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Résumé: Bien que plus rares aujourd’hui, les thrombopénies induites par l’héparine (TIH) demeurent une complication iatrogène grave qu’il faut savoir reconnaître. Une TIH résulte d’une réponse immune atypique à l’héparine avec la synthèse d’anticorps IgG spécifiques du facteur plaquettaire 4 (FP4) modifié et activant les plaquettes, les leucocytes et l’endothélium. Cette activation explique que la diminution des plaquettes soit associée à une hypercoagulabilité avec des thromboses dans près d’un cas sur deux. Le diagnostic est parfois évoqué par des manifestations cliniques atypiques (nécrose cutanée, hypotension, amnésie ou dyspnée après injection d’héparine). Le dépistage d’une TIH repose sur la surveillance des plaquettes, restreinte avec les héparines de bas poids moléculaire (HBPM) aux malades à risque, après chirurgie cardiaque, vasculaire ou orthopédique notamment, mais étendue à tous les cas traités par héparine non fractionnée (HNF). Le diagnostic doit être confirmé biologiquement même si la présomption clinique est forte. À cet égard, des tests de type Elisa rapides et spécifiques sont désormais disponibles pour la détection des anticorps anti-FP4/héparine. Toutefois, leur spécificité est médiocre et des tests fonctionnels évaluant l’agrégation plaquettaire ou la libération de sérotonine radiomarquée doivent souvent être réalisés. Pour le traitement d’une TIH, l’argatroban (antithrombine directe) est utilisable chez l’insuffisant rénal et sera dans ce cas préféré au danaparoïde sodique (héparinoïde principalement anti-Xa). Le fondaparinux (anti-Xa sélectif), recommandé par certains, est non validé dans cette indication, et ne peut être utilisé qu’en cas de suspicion. La prévention des TIH sera améliorée par la prescription des nouveaux anticoagulants oraux. [ABSTRACT FROM AUTHOR]

The Soil Moisture and Ocean Salinity satellite (SMOS) was launched in November 2009 and started delivering data in January 2010. The commissioning phase ended in May 2010. Subsequently, the satellite has been in operation for over six years while the retrieval algorithms from Level 1 (L1) to Level 2 (L2) underwent significant evolutions as knowledge improved. Moreover, other approaches for retrieval at L2 over land were investigated while Level 3 (L3) and Level 4 (L4) were initiated. In this paper, these improvements were assessed by inter-comparisons of the current L2 (V620) against the previous version (V551) and new products (using neural networks referred to as SMOS-NN) and L3 (referred to as SMOS-L3). In addition, a global evaluation of different SMOS soil moisture (SM) products (SMOS-L2, SMOS-L3, and SMOS-NN) was performed comparing products with those of model simulations and other satellites. Finally, all products were evaluated against in situ measurements of soil moisture (SM). To achieve such a goal a set of metrics to evaluate different satellite products are suggested. The study demonstrated that the V620 shows a significant improvement (including those at L1 improving L2) with respect to the earlier version V551. Results also show that neural network based approaches can often yield excellent results over areas where other products are poor. Finally, global comparison indicates that SMOS behaves very well when compared to other sensors/approaches and gives consistent results over all surfaces from very dry (African Sahel, Arizona), to wet (tropical rain forests). RFI (Radio Frequency Interference) is still an issue even though detection has been greatly improved through the significant reduction of RFI sources in several areas of the world. When compared to other satellite products, the analysis shows that SMOS achieves its expected goals and is globally consistent over different eco climate regions from low to high latitudes and throughout the seasons. [ABSTRACT FROM AUTHOR]

Clinical diagnostics in routine microbiology still mostly relies on bacterial growth, a time-consuming process that prevents test results to be used directly as key decision-making elements for therapeutic decisions. There is some evidence that Raman micro-spectroscopy provides clinically relevant information from a limited amount of bacterial cells, thus holding the promise of reduced growth times and accelerated result delivery. Indeed, bacterial identification at the species level directly from micro-colonies at an early time of growth (6 h) directly on their growth medium has been demonstrated. However, such analysis is suspected to be partly destructive and could prevent the further growth of the colony needed for other tests, e.g. antibiotic susceptibility testing (AST) . In the present study, we evaluated the effect of the powerful laser excitation used for Raman identification on micro-colonies probed after very short growth times. We show here, using envelope integrity markers (Syto 9 and Propidium Iodide) directly on ultra-small micro-colonies of a few tens of Escherichia coli and Staphylococcus epidermidis cells (3 h growth time), that only the cells that are directly impacted by the laser lose their membrane integrity. Growth kinetics experiments show that the non-probed surrounding cells are sometimes also affected but that the micro-colonies keep their ability to grow, resulting in normal aspect and size of colonies after 15 h of growth. Thus, Raman spectroscopy could be used for very early (< 3 h) identification of grown micro-organisms without impairing further antibiotics susceptibility characterization steps [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which is about t-positive B-cell malignancy in atypical chronic lymphocytic leukemia.

Fluorescence in situ hybridization (FISH) on interphase nuclei has been shown to be an efficient method for detecting aneuploidy in multiple myeloma (MM). The aim of this study was to test the feasibility of FISH techniques for detecting malignant cells in the harvests of MM patients submitted to autologous transplantation. As trisomy 9 (T9) is a frequent event in MM, we used it as a genetic marker of malignant plasma cells. T9 was detected in 45 out of 55 MM bone marrow samples (81.8%) using a chromosome 9 centromeric (C9C) probe. Twenty-four of the 55 MM patients were subjected to high-dose therapy followed by autologous unselected progenitor cell transplantation. Trisomy 9 was detected in 20 patients and was used as a marker of malignant cells. Upon karyotypic analysis, three of the four remaining patients without T9 showed an unbalanced translocation leading to a complete trisomy of the long arm of chromosome 1 (T1q). We thus used a 1q juxtacentromeric probe, pUC1.77, as another genetic marker of malignant plasma cells in these three further patients. FISH with C9C or pUC1.77 probes was performed on the harvests of these 23 patients and detected clonal cells in 11 transplants. The disease-free survival from graft was significantly longer for the patients who had no malignant cells in their transplant (P = 0.009). The median disease-free survival was 23 months in these patients, as compared to 12 months in the patients whose transplant was contaminated. As almost all MM are cytogenetically abnormal, FISH with adequate probes represents a simple, quantitative tool for rapid detection of malignant cells in the harvests. Our results also suggest that the presence of MM cells in the transplant may be predictive of poor outcome. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about the the biosynthesis of human leukocyte antigen published in the 2004 issue of "Leukemia."

Objectif décrire les caractéristiques cliniques des patients français atteints de CMMR-D. Sujet / matériels et méthodes le syndrome CMMR-D est un syndrome de prédisposition aux cancers de l’enfant dû à une mutation biallélique des gènes MMR. Il est méconnu des onco-pédiatres et probablement sous-diagnostiqué. Une revue a été menée à partir des dossiers cliniques des cas de CMMR-D diagnostiqués par des laboratoires de génétique en France de 1999 à 2013. Résultats principaux 28 patients ont développé 60 cancers, dont 17 hémopathies, 19 tumeurs cérébrales, 21 cancers du spectre du syndrome de Lynch, et 3 sarcomes. 19/28 patients ont développé plusieurs cancers. L’âge médian au diagnostic de première tumeur était 7 ans [1,23–33,53]. La survie globale à 5 ans était de 56% après le premier cancer. 40% des décès étaient liés à l’évolution de la première tumeur. 21/28 patients présentaient des taches café-au-lait ou des macules dépigmentées. L’histoire familiale évoquait un syndrome de Lynch dans 25% des familles, une consanguinité dans 1/3 des cas. Conclusion le syndrome CMMR-D prédispose à la survenue de cancers précoces et au pronostic sombre. Son diagnostic est difficile mais indispensable pour mettre en place une surveillance appropriée chez les patients et leurs apparentés. [ABSTRACT FROM AUTHOR]

Introduction: An increasing number of gene-specific therapies are being developed for inherited retinal degenerations (IRDs). Identification of well-characterized patients is an emerging need. We conducted the second multinational survey among the www.evicr.net and ERN-EYE members to understand the management and treatment of IRDs in Europe and compared it to the 2019 survey., Methods: An electronic survey questionnaire was developed and sent to 124 clinical centers (25 countries) by June/July 2021. Statistical analysis was performed with Excel and R., Results: The overall response rate was 44% but varied among countries. Only 9% of responding centers do not see IRD patients (2019 survey 14%), 42% follow at least 200 patients per year, 18% follow 500-999, and 2% more than 1,000. Databases exist in 86% of the centers (local 86%; national web based 12%). IRD patients are referred to www.evicr.net and ERN-EYE centers mainly by general ophthalmologists, patient self-referral, or medical retina specialists. Most IRD patients are first seen as adults. Signs and symptoms depend on age of onset: in infancy, nystagmus; at older age, night blindness and reduced visual field; reduced visual acuity is described at any age. Comprehensive ophthalmic examination always includes visual acuity and almost always visual field multimodal retinal imaging, electrophysiology, color vision testing, and refraction. Identification of genotypes is successful in 72% of centers in 40-80% of cases (2019 survey 69% of centers). The time for confirmation of the genetic diagnosis varies from 2-4 weeks to 24 months (2019 survey &gt;4 weeks ≤10 years). Genetic testing is covered by public health service in 83%, private health insurance in 29%, research funds in 24%; 5% do not have access to genetic testing (2019 survey 15%). The most striking result is the high increase in the involvement of centers in natural history and gene therapy trials that more than doubled for the latter., Discussion: This second multinational survey on management of IRDs in Europe highlights persistent important differences in the number of IRD patients managed per center, comparable diagnostic work-up, and increasing genotyping in diagnostic laboratories. The important increase in involvement of centers in natural history and gene therapy trials reflects the rapidly evolving field of gene therapy development. The survey provides important follow-up data for researchers, clinicians, caregivers, patient advocate groups, pharmaceutical companies, and investors., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: The aim of this study was to evaluate the current management of RPE65 biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) in Europe since market authorization of voretigene neparvovec (VN, LuxturnaTM) in 2018. By July 2022, over 200 patients have been treated outside the USA, of whom about 90% in Europe. We conducted among all centers of the European Vision Institute Clinical Research Network www.evicr.net and health care providers (HCPs) of the European Reference Network dedicated to Rare Eye Diseases (ERN-EYE) the second multinational survey on management of IRDs in Europe elaborated by www.evicr.net with a special focus on RPE65-IRD., Methods: An electronic survey questionnaire with 48 questions specifically addressing RPE65-IRD (2019 survey 35) was developed and sent by June 2021 to 95 www.evicr.net centers and 40 ERN-EYE HCPs and affiliated members. Of note, 11 centers are members of both networks. Statistical analysis was performed with Excel and R., Results: The overall response rate was 44% (55/124); 26 centers follow RPE65 biallelic mutation-associated IRD patients. By June 2021, 8/26 centers have treated 57 RPE65-IRD cases (1-19/center, median 6) and 43 planned for treatment (range 0-10/center, median 6). The overall age range was 3-52 years, and on average 22% of the patients did not (yet) qualify for treatment (range 2-60%/center, median 15%). Main reasons were too advanced (range 0-100, median 75%) or mild disease (range 0-100, median 0). Eighty-three percent of centers (10/12) that follow RPE65 mutation-associated IRD patients treated with VN participate in the PERCEIVE registry (EUPAS31153, www.encepp.eu. Quality of life and full-field stimulus test improvements had the highest scores of the survey-reported outcome parameters in VN treatment follow-up., Conclusion: This second multinational survey on management of RPE65-IRD by www.evicr.net centers and ERN-EYE HCPs in Europe indicates that RPE65-IRD might be diagnosed more reliably in 2021 compared to 2019. By June 2021, 8/26 centers reported detailed results including VN treatment. Main reasons for non-treatment were too advanced or mild disease, followed by absence of 2 class 4 or 5 mutations on both alleles or because of a too young age. Patient satisfaction with treatment was estimated to be high by 50% of the centers., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objectives: A regulatory T cell (Treg) insufficiency due to shortage of interleukin-2 (IL-2) is central to the pathophysiology of systemic lupus erythematosus (SLE). We performed a multicentre, double-blinded, randomised, placebo-controlled phase II proof-of-concept trial to evaluate the efficacy of low-dose IL-2 therapy in patients with SLE having moderate-to-severe disease activity while receiving standard treatment., Methods: We randomly assigned 100 patients in a 1:1 ratio to receive either 1.5 million IU/day of subcutaneous IL-2 (ILT-101) or placebo for 5 days followed by weekly injections for 12 weeks. Clinical efficacy was assessed at week 12 in a predefined hierarchical analysis of (1) the SLE responder index-4 (SRI-4) response as a primary end point, and of (2) relative and (3) absolute changes in the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index scores as key secondary end points., Results: The primary end point was not met in the intention-to-treat population (ILT-101: 68%, placebo: 58%; p=0.3439), due to a 100% SRI-4 response rate in the placebo group from the two sites from Bulgaria. A post hoc per-protocol analysis on a prespecified population that excluded patients from these two sites (n=53) showed a statistically significant difference for the SRI-4 response rate (ILT-101: 83.3%; placebo: 51.7%; p=0.0168), and for the two key secondary end points, accompanied by differences in several secondary exploratory end points. ILT-101 was well tolerated and there was no generation of antidrug antibodies., Conclusions: The post hoc hierarchical analysis of the primary and key secondary end points in a per-protocol population, complemented by the exploratory analyses of multiple other secondary end points, support that low-dose IL-2 is beneficial in active SLE., Trial Registration Number: NCT02955615., Competing Interests: Competing interests: PC, MR and DK are inventors for patents related to the therapeutic use of IL-2, which belongs to their academic institutions and have been licensed to ILTOO Pharma in which they hold interests. HPP, JG, DL and TV are employees of ILTOO Pharma., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Genotyping and sequencing technologies produce increasingly large numbers of genetic markers with potentially high rates of missing or erroneous data. Therefore, the construction of linkage maps is more and more complex. Moreover, the size of segregating populations remains constrained by cost issues and is less and less commensurate with the numbers of SNPs available. Thus, guaranteeing a statistically robust marker order requires that maps include only a carefully selected subset of SNPs., Results: In this context, the SeSAM software allows automatic genetic map construction using seriation and placement approaches, to produce (1) a high-robustness framework map which includes as many markers as possible while keeping the order robustness beyond a given statistical threshold, and (2) a high-density total map including the framework plus almost all polymorphic markers. During this process, care is taken to limit the impact of genotyping errors and of missing data on mapping quality. SeSAM can be used with a wide range of biparental populations including from outcrossing species for which phases are inferred on-the-fly by maximum-likelihood during map elongation. The package also includes functions to simulate data sets, convert data formats, detect putative genotyping errors, visualize data and map quality (including graphical genotypes), and merge several maps into a consensus. SeSAM is also suitable for interactive map construction, by providing lower-level functions for 2-point and multipoint EM analyses. The software is implemented in a R package including functions in C++., Conclusions: SeSAM is a fully automatic linkage mapping software designed to (1) produce a framework map as robust as desired by optimizing the selection of a subset of markers, and (2) produce a high-density map including almost all polymorphic markers. The software can be used with a wide range of biparental mapping populations including cases from outcrossing. SeSAM is freely available under a GNU GPL v3 license and works on Linux, Windows, and macOS platforms. It can be downloaded together with its user-manual and quick-start tutorial from ForgeMIA (SeSAM project) at https://forgemia.inra.fr/gqe-acep/sesam/-/releases., (© 2022. The Author(s).)