Recombinant myelin oligodendrocyte glycoprotein quality modifies evolution of experimental autoimmune encephalitis in macaques

The authors describe quantitatively and qualitatively different forms of experimental autoimmune encephalitis (EAE) in cynomolgus macaques. They found that bacterial contaminants within recombinant human myelin oligodendrocyte glycoprotein seemed to aggravate disease evolution. They provide anatomopathological features of fulminant and progressive forms of EAE, allowing them to distinguish specific factors influencing the evolution of this model of autoimmune demyelinating disease. Experimental autoimmune encephalitis (EAE) is a well-recognized model for the study of human acquired demyelinating diseases (ADD), a group of inflammatory disorders of the central nervous system (CNS) characterized by inflammation, myelin loss, and neurological impairment of variable severity. In rodents, EAE is typically induced by active immunization with a combination of myelin-derived antigen and a strong adjuvant as complete Freund's adjuvant (CFA), containing components of the mycobacterial wall, while myelin antigen alone or associated with other bacterial components, as lipopolysaccharides (LPS), often fails to induce EAE. In contrast to this, EAE can be efficiently induced in non-human primates by immunization with the recombinant human myelin oligodendrocyte glycoprotein (rhMOG), produced in Escherichia coli (E. coli), purified and formulated with incomplete Freund's adjuvant (IFA), which lacks bacterial elements. Here, we provide evidence indicating how trace amounts of bacterial contaminants within rhMOG may influence the course and severity of EAE in the cynomolgus macaque immunized with rhMOG/IFA. The residual amount of E. coli contaminants, as detected with mass spectrometry within rhMOG protein stocks, were found to significantly modulate the severity of clinical, radiological, and histologic hallmarks of EAE in macaques. Indeed, animals receiving the purest rhMOG showed milder disease severity, increased numbers of remissions, and reduced brain damage. Histologically, these animals presented a wider diversity of lesion types, including changes in normal-appearing white matter and prephagocytic lesions. Non-human primates EAE model with milder histologic lesions reflect more accurately ADD and permits to study of the pathogenesis of disease initiation and progression

Towards an In Vitro Model of Plasmodium Hypnozoites Suitable for Drug Discovery

Contains fulltext : 96475.pdf (publisher's version ) (Open Access)BACKGROUND: Amongst the Plasmodium species in humans, only P. vivax and P. ovale produce latent hepatic stages called hypnozoites, which are responsible for malaria episodes long after a mosquito bite. Relapses contribute to increased morbidity, and complicate malaria elimination programs. A single drug effective against hypnozoites, primaquine, is available, but its deployment is curtailed by its haemolytic potential in glucose-6-phosphate dehydrogenase deficient persons. Novel compounds are thus urgently needed to replace primaquine. Discovery of compounds active against hypnozoites is restricted to the in vivo P. cynomolgi-rhesus monkey model. Slow growing hepatic parasites reminiscent of hypnozoites had been noted in cultured P. vivax-infected hepatoma cells, but similar forms are also observed in vitro by other species including P. falciparum that do not produce hypnozoites. METHODOLOGY: P. falciparum or P. cynomolgi sporozoites were used to infect human or Macaca fascicularis primary hepatocytes, respectively. The susceptibility of the slow and normally growing hepatic forms obtained in vitro to three antimalarial drugs, one active against hepatic forms including hypnozoites and two only against the growing forms, was measured. RESULTS: The non-dividing slow growing P. cynomolgi hepatic forms, observed in vitro in primary hepatocytes from the natural host Macaca fascicularis, can be distinguished from similar forms seen in P. falciparum-infected human primary hepatocytes by the differential action of selected anti-malarial drugs. Whereas atovaquone and pyrimethamine are active on all the dividing hepatic forms observed, the P. cynomolgi slow growing forms are highly resistant to treatment by these drugs, but remain susceptible to primaquine. CONCLUSION: Resistance of the non-dividing P. cynomolgi forms to atovaquone and pyrimethamine, which do not prevent relapses, strongly suggests that these slow growing forms are hypnozoites. This represents a first step towards the development of a practical medium-throughput in vitro screening assay for novel hypnozoiticidal drugs

Prise en charge thérapeutique de l'épisode dépressif majeur chez l'adolescent

La dépression touche environ 3% des adolescents. Elle pose un problème en terme de santé publique, tant par son éventuelle morbidité immédiate, que par le risque de développement d'une pathologie future. Ce mal être décrit chez les adolescents, peut conduire à un diagnostic par excès d'un syndrome dépressif, ou, à contrario, un épisode dépressif majeur peut être sous-estimé face à une sémiologie atypique à cet âge. Actuellement, la prise en charge thérapeutique de l'épisode dépressif majeur chez l'adolescent repose prioritairement et principalement sur la psychothérapie. En effet, les médicaments antidépresseurs, prescrits chez l'adulte, sont déconseillés, à l'heure actuelle, chez les moins de 18 ans, en raison des effets indésirables redoutés. La présentation et l'analyse d'un cas clinique permettent de décliner l'ensemble de la stratégie thérapeutique de l'épisode dépressif chez l'adolescent, qualifié d'intensité modérée à sévère. Au travers de cette étude, il ressort bien que certaines situations nécessitent le recours à des médicaments pourtant déconseillés par les autorités compétentes.CLERMONT FD-BCIU-Santé (631132104) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Secondary school admissions in England 2001 to 2008: changing legislation, policy and practice

The distribution of pupils amongst schools is fundamental to concerns about equality of educational opportunity and it is for this reason that the process by which pupils are admitted to schools is of significance. This paper focuses on admissions criteria and practices used by English secondary schools in 2001 and 2008 in light of changes to legislation and the regulatory context. In 2008, unlike 2001, virtually all schools gave priority to children in care and very few used interviews. In a minority of schools, predominantly those responsible for their own admissions, criteria designed to ‘select in’ certain pupils were used, with partial selection by aptitude/ability increasing over time. An analysis of ‘supplementary information forms’ revealed that a minority of schools requested information that was prohibited and unrelated to admissions criteria. Notwithstanding some positive impacts, further changes could make the admissions process easier for parents/carers and enhance equality of educational opportunity

Effect of Salinity and Nitrogen Form in Irrigation Water on Growth, Antioxidants and Fatty Acids Profiles in Halophytes Salsola australis, Suaeda maritima, and Enchylaena tomentosa for a Perspective of Biosaline Agriculture

Cultivation of salt-tolerant crops help to face to irreversible global salinization of freshwater and soils. In New-Caledonia, three halophytes are candidates for saline crops, Salsola australis R.Br., Suaeda maritima (L.) Dumort and Enchylaena tomentosa R.Br. Their success and quality depend yet on availabilities of salinity and essential nutrients in agrosystems. So, we investigated effects of three salinities, i.e., control moderate and high, and five nitrogen ratios, i.e., 100:0, 75:25, 50:50, 25:75 or 0:100 NO3−-N:NH4+-N ratio on their growth and functional value for fatty acids and antioxidants. Results show that the leaf fatty acid and antioxidant profiles of species, emphasize their good potential to become functional crop products, based on comparison with other functional plants, dietetic recommendation, or functional indices. However, their total phenolic compounds (TPC) content can be influenced by N-ratio (Suaeda maritima and Enchylaena tomentosa) and their antioxidant activity index (AAI) can be influenced by salinity (Suaeda maritima), N-ratio (Salsola australis) or both (Enchylaenatomentosa). Their quantitative and/or qualitative fatty acid profiles can also be influenced by salinity (Enchylaena tomentosa), N-ratio (Suaeda maritima), or both (Salsola australis). Regarding these variations, involving salt tolerance and nitrogen nutrition mechanisms, we recommend suitable treatments to maintain or optimize the growth and the functional quality of leaves in the three species

Activités pharmaceutiques relatives aux essais cliniques de médicaments et dispositifs médicaux réalisées au sein des établissements de santé – guide professionnel

Background and objectivesThe hospital pharmacist, in charge of the pharmaceutical aspects of clinical trials plays a central role in the management and the proper use of investigational health products (IHP), in accordance with the Good Clinical Practices and Public Health Code. The working group “Clinical trials” of the CPCHU (French University Hospitals Pharmacists’ Commission) aimed to prepare national guidelines to describe the activities and involvement of the pharmacists, whatever the type of health care institution.MethodologyAfter an analysis of the existing literature, form and content requirements were set and the structure was established. The chapters were written in subgroups, with systematic revision and validation in plenary.ResultsThe professional guidelines are composed of 109 pages and are available as an interactive pdf file on the SFPC and CNCR websites. Topics covered in the guidelines are divided into 4 chapters, and include inserts of specific recommendations and/or some illustrations. There are 374 references, including 329 regulatory texts, and 5 appendices.Discussion–conclusionThese guidelines are a part of process of dissemination, standardization and securing practices, in order to help hospital pharmacists in the management of IHP and in the development or improvement of their own performance systems in terms of quality. Its pedagogical format also makes it a training tool for students, compounders and senior pharmacists. Its regular updating is necessary

Characterization of Phenotypes and Functional Activities of Leukocytes From Rheumatoid Arthritis Patients by Mass Cytometry.

International audienceBackground: Rheumatoid arthritis (RA) is the most common autoimmune rheumatic disease and leads to persistent chronic inflammation. The pathophysiology of the disease is complex, involving both adaptive and innate immunity. Among innate immune cells, neutrophils have been rarely studied due to their sensitivity to freezing and they are not being collected after Ficoll purification.Methods: We used mass cytometry to perform a multidimensional phenotypic characterization of immune cells from RA-treated patients, which included the simultaneous study of 33 intra- or extra-cellular markers expressed by leukocytes. We were able to focus our study on innate immune cells, especially neutrophils, due to a specific fixation method before freezing. In addition, blood samples were stimulated or not with various TLR agonists to evaluate whether RA-dependent chronic inflammation can lead to immune-cell exhaustion.Results: We show that RA induces the presence of CD11blow neutrophils (33.7 and 9.2% of neutrophils in RA and controls, respectively) associated with the duration of disease. This subpopulation additionally exhibited heterogeneous expression of CD16. We also characterized a CD11ahigh Granzyme Bhigh T-cell subpopulation possibly associated with disease activity. There was no difference in cytokine expression after the stimulation of immune cells by TLR agonists between RA and controls.Conclusion: Mass cytometry and our fixation method allowed us to identify two potential new blood subpopulations of neutrophils and T-cells, which could be involved in RA pathology. The phenotypes of these two potential new subpopulations need to be confirmed using other experimental approaches, and the exact role of these subpopulations is yet to be studied

Recurrent cystitis episodes are caused by "ordinary" uropathogenic Escherichia coli strains

Recurrent cystitis (i.e. more than 2 episodes over a 6-month period) is a public health concern as it impacts significantly the patients' quality of life. Both sporadic cystitis (SC) and recurrent cystitis (RC) are mainly caused by Uropathogenic Escherichia coli (UPEC). However, specific determinants associated with "recurrent" UPEC remain poorly characterized. → Objective: to describe genomic and phenotypic traits associated with recurrence and to explore within host genomic adaptation of sequential UPEC isolates

T1 Mapping From MPRAGE Acquisitions: Application to the Measurement of the Concentration of Nanoparticles in Tumors for Theranostic Use

International audienceBackground: The measurement of the concentration of theranostic agents in vivo is essential for the assessment of their therapeutic efficacy and their safety regarding healthy tissue. To this end, there is a need for quantitative T 1 measurements that can be obtained as part of a standard clinical imaging protocol applied to tumor patients. Purpose: To generate T 1 maps from MR images obtained with the magnetization-prepared rapid gradient echo (MPRAGE) sequence. To evaluate the feasibility of the proposed approach on phantoms, animal and patients with brain metastases. Study Type: Pilot. Phantom/Animal model/Population: Solutions containing contrast agents (chelated Gd 3+ and iron nanoparticles), male rat of Wistar strain, three patients with brain metastases. Field Strength/Sequence: A 3-T and 7-T, saturation recovery (SR), and MPRAGE sequences. Assessment: The MPRAGE T 1 measurement was compared to the reference SR method on phantoms and rat brain at 7-T. The robustness of the in vivo method was evaluated by studying the impact of misestimates of tissue proton density. Concentrations of Gd-based theranostic agents were measured at 3-T in gray matter and metastases in patients recruited in NanoRad clinical trial. Statistical Tests: A linear model was used to characterize the relation between T 1 measurements from the MPRAGE and the SR acquisitions obtained in vitro at 7-T. Results: The slope of the linear model was 0.966 (R 2 = 0.9934). MPRAGE-based T 1 values measured in the rat brain were 1723 msec in the thalamus. MPRAGE-based T 1 values measured in patients in white matter and gray matter amounted to 747 msec and 1690 msec. Mean concentration values of Gd 3+ in metastases were 61.47 μmol. Data Conclusion: The T 1 values obtained in vitro and in vivo support the validity of the proposed approach. The concentrations of Gd-based theranostic agents may be assessed in patients with metastases within a standard clinical imaging protocol using the MPRAGE sequence. Evidence Level: 2. Technical Efficacy: Stage 1

Randomized phase II trial in prostate cancer with hormone-sensitive OligometaSTatic relapse: Combining stereotactic ablative radiotherapy and durvalumab (POSTCARD GETUG P13): Study protocol

Background: As in other solid tumors, increasing evidence indicates that patients diagnosed with a limited number of prostate cancer metastases, so-called oligometastases, have a better prognosis than patients with extensive metastatic disease. Stereotactic body radiotherapy (SBRT) is now considered an option in this population.Programmed death-1 (PD-1) and its ligands (PD-L1) are targeted by immune checkpoint inhibitors. Preclinical studies have shown that the tumor immune microenvironment changes when combining radiotherapy with immunotherapy, especially with hypofractionated radiotherapy.The oligometastatic setting appears to be the most relevant clinical situation for evaluating the immune response generated by radiotherapy and immune checkpoint inhibitors in patients with an intact immune system.We hypothesize that durvalumab will enhance the immune response following SBRT targeting oligometastatic lesions. Our purpose is to demonstrate, via a randomized 2:1 phase II trial, that SBRT (3 fractions) with durvalumab in oligometastatic hormone-sensitive prostate cancer patients would improve progression-free survival in patients with prostate cancer with up to 5 metastases compared to patients who exclusively received SBRT. Methods: This is a multicentric randomized phase II study in French academic hospitals. Patients with prostate cancer and up to 5 metastases (lymph node and/or bone) were randomized into a 2:1 ratio between Arm A (experimental group), corresponding to durvalumab and SBRT to the metastases, and Arm B (control group), corresponding to SBRT alone to the metastases. The study aims to accrue a total of 96 patients within 3 years. The primary endpoint is two-year progression-free survival and secondary endpoints include androgen deprivation therapy-free survival, quality of life, toxicity, prostate cancer specific survival, overall survival, and immune response. Discussion: The expected benefit for the patients in the experimental arm is longer life expectancy with acceptable toxicity. We also expect our study to provide data for better understanding the synergy between immunotherapy and radiotherapy in oligometastatic prostate cancer