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GABA-independent activation of GABAB receptor by mechanical forces
No full textInternational audienceThe heterodimeric GABAB receptor, composed of GB1 and GB2 subunits, is a metabotropic G protein-coupled receptor (GPCR) activated by the neurotransmitter GABA. GABA binds to the extracellular domain of GB1 to activate G proteins through GB2. Here we show that GABAB receptors can be activated by mechanical forces, such as traction force and shear stress, in a GABA-independent manner. This GABA-independent mechano-activation of GABAB receptor is mediated by a direct interaction between integrins and the extracellular domain of GB1, indicating that GABAB receptor and integrin form a mechano-transduction complex. Mechanistically, shear stress promotes the binding of integrin to GB1 and induces an allosteric re-arrangement of GABAB receptor transmembrane domains towards an active conformation, culminating in receptor activation. Furthermore, we demonstrate that shear stress-induced GABAB receptor activation plays a crucial role in astrocyte remodeling. These findings reveal a role of GABAB receptor in mechano-transduction, uncovering a ligand-independent activation mechanism for GPCRs
Novel ruthenium(II) polypyridyl complexes conjugated with bis-dipicolylamine as antibacterial photosensitisers
No full textInternational audienceThe inexorable and rapid rise of antimicrobial resistance in various Gram-positive and Gram-negative bacteria strains is severely compromising our global healthcare system. Facing a diminishing quantity of effective antibiotics against the threat, alternative therapeutics and drugs such as photodynamic therapy and antibacterial photosensitisers are vital in treat- ing bacterial infections. Multiple reports of ruthenium(II) polypyridyl complexes possessing antibacterial activities make them attractive candidates as potential antibacterial photosensitisers. The present work reports the synthesis of a series of novel ruthenium(II) polypyridyl complexes conjugated with bis-dipicolylamine derivatives and their assessments as mem- brane-targeting antibacterial photosensitisers. Of the four conjugated complexes synthesised, conjugated complexes 4a and 4b were found to be bactericidal against methicillin-susceptible Staphylococcus aureus (ATCC 35923) and bacteriostatic against methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300) strains with a minimum inhibition concentra- tion of 64 µM under irradiated conditions. Conjugated complexes 4a, 4b and 4d were active against Gram-negative bacteria, Escherichia coli (ATCC BAA-196) at 128 µM in both irradiated and non-irradiated conditions. The conjugated complexes 4a and 4b were observed to have some bacterial interaction upon excitation at 559 nm wavelength viewed under fluorescence microscope at ×600 nm magnification. The findings demonstrated the capability of ruthenium(II) polypyridyl complexes conjugated with bis-dipicolylamine as possible theranostics agents due to their fluorescence properties and their antibacterial activities through photosensitisation
A heterozygous USB1 variant linked to immunodeficiency
No full textInternational audiencePoikiloderma with neutropenia is a genetic disorder characterized by skin abnormalities, nail dystrophy, bone anomalies, and neutropenia. USB1 encodes a phosphodiesterase essential for processing spliceosomal U6 RNA and some microRNAs, regulating their stability. This study describes a heterozygous de novo USB1 variant (p.P44L) identified in a patient with recurrent infections, hypogammaglobulinemia, and low neutrophil counts. Unlike previously reported mutations, p.P44L affects a conserved proline in the N-terminal domain, predicted to be critical for protein interactions and stability. Functional assays revealed that while U6 RNA processing remained intact, the variant altered protein interactions and subcellular localization, reducing nuclear presence and accumulation within nuclear speckles. In vitro, the variant did not prevent neutrophil differentiation but reduced clonal capacity. In zebrafish, it led to reduced neutrophils and pigmentation. These findings expand the spectrum of genetic traits associated with USB1 and suggest that a heterozygous variant affecting the N-terminal domain of USB1 impacts clinical phenotypes and that hypogammaglobulinemia may be associated with USB1 dysfunction
Assessment tools for the risk of pressure injury in children: A systematic review
No full textInternational audienceBackground: Pressure injuries in pediatric patients are associated with increased morbidity, mortality, and prolonged hospital stays, making the identification of effective risk assessment tools critical in clinical practice. Accurate risk assessment is essential in clinical practice. Although several assessment tools exist, their applicability and effectiveness vary across pediatric populations.Objective: To identify and evaluate tools designed to assess the risk of pressure injuries in children, focusing on their characteristics, validation populations, reliability, and applicability across different clinical contexts. Design: A systematic review was conducted. Methods: This systematic review (PROSPERO: CRD42024527687) was conducted in accordance with the Cochrane Handbook. Comprehensive searches were performed in five databases-PubMed, Google Scholar, CINAHL, Web of Science, and Embase-for studies published between January 2010 and March 2024. Eligible studies included those describing the development, use, or validation of pressure injury risk assessment tools in children. Two independent reviewers conducted the selection and appraisal process. Methodological quality was assessed using the QUADAS-2 and QAREL checklists, with general reference to COSMIN guidelines. Results: Of 964 records screened, 28 studies met the inclusion criteria, encompassing research from 15 countries, with Brazil being the most represented. Studies focused on pediatric and neonatal intensive care units, general wards, and surgical units. Ten different risk assessment tools were identified, including the Braden Q, Braden QD, and Glamorgan scales. The Braden QD scale-an adaptation of the Braden Q including medical device-related risk-was the most frequently evaluated. Other tools, such as the Pediatric Pressure Ulcer Prediction and Evaluation Tool and the Braden Q+P, were specifically developed or adapted for pediatric and neonatal use. Conclusions: All identified tools demonstrated acceptable validity and inter-rater reliability. However, no single tool proved universally applicable across all pediatric contexts. The Braden QD, Braden Q, and Glamorgan scales emerged as the most comprehensive, particularly in intensive care settings, aligning with National and European Pressure Ulcer Advisory Panel</div
Methodological concerns and clinical relevance: a critical appraisal of the meta-analysis on biosimilars versus originator follitropin alfa in ART
No full textInternational audienceNo abstract availabl
Intrathecal Anti-Akkermansia muciniphila IgG Responses in Multiple Sclerosis Patients Linked to CSF Immune Cells and Disease Activity
No full textInternational audienceBackground/Objectives: Gut microbial dysbiosis, leaky gut, and increased transepithelial translocation of commensal bacteria have been documented in multiple sclerosis (MS). Intrathecal IgGs specific for Akkermansia muciniphila, a gut bacterium, are increased in patients with MS and associated with clinical disability. Our objective here was to explore the putative involvement of intrathecal anti-A. muciniphila IgG in MS pathogenesis by characterizing patients with different anti-A. muciniphila IgG indices. Methods: Serum and intrathecal IgG specific for A. muciniphila and other gut bacteria, as well as routine cerebrospinal fluid (CSF) parameters, were measured in 61 patients with MS. Examination of these patients included immunophenotyping of CSF-infiltrating and paired circulating lymphocytes, intrathecal markers of neurodegeneration and inflammation, and a detailed characterization of demographic, clinical, and magnetic resonance imaging (MRI) features. Results: Plasma blasts (p < 0.01), B cells (p < 0.01), and Th2 cells (p < 0.01), which might be involved in antibody production, were increased in the CSF of these patients, as well as blood pro-inflammatory Th17 cells (p < 0.05). Anti-A. muciniphila IgG indices were negatively associated with blood-brain barrier (BBB) permeability and circulating monocytes (p < 0.001), and positively with brain lesion load (p < 0.01). Conclusions: The differences between patients with low and high anti-A. muciniphila IgG indexes regarding BBB permeability, CSF cell infiltrates, and pro-inflammatory peripheral immune cells, as well as imaging features, support a role of anti-A. muciniphila immune response in MS pathogenesis
Mild TBI Changes Brain and Plasma Neurosteroid Levels in Mice
No full textInternational audienceMild traumatic brain injury (mTBI) accounts for 80% of all TBI, may be associated with chronic impairments, and is difficult to diagnose due to a lack of objective markers. In this study, we investigated whether neurosteroids can serve as blood biomarkers for mTBI. Two cohorts of C57BL/6 mice were subjected to a model of mTBI combining impact with rotational acceleration or sham surgery. The first cohort underwent neurological testing for anxiety, balance, and locomotion before and after mTBI. For the second cohort, brains and plasma were collected 6 or 24 h after mTBI to measure steroid and neurosteroid levels by gas chromatography-tandem mass spectrometry. Traumatized mice exhibited significantly prolonged wake-up time from anesthesia, transiently increased beam-walk time, and mild astrogliosis compared with their control counterparts, but did not suffer from skull fractures, intracranial hemorrhage, or mortality. Isopregnanolone and 3b,5a-tetrahydrodeoxycorticosterone (ISODOC) were significantly decreased by more than 50% in brain parenchyma at 6 and 24 h after mTBI, while ISODOC was also significantly decreased in plasma (-75%). Therefore, ISODOC may be a candidate diagnostic biomarker for mTBI.</div
Early in‐hospital treatment of acute heart failure. Part 2 of the international expert opinion series on AHF management
No full textInternational audienceAcute heart failure (AHF) remains a major global health challenge, contributing significantly to morbidity, mortality and healthcare resource utilization. It is one of the leading causes of hospitalization, with persistently high readmission rates underscoring the need for improved early management strategies. Despite its prevalence, clear and evidence‐based guidance for the early evaluation and treatment of AHF is limited. Congestion is the primary reason for emergency admission, making rapid and effective decongestion a top priority, but diuretics are often underdosed in AHF patients. Medications proven to improve mortality are often not started. In this state‐of‐the‐art review, we address this critical gap by outlining a practical, evidence‐based framework for the early management of AHF. Key components include early identification of co‐existing conditions, bedside haemodynamic profiling, a structured diagnostic approach incorporating both standard and individualized assessments, a stepwise pharmacologic diuretic strategy beginning with high‐dose intravenous loop diuretics, and early in‐hospital initiation of guideline‐directed medical therapy
Blood biomarkers in left-sided valvular heart disease.
No full textInternational audienceValvular heart disease (VHD) is a common condition that poses several challenges from the standpoints of diagnosis and therapeutic management. While several studies have explored the role of blood biomarkers in assessing the severity and risk of progression of VHD, as well as in evaluating related cardiac damage and predicting the occurrence of adverse events, blood biomarkers are generally not considered criteria to trigger valve intervention in the latest European and American guidelines for VHD management. This review article provides an up-to-date overview of the utility of blood biomarkers to (i) assess the presence, severity, and progression of left-sided VHD; (ii) establish the presence and extent of cardiovascular damage; (iii) predict clinical outcomes before and after valve interventions; and (iv) identify patients at risk for early structural valve deterioration, valve thrombosis, and paravalvular leak
Intronic branchpoint-to-acceptor variants underlying inborn errors of immunity
No full textInternational audienceClinical laboratories searching for pathogenic variants focus mostly on the protein-coding region and corresponding essential splicing sites. Screening for variants in intronic regions requires dedicated bioinformatics tools and detailed experimental studies to confirm deleteriousness and pathogenicity. We report intronic variants in a cohort of eight patients from seven kindreds with unexplained inborn errors of immunity (IEI). Using ad hoc bioinformatics tools, we identified seven kindreds carrying three branchpoint variants at three loci (BTK, SH2D1A, and WAS) and four AG-gain acceptor site variants at another four loci (DOCK8, NFKB1, STXBP2, and UNC13D). The variants were located between positions −9 and −49 relative to the wild-type acceptor site. The deleteriousness and, thus, pathogenicity of these variants were confirmed by exon-captured transcriptome studies and flow cytometry analyses of protein production or function. Our findings indicate that intronic variants should be systematically screened and investigated, even in clinical laboratory settings