Small critical RNAs in the scrapie agent

Unconventional infectious agents cause transmissible spongiform encephalopathy (TSE) diseases including scrapie and bovine spongiform encephalopathy (BSE) in animals and Creutzfeldt-Jakob disease in humans. The protein only hypothesis claims that the TSE agent is composed solely of the protein called prion (PrP^sc^)^1^. This protein is the misfolded form of a host-encoded cellular protein, PrP^c^ exerting presumably a vital role at the synapse^2^. Even though now widely accepted, the prion concept fails to provide in certain circumstances^3-6^, a satisfying interpretation of the infectious phenomenon. Using the 263K scrapie-hamster model, we conducted a transmission study to search for a putative prion-associated factor indispensable for infectivity. Here we show that innocuous recombinant prion protein (recPrP) was capable, in a reproducible manner, of transmitting scrapie disease when the protein was [beta]–sheet converted in a solution containing PrP^sc^-derived RNA material. Analysis of the PrP-RNA mixture revealed the association of recPrP with two prominent populations of small RNA molecules having an average length of about ~27 and ~55 nucleotides. We conclude that the nature of the TSE agent seems to be composed of a nucleoprotein molecular complex, in which informative RNA molecules of small sizes are associated with the misfolded prion protein (PrP^sc^)

Mise au point de techniques analytiques pour la spéciation du sélénium dans les boues de stations d'épuration d'eaux résiduaires urbaines

Les stations d'épuration d'eaux résiduaires sont une des étapes du cycle du sélénium dans l'environnement et contribuent à sa redistribution dans le milieu naturel. Très peu étudié jusqu'à présent dans ces milieux, le sélénium n'en est pas moins un élément très important du point de vue écotoxicologique, sa teneur dans les boues de stations d'épuration destinées à l'épandage agricole faisant par ailleurs l'objet d'une norme.Nous avons mis au point des techniques permettant la détermination spécifique de l'élément total dans ce type d'échantillon, par minéralisation classique ou assistée par micro-ondes et dosage par Voltamétrie de Redissolution Cathodique Différentielle Pulsée (DPCSV) et Spectrométrie d'Absorption Atomique ElectroThermique (ETAAS). Le contrôle qualité a été effectué sur deux échantillons certifiés fournis par le Bureau Communautaire de Référence (BCR) : la boue CRM 145 R et la boue CRM 007.Cependant, lorsqu'on parle de risque toxicologique, il est important de s'intéresser à la détermination des différentes formes sous lesquelles cet élément peut être présent. Nous avons pour cela réalisé des extractions parallèles (spéciation de phases) du sélénium contenu dans les boues afin de déterminer quel pourcentage du sélénium total est réellement et potentiellement disponible pour les végétaux lors d'un épandage sur sol agricole. La spéciation d'espèces a été brièvement abordée dans le but de déterminer les teneurs en Se(IV) et Se(VI), espèces les plus toxiques.The great effort undertaken for about twenty years to improve the quality of surface waters has led to the construction of numerous waste water treatment plants, generating an increasing amount of sludge. Waste water and sludge treatment processes represent an important point in the hydrological cycle at which the disposal of substantial quantities of trace elements to the environment may be regulated. From the law on waste recovery and disposal in 1975 to the European guideline about wastes in 1991, the priority has been given to waste recovery and recycling. With increasing pressure to ban all sludge dumping at sea, and considering the prohibitive costs of land-filling and incineration, there is a great tendency to dispose of sludge on land (40% in 1988 to 60% in 1992).Although numerous studies have demonstrated the intrinsic value of sludge for soil amendment, given its nitrogen, phosphorus and homogeneous organic matter content, evidence has accumulated in recent years that numerous environmental problems can arise because of the presence in sludges of high amounts of certain trace elements (potentially toxic to plants and to human beings and liable to be concentrated along the food chain), among which selenium is particularly interesting.Selenium presents a complex case, as it is also an essential element for living organisms (including humans). The amendment with sewage sludge is sometimes used to increase the selenium content in crops, and afterwards in cattle, when there is a proven lack of this element in a given place. Nevertheless the boundary between essentiality and toxicity is relatively narrow and is expressed at trace levels. It is thus particularly important to survey the selenium concentrations encountered in sewage sludge, especially as guidelines and regulations concerning these data will probably be strengthened. Presently, in France, sludge must not contain more than 200 mg Se·kg-1 dry weight and must not be used on soils containing more than 10 mg Se·kg-1 dry weight (AFNOR U 44-041 norm). This norm concerns only the total amount of selenium contained in sludge and does not take into account the different species (organic and inorganic Se(-II), Se(0), Se(IV) and Se(VI)) that could be present.First of all we had to develop methods for the classical and microwave-assisted wet digestion of sewage sludge, and the determination of their total selenium concentration by Differential Pulse Cathodic Stripping Voltammetry (DPCSV) and ElectroThermal Atomic Absorption Spectrometry (ETAAS). Quality assurance involved the analysis of two BCR (Community Bureau of Reference) certified sewage sludge reference materials (CRM 145 R and CRM 007) and the different techniques were then applied to natural samples from a representative French sewage treatment plant located in the city of Tarbes (South-West of France). The mixture HNO3-H2O2-H2O led to the best results for the digestion and analysis of certified samples, caused few problems for the analysis by DPCSV and ETAAS, and was therefore retained. The decrease of the digestion duration obtained by the use of microwaves was particularly interesting (from one to three days on a hot plate to less than one hour by the Microdigest 301 (PROLABO, France)), and reproducibility was also acceptable (between 3 and 10%). Concentrations obtained for the sewage sludge from the Tarbes treatment plant were very much lower than those for NF U 44-041: 1.08±0.11 mg Se·kg-1 dry weight.However knowledge of speciation, that is to say the determination of the different physicochemical forms of selenium present in a given medium, is necessary when speaking of the toxicological risk represented by an element. The mobility of selenium and its toxicity to the biosphere are related to its association with various sludge or soil constituents as well as to its total concentration. "Soft" or partial extraction techniques are necessary when the aim of the study to determine trace element speciation. The extractants used must separate selenium from the matrix without inducing any loss or change in the partitioning of individual chemical species. In parallel extractions the mechanisms involved for each extractant must correspond to processes occurring in nature and are then associated with special fractions of selenium: soluble, exchangeable, "oxidizable", and "mineral" fractions .Parallel extractions with three types of extractants were chosen for this study and applied first to CRM 007: warm water (soluble fraction), ammonium phosphate-citric acid (soluble + exchangeable fraction) and sodium hydroxide (soluble + exchangeable + "oxidizable" fraction). The soluble, exchangeable, "oxidizable" and "mineral" fractions represent respectively : 11%, 14%, 39% and 36%. The same procedure was then applied to natural samples from Tarbes giving the following results: 36% soluble, 22% exchangeable, 42% "oxidizable". The sodium hydroxide extraction procedure allowed us to extract the entire Se content of this sludge (1.07±0.03 mg Se·kg-1 dry weight), showing that all the selenium present is potentially available after agricultural land application. It was then possible in this fraction to deal with the species speciation of selenium by the mean of a separation of inorganic and organic species on an Amberlite CG-400 resin and a specific analysis by DPCSV. Se(IV) and Se(VI) represent respectively between 30 and 40% and between 2 and 20% of total selenium in the sludges from Tarbes

Infecção por VIH entre imigrantes na Guiana Francesa: alto risco durante os primeiros anos após a chegada

Introduction. Over 75% of HIV patients in French Guiana are foreigners most of whom are actually infected locally. Objectives. We aimed to estimate the distribution of infections in time after arrival using a retrospective cohort. Methods. CD4 erosion modelling allowed to estimate the date of infection which was compared to the date of arrival in French Guiana in the subset of foreign patients that were estimated to have acquired HIV locally. Results. Among patients estimated to have been infected in French Guiana and having arrived after 1999, over half had been infected within 4 years and that a quarter of patients had acquired HIV within the 2 first years after arrival (median 3.9 years IQR=2.1-7.8 years). Conclusions. The added value of the present results is to show the rapid infection dynamics after arrival and emphasize the necessity of increasingly proactive combined prevention in recently arrived immigrants.Introdução. Mais de 75% dos pacientes com HIV na Guiana Francesa são estrangeiros, a maioria dos quais estão realmente infectados localmente. Objetivos. O nosso objetivo era estimar a distribuição das infecções no tempo após a chegada, utilizando uma coorte retrospectiva. Métodos. A modelagem da erosão CD4 permitiu estimar a data da infecção que foi comparada à data de chegada na Guiana Francesa no subconjunto de pacientes estrangeiros que foram estimados como tendo adquirido o HIV localmente.Resultados. Entre os pacientes estimados como tendo sido infectados na Guiana Francesa e tendo chegado após 1999, mais da metade tinha sido infectada dentro de 4 anos e que um quarto dos pacientes tinha adquirido o HIV dentro dos 2 primeiros anos após a chegada (mediana de 3,9 anos IQR=2,1-7,8 anos). Conclusões. O valor agregado dos resultados atuais é mostrar a rápida dinâmica da infecção após a chegada e enfatizar a necessidade de uma prevenção combinada cada vez mais proativa nos imigrantes recém-chegados

Quizz en Infectiologie

National audienc

H008 Le blocage des récepteurs AT1 de L′angiotensine II inhibe L′hypertrophie ventriculaire gauche et L′activation de FHL1 chez la souris hétérozygote déficiente en cMyBP-C

Les mutations de la protéine C cardiaque (cMyBP-C) sont une cause de cardiomyopathies hypertrophiques (CMH). Les souris transgéniques hétérozygotes défi cientes en cMyBP-C (HET) présentent une CMH d′apparition tardive à fonction systolique conservée. Le système rénine angiotensine (SRA) cardiaque joue un rôle important dans l′hypertrophie, mais son rôle dans le développement d′une CMH génétiquement déterminée a été peu étudié.Cette étude évaluait le rôle du SRA dans l′induction de la CMH chez la souris HET. Des souris HET et sauvages (WT), âgées de 5 mois, ont été traitées par irbésartan (50mg/kg/jour) ou placebo pendant 8 semaines. L′expression dans le ventricule gauche (VG) des gènes de l′enzyme de conversion de l′angiotensine I (ACE), du récepteur AT1 de l′angiotensine II (AGTR1), de la calcineurine A (PPP3CB) de la calcipressin 1 (RCAN1), et de FHL1 (four and a half LIM domains 1, une protéine associée à cMyBP-C au sein du sarcomère) a été analysée par RT-qPCR.Après 8 semaines de traitement, la pression artérielle est normale dans tous les groupes. Le poids du VG/poids du corps des souris HET est augmenté par rapport aux WT (3,9±0,3 vs. 3,3±0,4mg/g; p<0.01) dans le groupe placebo. Dans les groupes traités par irbésartan, ce rapport est comparable pour les souris HET (3,4±0,5mg/g) et WT (3,2±0,4mg/g; p=ns). L′expression des gènes de l′ACE, PPP3CB et RCAN1 est comparable entre les souris HET et WT et n′est pas affectée par le traitement par irbésartan. L′expression d′AGTR1 est similaire chez les souris HET et WT traitées par placebo mais augmente après traitement par irbésartan uniquement chez les souris HET. A l′inverse, l′expression de FHL1 est activée chez les souris HET par rapport aux souris WT mais cette augmentation est prévenue par le traitement par irbésartan.En conclusion, chez la souris cMyBP-C, le développement de l′hypertrophie est accompagné par une augmentation de l′expression du gène FHL1 dans le VG. Le traitement par irbésartan inhibe l′hypertrophie et l′activation de l′expression de FHL1 don′t le mécanisme reste à déterminer

Recipients of electric-powered indoor/outdoor wheelchairs provided by a National Health Service: A cross-sectional study

This is the post-print version of the final paper published in Archives of Physical Medicine and Rehabilitation. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2013 by the American Congress of Rehabilitation Medicine.OBJECTIVE: To describe the characteristics, across all ages, of powered wheelchair users and the assistive technology prescribed by a regional specialist wheelchair service DESIGN: Cross-sectional study SETTING: Regional wheelchair service provided to those fulfilling strict eligibility criteria by a National Health Service serving a population of 3 million. PARTICIPANTS: 544 Electric Powered Indoor/outdoor wheelchair (EPIOC) users. INTERVENTIONS: Not applicable MAIN OUTCOME MEASURES: Demographic, clinical/diagnostic details of EPIOC recipients including pain, (kypho)scoliosis and ventilators. Technical features including specialised (adaptive) seating (SS), tilt in space (TIS), and modified control systems. Factors were related to age groups: 1 (0-15), 2 (16-24), 3 (25-54), 4 (55-74) and 5 (75+). RESULTS: 262 men mean age 41.7 (range 8-82, sd 20.7) and 282 women mean age 47.2 (range 7-92, sd 19.7) years were studied. Neurological/neuromuscular conditions predominated (81%) with cerebral palsy (CP) (18.9%) and multiple sclerosis (16.4%). Conditions presenting at birth or during childhood constituted 39%. 99 had problematic pain, 83 a (kypho)scoliosis and 11 used ventilators. SS was provided to 169 users (31%), the majority had CP or muscular dystrophy. TIS was used by 258 (53%). Younger people were more likely to receive TIS than older ones. Only 92 had SS and TIS, mean age 29 (range 8-72, sd 17.8) years. 52 used modified control systems. CONCLUSIONS: The diversity of EPIOC users across age and diagnostic groups is shown. Their complex interrelationships with these technical features of EPIOC prescription are explored. Younger users were more complex due to age-related changes. This study provides outcomes of the EPIOC prescription for this heterogeneous group of very severely disabled people

Respective roles of social deprivation, health literacy, and clinical factors for COVID-19: a case-control study in hospitalized patients

IntroductionTo investigate the association between social deprivation and COVID-19 among hospitalized patients in an underprivileged department of the greater Paris area.MethodsIndividuals hospitalized for COVID-19 between March 1st and October 31, 2020, were included, matched on age and sex, and compared with patients hospitalized for any other reason with negative RT-PCR for SARS-CoV-2, through a case-control study. Clinical, socio-demographic characteristics, health literacy, and social deprivation, assessed by the EPICES score, were collected. Factors associated with COVID-19 in hospitalized patients were assessed using univariate and multivariate logistic regression models.Results69 cases and 180 controls were included. Participants were mostly men (N = 148: 59.4%) aged 65 or older (N = 109: 44.1%). Median EPICES score was 43.2 (IQR 29.4–62.9). EPICES score &gt; 30.17 (precariousness threshold) was not significantly associated with COVID-19 in hospitalized patients (adjusted odds ratio (aOR) = 0.46; 95% Confidence Interval (CI) [0.21–1.01]). Advanced age, higher BMI, professional activity, home area of less than 25 m2 per person, and low health literacy, were significantly associated with COVID-19 in hospitalized patients.DiscussionThis study highlights probable risk factors for specific exposition in disadvantaged area: maintenance of professional activity, smaller home area, and low health literacy

Evaluating Current Guidelines for Cardiopulmonary Resuscitation using an Integrated Computational Model of the Cardiopulmonary System

ObjectiveWe aimed to use a high-fidelity computational model that captures key interactions between the cardiovascular and pulmonary systems to investigate whether current CPR protocols could potentially be improved.MethodsWe developed and validated the computational model against available human data. We used a global optimisation algorithm to find CPR protocol parameters that optimise the outputs associated with return of spontaneous circulation in a cohort of 10 virtual subjects.ResultsCompared with current protocols, myocardial tissue oxygen volume was more than 5 times higher, and cerebral tissue oxygen volume was nearly doubled, during optimised CPR. While the optimal maximal sternal displacement (5.5 cm) and compression ratio (51%) found using our model agreed with the current American Heart Association guidelines, the optimal chest compression rate was lower (67 compressions min−1). Similarly, the optimal ventilation strategy was more conservative than current guidelines, with an optimal minute ventilation of 1500 ml min−1 and inspired fraction of oxygen of 80%. The end compression force was the parameter with the largest impact on CO, followed by PEEP, the compression ratio and the CC rate.ConclusionsOur results indicate that current CPR protocols could potentially be improved. Excessive ventilation could be detrimental to organ oxygenation during CPR, due to the negative haemodynamic effect of increased pulmonary vascular resistance. Particular attention should be given to the chest compression force to achieve satisfactory CO. Future clinical trials aimed at developing improved CPR protocols should explicitly consider interactions between chest compression and ventilation parameters

The Role of Cardiac Myosin Binding Protein C3 in Hypertrophic Cardiomyopathy- Progress and Novel Therapeutic Opportunities

Hypertrophic cardiomyopathy (HCM) is a common autosomal dominant genetic cardiovascular disorder marked by genetic and phenotypic heterogeneity. Mutations in the gene encodes the cardiac myosin-binding protein C, cMYBPC3 is amongst the various sarcomeric genes that are associated with HCM. These mutations produce mutated mRNAs and truncated cMyBP-C proteins. In this review, we will discuss the implications and molecular mechanisms involved in MYBPC3 different mutations. Further, we will highlight the novel targets that can be developed into potential therapeutics for the treatment of HMC. This article is protected by copyright. All rights reserve