New Microbicidal Functions of Tracheal Glands: Defective Anti-Infectious Response to Pseudomonas aeruginosa in Cystic Fibrosis

Tracheal glands (TG) may play a specific role in the pathogenesis of cystic fibrosis (CF), a disease due to mutations in the cftr gene and characterized by airway inflammation and Pseudomonas aeruginosa infection. We compared the gene expression of wild-type TG cells and TG cells with the cftr ΔF508 mutation (CF-TG cells) using microarrays covering the whole human genome. In the absence of infection, CF-TG cells constitutively exhibited an inflammatory signature, including genes that encode molecules such as IL-1α, IL-β, IL-32, TNFSF14, LIF, CXCL1 and PLAU. In response to P. aeruginosa, genes associated with IFN-γ response to infection (CXCL10, IL-24, IFNγR2) and other mediators of anti-infectious responses (CSF2, MMP1, MMP3, TLR2, S100 calcium-binding proteins A) were markedly up-regulated in wild-type TG cells. This microbicidal signature was silent in CF-TG cells. The deficiency of genes associated with IFN-γ response was accompanied by the defective membrane expression of IFNγR2 and altered response of CF-TG cells to exogenous IFN-γ. In addition, CF-TG cells were unable to secrete CXCL10, IL-24 and S100A8/S100A9 in response to P. aeruginosa. The differences between wild-type TG and CF-TG cells were due to the cftr mutation since gene expression was similar in wild-type TG cells and CF-TG cells transfected with a plasmid containing a functional cftr gene. Finally, we reported an altered sphingolipid metabolism in CF-TG cells, which may account for their inflammatory signature. This first comprehensive analysis of gene expression in TG cells proposes a protective role of wild-type TG against airborne pathogens and reveals an original program in which anti-infectious response was deficient in TG cells with a cftr mutation. This defective response may explain why host response does not contribute to protection against P. aeruginosa in CF

Gliomatosis cerebri presenting as rapidly progressive dementia and parkinsonism in an elderly woman: a case report

<p>Abstract</p> <p>Introduction</p> <p>Dementia is one of the most important neurological disorders in the elderly. Dementia of tumoral origin is rare and parkinsonism of neoplastic origin is unusual. We herein report a case of gliomatosis cerebri, a very rare brain tumor seldom affecting the elderly, which presented as rapidly progressive dementia and parkinsonism.</p> <p>Case presentation</p> <p>An 82-year-old woman very rapidly developed progressive dementia and akineto-rigid parkinsonism. Brain CT scan was normal. Cerebral magnetic resonance imaging (MRI) with gadolinium injection highlighted a diffuse tumor-related infiltration involving both lobes, the putamen, the pallidum, the substantia nigra, and the brainstem, corresponding to the specific description and definition of gliomatosis cerebri.</p> <p>Conclusion</p> <p>This atypical presentation of a gliomatosis cerebri, and the infiltration of the substantia nigra by the tumor, merits attention.</p

Clinical relevance of cell-free DNA quantification and qualification during the first month after lung transplantation

BackgroundMany studies have reported the relevance of donor-derived cfDNA (dd-cfDNA) after lung transplantation (LTx) to diagnose and monitor acute rejection (AR) or chronic rejection or infection (INF). However, the analysis of cfDNA fragment size has not been studied. The aim of this study was to determine the clinical relevance of dd-cfDNA and cfDNA size profiles in events (AR and INF) during the first month after LTx.MethodsThis prospective, single-center study includes 62 LTx recipients at the Marseille Nord Hospital, France. Total cfDNA quantification was performed by fluorimetry and digital PCR, dd-cfDNA by NGS (AlloSeq cfDNA-CareDX®), and the size profile by BIABooster (Adelis®). A bronchoalveolar lavage and transbronchial biopsies at D30 established the following groups: not-injured and injured graft (AR, INF, or AR+INF).ResultsQuantification of total cfDNA was not correlated with the patient’s status at D30. The percentage of dd-cfDNA was significantly higher for injured graft patients at D30 (p=0.0004). A threshold of 1.72% of dd-cfDNA correctly classified the not-injured graft patients (negative predictive value of 91.4%). Among recipients with dd-cfDNA &gt;1.72%, the quantification of small sizes (80-120bp) &gt;3.70% identified the INF with high performance (specificity and positive predictive value of 100%).ConclusionWith the aim of considering cfDNA as a polyvalent non-invasive biomarker in transplantation, an algorithm combining the quantification of dd-cfDNA and small sizes of DNA may significantly classify the different types of allograft injuries

Natural Killer Cells Exhibit a Peculiar Phenotypic Profile in Systemic Sclerosis and Are Potent Inducers of Endothelial Microparticles Release

The pathophysiology of systemic sclerosis (SSc) involves early endothelial and immune activation, both preceding the onset of fibrosis. We previously identified soluble fractalkine and circulating endothelial microparticles (EMPs) as biomarkers of endothelial inflammatory activation in SSc. Fractalkine plays a dual role as a membrane-bound adhesion molecule expressed in inflamed endothelial cells (ECs) and as a chemokine involved in the recruitment, transmigration, and cytotoxic activation of immune cells that express CX3CR1, the receptor of fractalkine, namely CD8 and γδ T cells and natural killer (NK) cells. We aimed to quantify circulating cytotoxic immune cells and their expression of CX3CR1. We further investigated the expression profile of NK cells chemokine receptors and activation markers and the potential of NK cells to induce EC activation in SSc. We performed a monocentric study (NCT 02636127) enrolling 15 SSc patients [15 females, median age of 55 years (39–63), 11 limited cutaneous form and 4 diffuse] and 15 healthy controls. Serum fractalkine levels were significantly increased in SSc patients. Circulating CD8 T cells numbers were decreased in SSc patients with no difference in their CX3CR1 expression. Circulating γδ T cells and NK cells numbers were preserved. CX3CR1 expression in CD8 and γδ T cells did not differ between SSc patients and controls. The percentage and level of CX3CR1 expression in NK cells were significantly lowered in SSc patients. Percentages of CXCR4, NKG2D, CD69-expressing NK cells, and their expression levels were decreased in NK cells. Conversely, CD16 level expression and percentages of CD16+ NK cells were preserved. The exposure of human microvascular dermic EC line (HMVEC-d) to peripheral blood mononuclear cells resulted in similar NK cells degranulation activity in SSc patients and controls. We further showed that NK cells purified from the blood of SSc patients induced enhanced release of EMPs than NK cells from controls. This study evidenced a peculiar NK cells phenotype in SSc characterized by decreased chemokine and activation receptors expression, that might reflect NK cells involvement in the pathogenic process. It also highlighted the role of NK cells as a potent mechanism inducing endothelial activation through enhanced EMPs release

L'ablation dans le traitement des arythmies cardiaques : vers de nouvelles stratégies thérapeutiques

Cardiac arrhythmias are a major public health challenge due to their ever-increasing prevalence, resulting in higher care needs and deaths. Drug treatments prescribed in first line are often ineffective or poorly tolerated by patients, and do not always allow the associated symptoms and complications to be limited. An alternative therapy is now recommended in standard of care: cardiac ablation, which has led to improved patient management in the past few years. Although safe and effective, the thermal energies commonly used for this procedure (cryoablation and radiofrequency) still have drawbacks that are being addressed through the development of new techniques. Electroporation is currently the focus of attention, with initial results showing great promise in terms of efficacy and safety. Could this new technology revolutionize the treatment of patients with cardiac arrhythmias?Les troubles du rythme cardiaques constituent un enjeu majeur de santé publique du fait de leur prévalence qui ne cesse d’augmenter, engendrant une hausse de la demande de soins et des décès. Les traitements médicamenteux prescrits en première intention sont souvent inefficaces ou mal tolérés par les patients, ne permettant pas toujours de limiter les symptômes et les complications associés. Une alternative thérapeutique est aujourd’hui recommandée en pratique courante : l’ablation cardiaque, qui a permis une amélioration de la prise en charge des patients ces dernières années. Bien que sûres et efficaces, les énergies thermiques couramment employées pour cette intervention (cryoablation et radiofréquence) présentent encore des inconvénients que l’on cherche à corriger par le développement de nouvelles techniques. L’électroporation est actuellement au centre de l’attention, avec des premiers résultats très prometteurs en termes d’efficacité et de sécurité. Cette nouvelle technologie pourra-t-elle révolutionner le traitement des patients atteints d’arythmies cardiaques

Investigating Infectious Organisms of Public Health Concern Associated with Wild Meat

International audienceThe wild meat trade poses a significant threat to public health as it facilitates the spillover of zoonotic pathogens through high-risk activities such as the hunting, butchering, trade, and consumption of wild animals. Despite the health risks and association with marking epidemics including SARS, Ebola, and COVID-19, the global wild meat trade continues to thrive. To summarize the evidence available, primary literature published between 2000 and 2022 was systematically and critically assessed for evidence of zoonotic pathogens or other infectious organisms detected in samples directly from wild meat, from animals hunted for wild meat, or from humans exposed through high-risk activities. Within the 97 articles analyzed, a total of 114 pathogen genera (15 viruses, 40 bacteria, 54 parasites, and 5 fungi) were detected in wild meat animals belonging to 168 vertebrate species including mammals, reptiles and birds sampled in 32 countries. In the context of wild meat specifically, infectious organisms were differentiated between those with zoonotic potential (32% of reported genera), ectoparasitic vectors (1%), and possible opportunistic or environmental contaminants. Thirteen viral, four bacterial, and one parasitic genera were also documented in humans participating in wild meat trade activities, supporting pathogen spillover potential. Most studies employed a targeted approach to evaluate the presence of (i.e., polymerase chain reaction (PCR); n = 65) or exposure to (i.e., ELISA; n = 19) a specific pathogen, while only one study employed broad-spectrum metabarcoding techniques. The diversity of infectious organisms associated with wild meat are highlighted through this review and could be used to guide policy development. However, the common use of a selected set of targeted detection assays likely biases the exploration of pathogen diversity, therefore potentially preventing the discovery of “disease x”. The global health risk demonstrated should make the illegal wild meat trade a priority for law-enforcement agencies and future research

Fatal Pandoraea nosoerga infection after combined liver-lung transplantation for cystic fibrosis: a recontamination by the pre-transplantation strain

International audienc