Status report on GANIL-SPIRAL1

International audienceThe GANIL facility (Caen, France) (Figure 1) is dedicated to the acceleration of heavy ion beams for nuclear physics, atomic physics, radiobiology and material irradiation. The production of radioactive ion beams for nuclear physics studies represents the main part of the activity. Two complementary methods are used: the Isotope Separation On-Line (ISOL, the SPIRAL1 facility) and the In-Flight Separation techniques (IFS). SPIRAL1, the ISOL facilty, is running since 2001, producing and post-accelerating radioactive ion beams. The energy range available goes from 1.2 MeV/A to 25 MeV/A with a compact cyclotron (CIME, K=265). The running mode of this machine will be recalled as well as a review of the operation from 2001 to 2006. A point will be done on the past, present and future projects which allow to continue to develop the capacities of this equipment and to answer the new demands from the physicists, such as new beamlines for low or high energy experiments, new diagnotics of control or the adaptation of an identification system using Silicon, Germanium or plastic detectors in the requirements of the operation evironnement

Control electronics for the CIME RF system

International audienceThe paper describes the characteristics of the amplitude and phase loops for the accelerating voltage, thecontrol system which manages securities, sparks and multipactor problems for the cavities. Design methods andresults during first power tests are presented

Magnetic resonance imaging in pulmonary hypertension: an overview of current applications and future perspectives.

Pulmonary hypertension is an heterogeneous group of diseases characterised by increased pulmonary arterial pressures which impact on the upstream right ventricle. Pulmonary hypertension can be challenging to diagnose, classify and monitor when specific therapies are applicable. Cardiac magnetic resonance (CMR) imaging has greatly evolved in the last decades and is a promising tool to non-invasively follow pulmonary hypertension patients. CMR provides a comprehensive evaluation of the heart and is therefore the gold standard for quantification of right ventricular volumes, mass and function, which are critical for pulmonary hypertension prognosis. In addition, innovative MR techniques allow an increasingly precise evaluation of pulmonary haemodynamics and lung perfusion. This review highlights the main advantages offered by CMR in pulmonary hypertension and gives an overview of putative future applications. Although right heart catheterisation remains mandatory in the diagnostic algorithm, CMR could play an increasingly important role in the coming years in monitoring pulmonary hypertension patients

Phenotypic Diversity of Vascular Smooth Muscle Cells in Pulmonary Arterial Hypertension: Implications for Therapy.

Pulmonary arterial hypertension (PAH) is a progressive incurable condition that is characterized by extensive remodeling of the pulmonary circulation, leading to severe right-sided heart failure and death. Similar to other vascular contractile cells, pulmonary arterial smooth muscle cells play central roles in physiological and pathologic vascular remodeling because of their remarkable ability to dynamically modulate their phenotype to ensure contractile and synthetic functions. The dysfunction and molecular mechanisms underlying their contribution to the various pulmonary vascular lesions associated with PAH have been a major focus of research. The aim of this review is to describe the medial and nonmedial origins of contractile cells in the pulmonary vascular wall and present evidence of how they contribute to the onset and progression of PAH. We also highlight specific potential target molecules and discuss future directions that are being explored to widen the therapeutic options for the treatment of PAH

Association between small airway dysfunction and cardiac conditions: a Swiss urban population cross-sectional study.

Small airway dysfunction (SAD) may be an early sign of cardiopulmonary overload due to small airway mucosal thickening or be related to the oxidative stress characteristic of cardiovascular diseases. A high prevalence of SAD coexisting with chronic heart failure may be associated with an increase in all-cause mortality. We analysed the association between SAD and cardiac conditions in the PneumoLaus study. PneumoLaus is based on the Swiss general urban population cohort CoLaus|PsyCoLaus. SAD was defined by maximal mid-expiratory flow (MMEF) before bronchodilatation <65% predicted or MMEF<lower limit of normal (LLN) based on GLI-2012. Self-reported cardiac events were defined as new occurrence of any cardiac condition since baseline analysis (approximately 10 years before spirometry). Adjudicated cardiac conditions correspond to the confirmed diagnosis in the local medical record. We performed analyses with SAD criteria adjusted for age, sex, smoking duration, smoking status and body mass index (model 1). A second model was additionally adjusted for N-terminal pro-brain natriuretic peptide (NT-proBNP). Among 3342 subjects that underwent spirometry, 473 (14.2%) reported a new cardiac condition. SAD defined as MMEF<65% predicted or MMEF<LLN was associated with self-reported cardiac conditions (OR 1.38, 95% CI 1.05-1.82 and OR 1.60, 95% CI 1.07-2.40) for model 1). This association persisted for SAD defined MMEF<LLN after adjustment for NT-proBNP. Adjudicated cardiac conditions were associated with SAD (defined as MMEF<LLN) in the unadjusted model and in model 1 (OR 1.85, 95% CI 1.05-3.27). SAD defined as MMEF<LLN was associated with self-reported and adjudicated cardiac conditions

Association of Pulmonary Hypertension With Trastuzumab Emtansine: An Analysis of French Pulmonary Hypertension Registry and WHO Pharmacovigilance Database.

Trastuzumab emtansine has been recently suspected to be associated with the development of pulmonary arterial hypertension (PAH). Is there an association between trastuzumab, trastuzumab emtansine, or trastuzumab deruxtecan and the development of PAH? Characteristics of incident PAH cases treated with trastuzumab, trastuzumab emtansine, or trastuzumab deruxtecan were analyzed from the French Pulmonary Hypertension Registry, the VIGIAPATH program, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization pharmacovigilance database using a broad definition of pulmonary hypertension (PH) and a narrow definition of PAH. A signal of disproportionate reporting was deemed significant if the lower boundary of the 95% credibility interval of the information component (IC) was superior to 0. The variables were expressed as median (interquartile range [IQR]). In the French PH Registry, we identified 8 incident cases of PAH after trastuzumab emtansine exposure and none with trastuzumab alone or trastuzumab deruxtecan. All cases occurred in female patients (age, 56; IQR, 49-61 years) with breast cancer. The delay between first exposure and PAH diagnosis was 43 months (IQR, 4.5-55). At diagnosis, 5 were in New York Heart Association functional class III/IV with severe hemodynamic impairment (mean pulmonary artery pressure, 42 mm Hg; cardiac index, 2.51 L/min/m <sup>2</sup> ; pulmonary vascular resistance, 9.7 Wood units). Disproportionality analysis showed that only trastuzumab emtansine demonstrated a significant signal of disproportionate reporting using both a broad definition of PH (IC, 1.46; 0.86-1.95) and a narrow definition of PAH (IC, 1.76; 0.83-2.46). Trastuzumab displayed a significant signal using only the broad definition of PH, whereas trastuzumab deruxtecan was not associated with any significant signals of disproportionate reporting. Our results suggest that more patients exposed to trastuzumab emtansine developed PH compared with trastuzumab alone. Further assessment of this safety signal and exploration of pathophysiologic mechanisms is needed

Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets

Tuberculosis remains a serious threat to human health world-wide, and improved efficiency of medical treatment requires a better understanding of the pathogenesis and the discovery of new drugs. In the present study, we performed a whole-cell based screen in order to complete the characterization of 168 compounds from the GlaxoSmithKline TB-set. We have established and utilized novel previously unexplored host-model systems to characterize the GSK compounds, i.e. the amoeboid organisms D. discoideum and A. castellanii, as well as a microglial phagocytic cell line, BV2. We infected these host cells with Mycobacterium marinum to monitor and characterize the anti-infective activity of the compounds with quantitative fluorescence measurements and high-content microscopy. In summary, 88.1% of the compounds were confirmed as antibiotics against M. marinum, 11.3% and 4.8% displayed strong anti-infective activity in, respectively, the mammalian and protozoan infection models. Additionally, in the two systems, 13-14% of the compounds displayed pro-infective activity. Our studies underline the relevance of using evolutionarily distant pathogen and host models in order to reveal conserved mechanisms of virulence and defence, respectively, which are potential "universal" targets for intervention. Subsequent mechanism of action studies based on generation of over-expresser M. bovis BCG strains, generation of spontaneous resistant mutants and whole genome sequencing revealed four new molecular targets, including FbpA, MurC, MmpL3 and GlpK

Nouvelles définition et classification de l’hypertension pulmonaire [Revised definition and classification of pulmonary hypertension]

REVISED DEFINITION AND CLASSIFICATION OF PULMONARY HYPERTENSION. Pulmonary hypertension (PH) is a manifestation of a diverse group of diseases characterised by elevated mean pulmonary artery pressure (mPAP), measured by right heart catheterisation. The European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension, published in 2022, propose a new haemodynamic definition of PH by lowering the threshold for mPAP to 20 mmHg. Precapillary PH is now defined as mPAP > 20 mmHg associated with normal pulmonary artery wedge pressure (≤ 15 mmHg) and increased pulmonary vascular resistance (> 2 Wood units). These criteria were endorsed during the 7th World Symposium on Pulmonary Hypertension in 2024. The 2022 ESC/ERS guidelines also include a revision of the clinical classification of PH, maintaining the distinction between five entities based on the underlying pathophysiology