologies and guidelines for assessing these disruptors. A key aspect of these efforts is the development of standardized testing protocols and guidelines that aim to provide consistent and reliable methods for identifying and characterizing endocrine disruptors. When evaluating the potential endocrine-disrupting activity of chemicals, no single test is capable of detecting all relevant endocrine-disrupting agents. The test battery approach is designed to reduce the risk of false negative results for compounds with toxic potential. A weight-of-evidence approach is therefore necessary for endocrine disruptor evaluation. This approach considers various types of data from multiple sources, assessing the overall strength, consistency, and reliability of the evidence. OECD guidelines are highly regarded for their scientific rigor, transparency, and consensus-based development process. It is crucial to explore and develop new methodologies that can effectively evaluate the risks associated with potential endocrine disruptors. Integrating these methods into a comprehensive weight-of-evidence framework will enhance risk assessments and facilitate informed decisions regarding the regulation and management of these substances, ensuring the protection of human health and the environment from their adverse effects.

Multifunctional dietary interventions, low-grade inflammation and cardiometabolic profile: a scoping review.

Background: Growing evidence highlights the significant impact of diet to modify low-grade inflammation closely linked to cardiometabolic profile. Multifunctionnal diets, combining several compounds have been shown to beneficially impact metabolic parameters. Objective: This study synthesizes the knowledge on the impact of RCTs combining dietary multifunctional compounds on low-grade inflammation in humans. We investigate whether the effects of dietary multifunctional interventions on inflammatory markers were parallel to alterations of cardiometabolic parameters. Methodology: We considered both the integrated dietary interventions (ID, i.e. global diets such as Mediterranean, Nordic…) and the dietary interventions based on selected bioactive mix (BM) compounds, in healthy individuals and those at cardiometabolic risk. Out of 221 screened publications, we selected 27 studies: 11 for BM (polyphenols and/or omega-3 fatty acids and/or antioxidants and/or dietary fiber) and 16 for ID (Mediterranean, paleo, Nordic, Dietary Approaches to Stop Hypertension (DASH) diet…). Results: ID studies reflected significant improvements in inflammatory markers (CRP, IL-6, IL-10, IL-1b), concomitantly with beneficial changes in metabolic parameters. In BM studies, pronounced effects on low-grade inflammatory markers were observed, while improvements in metabolic parameters were not consistent. Both types of studies suggested a favorable impact on oxidative stress, a factor closely linked to the inflammatory profile. Conclusion: Our findings showed that multifunctional RCT diets have differential role in managing low-grade inflammation and cardiometabolic health, with a large heterogeneity in explored inflammatory markers. Further research is imperative to elucidate the link between low-grade inflammation and other cardiometabolic risk factors, such as intestinal inflammation or postprandial inflammatory dynamics, aiming to attain a comprehensive understanding of the mechanisms involved in these processes. These future investigations not only have the potential to deepen our insights into the connections among these elements but also pave the way for significant advancements in the prevention and management of conditions related to the cardiovascular and metabolic systems.

A new classification allowing assessment of instrumental vaginal-birth practices.

BACKGROUND: Instrumental vaginal birth, a very common intervention in obstetrics, concerns nearly one in eight women in France. Instrumentally assisted vaginal childbirth can be for maternal and/or fetal indications. Although it reduces recourse to caesarean section, it is subject to risks. Practices concerning instrumental birth are disparate, varying among different practitioners, maternity units and countries, and it is essential to be able to evaluate them. Our objective was to create a classification tool of women requiring instrumental birth to facilitate the analysis of practices within our maternity unit as well as to enable temporal and geographical comparisons. MATERIALS AND METHODS: We propose a simple and robust classification based on the same principles as Robson's classification. It is made up of seven totally inclusive and mutually exclusive groups. Our classification was refined and validated using the Delphi method by a panel of 14 experts from throughout France, and tested in our maternity unit using data from throughout 2021. RESULTS: The seven clinically relevant groups are based on five obstetric criteria (multiplicity, presentation, gestational age, previous type of birth, induction of labor). To classify each woman in a group, five successive questions are posed in a predefined order. The classification has been validated by the experts with highly satisfactory overall agreement. CONCLUSION: In order to improve the quality of care, we propose a tool to standardize the evaluation of instrumental vaginal birth practice (called the "Isère classification", after the county where we work in south-eastern France). It will also facilitate the comparison the practices among different maternity units in a network, a country or even among different countries.

Change in the perceived reproductive age window and delayed fertility in Europe.

While extensive literature documents the massive fertility delay of recent decades, knowledge about whether and how attitudes towards the timing of births have changed in Europe remains limited. Using data from two rounds of the European Social Survey, we investigate these changes and their association with macro-level fertility indicators in 21 countries. Between 2006-07 and 2018-19, societal consensus regarding the existence of optimal childbearing ages remained strong and became more in favour of later parenthood. Decomposition analyses show that these shifts were driven only partially by changes in population composition, supporting the idea that a general attitudinal change in favour of later childbearing is underway. We also find a trend towards gender convergence in upper age limits driven by the increasing social recognition of an age deadline for men's childbearing. Although shifts in perceived reproductive age windows occurred during periods of birth postponement, they corresponded only loosely to country-level changes in fertility.

[The Nobel Prize in Physiology or Medicine 2023: Katalin Karikó and Drew Weissman - A vaccine revolution driven by fundamental research in immunology and molecular biology]. / Prix Nobel de physiologie ou médecine 2023 : Katalin Karikó et Drew Weissman - Une révolution vaccinale portée par la recherche fondamentale en immunologie et en biologie moléculaire.

Title: Prix Nobel de physiologie ou médecine 2023 : Katalin Karikó et Drew Weissman - Une révolution vaccinale portée par la recherche fondamentale en immunologie et en biologie moléculaire. Abstract: Le 2 octobre 2023, le prix Nobel de physiologie ou médecine a été décerné à Katalin Karikó et Drew Weissman, tous deux professeurs à l'université de Pennsylvanie, pour leur « découverte concernant les modifications des nucléosides qui ont permis le développement de vaccins ARN efficaces contre le COVID-19 ¼. Le communiqué du comité Nobel indique que « grâce à leurs découvertes exceptionnelles qui ont changé radicalement notre compréhension des mécanismes par lesquels l'ARN messager interagit avec notre système immunitaire, ces deux lauréats ont contribué au développement, avec une rapidité sans précédent, d'un vaccin contre l'une des plus grandes menaces des temps modernes affectant la santé humaine ¼.

Postprandial lipid and vascular responses following consumption of a commercially-relevant interesterified palmitic acid-rich spread in comparison to functionally-equivalent non-interesterified spread and spreadable butter: a randomised controlled trial in healthy adults.

Background: Interesterification is an industrial processing technique used widely where hard fats are essential for functionality and consumer acceptability, e.g. margarines and lower fat spreads. Objective: The aim of this study was to compare acute cardiovascular effects of functionally equivalent spreads (similar solid fat content) made with interesterified (IE) or non-IE palm-based fats, or spreadable butter. Methods: A randomised, controlled, 4-armed crossover, double-blind study (25 men, 25 women; 35-75 years; healthy; mean BMI 24.5, SD 3.8), compared effects of mixed nutrient meals containing 50 g fat from functionally equivalent products [IE spread, non-IE spread and spreadable butter (SB), with rapeseed oil (RO) as a reference treatment: with 16.7%, 27.9%, 19.3% and 4% palmitic acid, respectively] on 8 h postprandial changes in plasma triacylglycerol (TAG) and endothelial dysfunction (flow-mediated dilatation; FMD). Circulating reactive oxygen species (estimated using a neutrophil oxidative burst assay), glucose, insulin, NEFA, lipoprotein particle profiles, inflammatory markers (glycoprotein acetylation (Glyc-A) and IL-6), and biomarkers of endotoxemia were measured. Results: Postprandial plasma TAG concentrations after test meals were similar. However following RO versus the 3 spreads, there were significantly higher postprandial apolipoprotein B concentrations, and small HDL and LDL particle concentrations, and lower postprandial extra-large, large, and medium HDL particle concentrations, as well as smaller average HDL and LDL particle sizes. There were no differences following IE compared to the other spreads. Postprandial FMD% did not decrease after high-fat test meals, and there were no differences between treatments. Postprandial serum IL-6 increased similarly after test meals, but RO provoked a greater increase in postprandial concentrations of glycoprotein acetyls (GlycA), as well as 8 h sCD14, an endotoxemia marker. All other postprandial outcomes were not different between treatments. Conclusions: In healthy adults, a commercially-available IE-based spread did not evoke a different postprandial triacylglycerol, lipoprotein subclass, oxidative stress, inflammatory or endotoxemic response to functionally-equivalent, but compositionally-distinct alternative spreads. Clinical trial registry number: NCT03438084 (https://ClinicalTrials.gov).

Differences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigations.

Glutamine synthetases (GS) catalyze the ATP-dependent ammonium assimilation, the initial step of nitrogen acquisition that must be under tight control to fit cellular needs. While their catalytic mechanisms and regulations are well-characterized in bacteria and eukaryotes, only limited knowledge exists in archaea. Here, we solved two archaeal GS structures and unveiled unexpected differences in their regulatory mechanisms. GS from Methanothermococcus thermolithotrophicus is inactive in its resting state and switched on by 2-oxoglutarate, a sensor of cellular nitrogen deficiency. The enzyme activation overlays remarkably well with the reported cellular concentration for 2-oxoglutarate. Its binding to an allosteric pocket reconfigures the active site through long-range conformational changes. The homolog from Methermicoccus shengliensis does not harbor the 2-oxoglutarate binding motif and, consequently, is 2-oxoglutarate insensitive. Instead, it is directly feedback-inhibited through glutamine recognition by the catalytic Asp50'-loop, a mechanism common to bacterial homologs, but absent in M. thermolithotrophicus due to residue substitution. Analyses of residue conservation in archaeal GS suggest that both regulations are widespread and not mutually exclusive. While the effectors and their binding sites are surprisingly different, the molecular mechanisms underlying their mode of action on GS activity operate on the same molecular determinants in the active site.

Efficacy and Safety of Rituximab-Based Treatments in Angioedema With Acquired C1-Inhibitor Deficiency.

BACKGROUND: Angioedema (AE) due to acquired C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is related to excessive consumption of C1-INH or to anti-C1-INH antibodies, and is frequently associated with lymphoproliferative syndromes or monoclonal gammopathies. Standard of care for prophylactic treatment in this condition is not established. Rituximab may be effective to prevent attacks, especially if the lymphoid hemopathy is controlled, but data are scarce. OBJECTIVE: To evaluate efficacy of rituximab in AAE-C1-INH. METHODS: A retrospective multicenter study was carried out in France, including patients with AAE-C1-INH treated with rituximab between April 2005 and July 2019. RESULTS: Fifty-five patients with AAE-C1-INH were included in the study, and 23 of them had an anti-C1-INH antibody. A lymphoid malignancy was identified in 39 patients, and a monoclonal gammopathy in 9. There was no associated condition in 7 cases. Thirty patients received rituximab alone or in association with chemotherapy (n = 25). Among 51 patients with available follow-up, 34 patients were in clinical remission and 17 patients had active AE after a median follow-up of 3.9 years (interquartile range, 1.5-7.7). Three patients died. The presence of anti-C1-INH antibodies was associated with a lower probability of AE remission (hazard ratio, 0.29 [95% CI, 0.12-0.67]; P = .004). Relapse was less frequent in patients with lymphoma (risk ratio, 0.27 [95% CI, 0.09-0.80]; P = .019) and in patients treated with rituximab and chemotherapy (risk ratio, 0.31 [95% CI, 0.12-0.79]; P = .014). CONCLUSIONS: Rituximab is an efficient and well-tolerated therapeutic option in AE, especially in lymphoid malignancies and in the absence of detectable anti-C1-INH antibodies.

Inhibition of intestinal FXR activity as a possible mechanism for the beneficial effects of a probiotic mix supplementation on lipid metabolism alterations and weight gain in mice fed a high fat diet.

Supplementation with probiotics has emerged as a promising therapeutic tool to manage metabolic diseases. We investigated the effects of a mix of Bifidobacterium animalis subsp. lactis LA804 and Lactobacillus gasseri LA806 on high-fat (HF) diet -induced metabolic disease in mice. Supplementation with the probiotic mix in HF diet-fed mice (HF-Pr2) reduced weight and fat mass gains, decreased hepatic lipid accumulation, and lowered plasma triglyceride peak during an oral lipid tolerance test. At the molecular level, the probiotic mix protected against HF-induced rise in mRNA levels of genes related to lipid uptake, metabolism, and storage in the liver and white adipose tissues, and strongly decreased mRNA levels of genes related to inflammation in the white adipose tissue and to oxidative stress in the liver. Regarding intestinal homeostasis, the probiotic mix did not prevent HF-induced gut permeability but slightly modified microbiota composition without correcting the dysbiosis induced by the HF diet. Probiotic supplementation also modified the cecal bile acid (BA) profile, leading to an increase in the Farnesoid-X-Receptor (FXR) antagonist/agonist ratio between BA species. In agreement, HF-Pr2 mice exhibited a strong inhibition of FXR signaling pathway in the ileum, which was associated with lipid metabolism protection. This is consistent with recent reports proposing that inhibition of intestinal FXR activity could be a potent mechanism to overcome metabolic disorders. Altogether, our results demonstrate that the probiotic mix evaluated, when administered preventively to HF diet-fed mice could limit obesity and associated lipid metabolism disorders, likely through the inhibition of FXR signaling in the intestinal tract.

Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling.

Phospholipase A/acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3-/- and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation. Accordingly, CRISPR-Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function.