Ultrahigh Strength and Plasticity Mechanisms of Si and SiC Nanoparticles Revealed by First-Principles Molecular Dynamics.

It is now well established that materials are stronger when their dimensions are reduced to the submicron scale. However, what happens at dimensions such as a few tens of nanometers or lower remains largely unknown, with conflicting reports on strength or plasticity mechanisms. Here, we combined first-principles molecular dynamics and classical force fields to investigate the mechanical properties of 1-2 nm Si and SiC nanoparticles. These compression simulations unambiguously reveal that the strength continues to increase down to such sizes, and that in these systems the theoretical bulk strength can be reached or even exceeded in some cases. Most of the nanoparticles yield by amorphization at strains greater than 20%, with no evidence of the ß-tin phase for Si. Original and unexpected mechanisms are also identified, such as the homogeneous formation of a dislocation loop embryo for the ⟨111⟩ compression of SiC nanoparticles, and an elastic softening for the ⟨001⟩ compression of Si nanoparticles.

Sputum Inflammatory Patterns are Associated with Distinct Clinical Characteristics in Subjects with Occupational Asthma Independently from the Causal Agent.

BACKGROUND AND OBJECTIVES: Clinical heterogeneity in sensitizer-induced occupational asthma (OA) and its relationship to airway inflammatory profiles remain poorly elucidated. To further characterize the interactions between induced sputum inflammatory patterns, asthma-related outcomes and the high- or low-molecular-weight category of causal agents in a large cohort of subjects with OA. METHODS: This multicenter, retrospective, cross-sectional study was conducted among 296 subjects with OA ascertained by a positive specific inhalation challenge who completed induced sputum assessment before and 24 hours after challenge exposure. RESULTS: Multivariate logistic regression analysis revealed that sputum eosinophilia ≥3% was significantly associated with a high dose of inhaled corticosteroid (odds ratio [95% confidence interval], 1.31 [1.11-1.55] for each 250-µg increment in daily dose), short-acting b2-agonist use less than once a day (3.54 [1.82-7.00]), and the level of baseline nonspecific bronchial hyperresponsiveness (mild: 2.48 [1.21-5.08]); moderate/severe: 3.40 [1.44-8.29]). Sputum neutrophilia ≥76% was associated with age (1.06 [1.01-1.11]), male gender (3.34 [1.29-9.99]), absence of corticosteroid use (5.47 [2.09-15.16]), short-acting b2-agonist use once or more a day (4.09 [1.71-10.01]), ≥2 severe exacerbations during the last 12 months at work (4.22 [1.14-14.99]), and isolated early reactions during the SIC (4.45 [1.85-11.59]). CONCLUSIONS: The findings indicate that sputum inflammatory patterns in subjects with OA are associated with distinct phenotypic characteristics and further highlight the differential effects of neutrophils and eosinophils on asthma-related outcomes. These associations between inflammatory patterns and clinical characteristics share broad similarities with what has been reported in nonoccupational asthma and are not related to the type of causal agent.

[Medical biostatistics with GMRC Shiny Stats - learning by doing]. / Biostatistiques médicales avec GMRC Shiny Stats ­ un outil de formation par la pratique.

Biostatistics are omnipresent in the scientific and medical literature and are an essential skill for any health student. We have developed a practical training tool - GMRC Shiny stats - an interactive application specifically dedicated to medical data statistical analysis. The application has been designed to provide an analysis workflow corresponding to the usual progression of an experienced statistician during data analysis. The most common statistical analyses can be performed (descriptive statistics, inferences according to frequentist methods, survival analyses, correlation, agreement measurements, etc.). GMRC Shiny stats is intuitive and user-friendly and assists students in choosing the most appropriate statistical tests. With all these functionalities, students can learn statistical analysis by doing. Getting involved in the statistical analysis and processing of their own data is likely to improve their biostatistics skills.

Reverse Transcriptase in Action: FRET-Based Assay for Monitoring Flipping and Polymerase Activity in Real Time.

Reverse transcriptase (RT) of human immunodeficiency virus-1 (HIV-1) is a multifunctional enzyme that catalyzes the conversion of the single stranded viral RNA genome into double-stranded DNA, competent for host-cell integration. RT is endowed with RNA- and DNA-dependent DNA polymerase activity and DNA-directed RNA hydrolysis (RNase H activity). As a key enzyme of reverse transcription, RT is a key target of currently used highly active antiretroviral therapy (HAART), though RT inhibitors offer generally a poor resistance profile, urging new RT inhibitors to be developed. Using single molecule fluorescence approaches, it has been recently shown that RT binding orientation and dynamics on its substrate play a critical role in its activity. Currently, most in vitro RT activity assays, inherently end-point measurements, are based on the detection of reaction products by using radio-labeled or chemically modified nucleotides. Here, we propose a simple and continuous real-time Förster resonance energy transfer (FRET) based-assay for the direct measurement of RT's binding orientation and polymerase activity, with the use of conventional steady-state fluorescence spectroscopy. Under our working conditions, the change in binding orientation and the primer elongation step can be visualized separately on the basis of their opposite fluorescence changes and their different kinetics. The assay presented can easily discriminate non-nucleoside RT inhibitors from nucleoside RT inhibitors and determine reliably their potency. This one-step and one-pot assay constitutes an improved alternative to the currently used screening assays to disclose new anti-RT drugs and identify at the same time the class to which they belong.

[Pseudolymphoma of the skin: ambiguous terminology: a survey among dermatologists and pathologists]. / Le pseudolymphome cutané: une sémantique ambiguë. Enquête auprès des dermatologues et des pathologistes.

BACKGROUND: Cutaneous pseudolymphomas (CPL) are diseases that simulate cutaneous lymphomas both clinically and histologically but have a benign course. It can be very difficult, if not impossible, to differentiate pseudolymphoma from lymphoma and there is some semantic ambiguity about the term pseudolymphoma. The aim of this study was to determine the exact meaning attributed to the term pseudolymphoma by a representative sample of French dermatologists and pathologists. MATERIALS AND METHODS: We designed two types of questionnaire, one for dermatologists and the other for pathologists, and sent them out to 274 dermatologists and to 110 pathologists. RESULTS: We received responses from 122 dermatologists (44.5%) and 64 pathologists (58.1%). In the dermatologist group, 56% consider that CPL is not a clearly defined entity, while 58% consider it a benign disease and only 18% feel that most CPLs are related to a precise cause; 72% of dermatologists perform a routine checkup, 58% initiate treatment and 84% conduct follow-up in the case of CPL. Among pathologists, 61% consider that CPL is not a clearly defined entity, 82% feel that cutaneous pseudolymphoma, cutaneous lymphoid hyperplasia and cutaneous lymphocytoma are the same entity, and 75% consider that CPL are benign; 92% perform routine immunohistochemistry studies and only 26% screen for clonality. Bivariate statistical analysis showed that pathologists consider pseudolymphomas as benign entities frequently than dermatologists (χ(2) test: P=0.02; Fisher's exact test: P=0.01) and that there are more pathologists than dermatologists who see more than four pseudolymphomas per year (χ(2) test: P<0.001; Fisher's exact test: P<0.001). Multivariate analysis clearly identified a tendency among doctors viewing pseudolymphomas as a distinct entity to also consider them benign (Odds Ratio 0.29, CI 97.5% 0.14-0.58), irrespective of speciality or type of practice (hospital practice, private practice or both). DISCUSSION: This study demonstrates that, in France, the term pseudolymphoma is an ambiguous notion. We believe that cases in which it is impossible to differentiate pseudolymphoma from cutaneous lymphoma should be referred to as lymphoproliferations of undetermined significance, since more than 50% of physicians consider that the term pseudolymphoma designates a resolutely benign entity.

Hippocampal dysgenesis and variable neuropsychiatric phenotypes in patients with Bardet-Biedl syndrome underline complex CNS impact of primary cilia.

The Bardet-Biedl syndrome (BBS) is a rare ciliopathy clinically defined by the association of retinitis pigmentosa, polydactyly, obesity, kidney disease and cognitive impairment. The cognitive functioning, behavioral phenotype, prevalence of psychiatric diseases and memory performances of a cohort of 34 patients with BBS were evaluated and a systemic brain magnetic resonance imaging (MRI) was performed. The patients' cognitive functioning was of marked variable efficiency ranging from normal to disabling performances. Neuropsychological disorders such as slow thought process, attention difficulties and obsessive-compulsive traits were observed. Our main finding was hippocampal dysgenesis, diagnosed by MRI, found in 42.31% of the patients in this cohort. Moreover, we show that BBS proteins are expressed in the human hippocampus and in the human brain in the normal subject. Recent literature in the murine model shows that hippocampal neurogenesis, in particular in the adult mouse, requires an intact primary cilia. These results encourage us to further investigate the possible role of BBS proteins in the hippocampus and related central nervous system structures.

Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer.

BACKGROUND: DNA mismatch repair system deficiency (dMMR) is found in 15% of colorectal cancers (CRCs). Two methods are used to determine dMMR, immunohistochemistry (IHC) of MMR proteins and molecular testing of microsatellite instability (MSI). Only studies with a low number of patients have reported rates of discordance between these two methods, ranging from 1% to 10%. MATERIALS AND METHODS: Overall, 3228 consecutive patients with CRCs from two centers were included. Molecular testing was carried out using the Pentaplex panel and IHC evaluated four (MLH1, MSH2, MSH6, and PMS2; cohort 1; n = 1085) or two MMR proteins (MLH1 and MSH2; cohort 2; n = 2143). The primary endpoint was the rate of discordance between MSI and MMR IHC tests. RESULTS: Fifty-one discordant cases (1.6%) were initially observed. Twenty-nine out of 51 discordant cases were related to IHC misclassifications. In cohort 1, after re-reading IHC and/or carrying out new IHC, 16 discordant cases were reclassified as nondiscordant. In cohort 2, after the addition of MSH6/PMS2 IHC and re-examination, 13 were reclassified as nondiscordant. In addition, 10 misclassifications of molecular tests were identified. Finally, only 12 discordant cases (0.4%) remained: 5 were proficient MMR/MSI and 7 were dMMR/microsatellite stable. CONCLUSIONS: Our study confirmed the high degree of concordance between MSI and MMR IHC tests. Discordant cases must be reviewed, and if needed, tests must be repeated and analyzed by an expert team.

Binary rototranslational hyper-Rayleigh spectra of H(2)-He gas mixture.

The collision-induced rototranslational hyper-Rayleigh spectra of gaseous H(2)-He mixture are computed and discussed in the binary regime. As the input data we use our ab initio computed H(2)-He collision-induced first dipole hyperpolarizability tensor Deltabeta(R). Both the vector and the septor part of the H(2)-He hyper-Rayleigh spectra are evaluated at room temperature (T=295 K). The spectra are calculated assuming the full quantum computations based on the Schrödinger equation of the relative translational motion in the isotropic H(2)-He potential as well as using semiclassical methods.

Spi-1/PU.1 is a positive regulator of the Fli-1 gene involved in inhibition of erythroid differentiation in friend erythroleukemic cell lines.

Spi-1/PU.1 and Fli-1 are two members of the ETS family of transcription factors whose expression is deregulated by proviral insertion in most erythroleukemic cell lines induced by the spleen focus-forming virus (SFFV) and Friend murine leukemia virus (F-MuLV) components of the Friend viral complex, respectively. In this study, we present evidence that transcription of the Fli-1 gene is positively regulated by Spi-1/PU.1 in SFFV-transformed cell lines: (i) all SFFV-transformed cell lines expressing Spi-1/PU.1 are characterized by a specific pattern of Fli-1 gene transcripts initiated in the -200 region instead of position -400 as reported for F-MuLV-transformed cell lines; (ii) these Fli-1 transcripts initiated in the -200 region are downregulated in parallel with that of Spi-1/PU.1 during hexamethylenebisacetamide (HMBA) induced differentiation; and (iii) Fli-1 transcription is upregulated in SFFV cells lines following stable transfection of a Spi-1/PU.1 expression vector. Furthermore, we found by transient transfection assays that the -270/-41 region of the Fli-1 gene displays promoter activity which is transactivated by Spi-1/PU.1. This promoter is strictly dependent on the integrity of two highly conserved ETS DNA binding sites that bind the Spi-1/PU.1 protein in vitro. Finally, we show that transfection of constitutive or inducible Fli-1 expression vectors in SFFV-transformed cells inhibits their erythroid differentiation induced by HMBA. Overall, these data indicate that Fli-1 is a target gene of the Spi-1/PU.1 transcription factor in SFFV-transformed cell lines. We further suggest that deregulated synthesis of Fli-1 may trigger a common mechanism contributing to erythroleukemia induced by either SFFV or F-MuLV.

[The control of radiation protection in the field of radiotherapy by the French Nuclear Safety Authority (ASN)]. / Les actions de contrôle de l'Autorité de sûreté nucléaire (ASN) dans le domaine de la radiothérapie.

During the last months, several incidents at radiotherapy services occurred in France; one of these accidents led to the death of several patients or required further heavy surgical acts. In this context, ASN (Autorité de sûreté nucléaire) issued an experimental guide for the notification of radiation protection events and achieved, in dialogue with professional organisations, a new scale intended to facilitate public information on radiotherapy incidents. ASN is also fully involved in the preparation of the action plan managed by the Health ministry in order to improve the safety of treatment in radiotherapy.

Critical shoulder angle: Measurement reproducibility and correlation with rotator cuff tendon tears.

BACKGROUND: Associations have been reported linking rotator cuff tears (RCTs) to both greater lateral extension of the acromion and greater inclination of the glenoid cavity. These two factors combined can be assessed using a recently introduced parameter, the critical shoulder angle (CSA). The primary objective of this study was to confirm the association linking a high CSA value to RCTs, and the secondary objective was to assess the reproducibility of CSA measurement using a goniometer. HYPOTHESIS: The null hypothesis was that the CSA value in a group of patients with RCTs was not significantly different from that in patients with anterior shoulder instability and a Bankart lesion, taken as the general population for this study. METHODS: After a power estimation, we retrospectively included 28 patients with a mean age of 55.5 years who had surgery for RCTs and 27 patients with a mean age of 27.2 years who underwent anterior labral repair. Two surgeons used a goniometer to measure the CSA in each patient. Reproducibility was assessed based on Bland-Altman plots and Pearson's correlation coefficient. RESULTS: The mean CSA was significantly higher (P=0.02) in the RCT group (36.4°±4.4°; range: 30°-46°) than in the labral-repair group (33.3°±3.8°; range: 25°-41°). Intra-observer reproducibility was 96.7% and inter-observer reproducibility was 95.5%. CONCLUSION: Our results support previously published evidence that the CSA is significantly greater in patients with RCTs. Thus, an anatomical difference seems to exist between patients with RCTs and the general population. The CSA measured on a standard radiograph using a goniometer provides a reproducible assessment of this anatomical difference. LEVEL OF EVIDENCE: IV, case-control epidemiological study with a power estimation.

Can the presence of an infection be predicted before a revision total hip arthroplasty? Preliminary study to establish an infection score.

INTRODUCTION: The diagnosis of periprosthetic joint infection can be challenging, in part because there is no universal diagnostic test. Current recommendations include several diagnostic criteria, and are mainly based on the results of deep microbiological samples; however, these only provide a diagnosis after surgery. A predictive infection score would improve the management of revision arthroplasty cases. The purpose of this study was to define a composite infection score using standard clinical, radiological and laboratory data that can be used to predict whether an infection is present before a total hip arthroplasty (THA) revision procedure. HYPOTHESIS: The infection score will make it possible to differentiate correctly between infected and non-infected patients in 75% of cases. MATERIAL AND METHODS: One hundred and four records from patients who underwent THA revision for any reason were analysed retrospectively: 43 with infection and 61 without infection. There were 54 men and 50 women with an average age of 70±12 years (range 30-90). A univariate analysis was performed to look for individual discriminating factors between the data in the medical records of infected and non-infected patients. A multivariate analysis subsequently integrated these factors together. A composite score was defined and its diagnostic effectiveness was evaluated as the percentage of correctly classified records, along with its sensitivity and specificity. RESULTS: The score consisted of the following individually weighed factors: body mass index, presence of diabetes, mechanical complication, wound healing disturbance and fever. This composite infection score was able to distinguish correctly between the infected patients (positive score) and non-infected patients (negative score) in 78% of cases; the sensitivity was 57% and the specificity 93%. DISCUSSION: Once this score is evaluated prospectively, it could be an important tool for defining the medical - surgical strategy during THA revision, no matter the reason for revision. LEVEL OF EVIDENCE: Level IV - retrospective study.

Identification of two critical base pairings in 5' untranslated regions affecting translation efficiency of synthetic uncapped globin mRNAs.

We observed a marked difference between the in vitro translation efficiency of two uncapped synthetic mRNAs, displaying the entire human alpha or beta globin mRNA sequences and some additional non-globin sequences in 5'. The comparison of the translation efficiencies of chimeric mRNAs indicated that the alpha 5' untranslated region (5' UTR) is responsible for a low translation efficiency that cannot be explained neither by primary sequence nor by the overall stability of 5' UTR secondary structures only. By point mutations in this alpha 5' UTR, we identified two base pairings at position -1 and -2 preceding the initiation codon which are associated with a negative effect on translation efficiency.

Coactivation of human alpha1- and alpha2-globin genes in single induced MEL cells containing one human alpha-globin locus.

We developed a reverse-transcription polymerase chain reaction assay, performed on single isolated cells, to demonstrate the coexpression of human alpha1- and alpha2-globin mRNA in induced mouse erythroleukemic cells containing a single human alpha-globin locus. These results indicate that both alpha1 and alpha2 genes are activated from the same alpha-globin gene locus implying that HS-40-dependent transcriptional activation is mediated, either by a simultaneous interaction of HS-40 with both a alpha1 and alpha2-globin gene promoters, or by a dynamic process characterized by alternative, but short-lived, interactions with each alpha-globin gene promoter.

3' non-translated region of human alpha-globin messenger RNA does not affect translation efficiency.

The relative translation efficiency of three synthetic alpha-globin mRNAs differing by their 3' non-translated end was measured in vitro in a rabbit reticulocyte lysate. Results showed that substituting the 3' non-translated end of human alpha 2 globin mRNA by the 3' non-translated end of chimpanzee alpha 1 or alpha 2 mRNAs has no effect on translation efficiency. In contrast, the introduction of the alpha-Quong-Sze mutation (alpha 125, Leu----Pro) in human alpha 2 mRNA led to a 50% apparent reduction in globin synthesis due to the instability of the alpha-Quong-Sze globin chain. We conclude that human alpha 1 and alpha 2 globin mRNAs have the same translation efficiency, and that the reduction, previously reported, in the kinetics of alpha-globin synthesis by alpha 2 mRNA carrying the alpha-Quong-Sze mutation is due to the instability of the alpha-Quong-Sze globin chain only.

A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss.

Mutations in the GJB2 gene encoding connexin26 (CX26) account for up to 50% of cases of autosomal recessive hearing loss. In contrast, only one GJB2 mutation has been reported to date in an autosomal dominant form of isolated prelingual hearing loss. We report here a novel heterozygous 605G-->T mutation in GJB2 in all affected members of a large family with late childhood onset of autosomal dominant isolated hearing loss. The resulting C202F substitution, which lies in the fourth (M4) transmembrane domain of CX26, may impair connexin oligomerisation. Finally, our study suggests that GJB2 should be screened for heterozygous mutations in patients with autosomal dominant isolated hearing impairment, whatever the severity of the disease.

Unexpected and coordinated expression of Spi-1, Fli-1, and megakaryocytic genes in four Epo-dependent cell lines established from transgenic mice displaying erythroid-specific expression of a thermosensitive SV40 T antigen.

Most erythroleukemic cell lines established in vitro coexpress erythrocytic and megakaryocytic markers that often are associated with expression of Spi-1 and/or Fli-1 transcription factors known as transactivators of megakaryocyte-specific promoters. In the present study, we examined the possibility of establishing new cell lines keeping strictly erythroid-specific properties in vitro through the targeted and conditional immortalization of erythrocytic progenitors. For that purpose, we established several lines of transgenic mice displaying erythroid-specific expression of a thermosensitive SV40 T antigen. As expected, these transgenic mice developed splenomegaly due to the massive amplification of Ter 119 positive erythroid nucleated cells expressing T antigen. Despite this drastic effect in vivo, the in vitro immortalization of erythropoietin-dependent erythroid progenitors unexpectedly occurred at low frequency, and all four cell lines established expressed both erythrocytic (globins) and megakaryocytic markers (glycoprotein IIb, platelet factor 4) as well as Spi-1 and Fli-1 transcripts at permissive temperature. Switching the cells to the nonpermissive temperature led to a marked increase in globin gene expression and concomitant decrease in expression of Spi-1, Fli-1, and megakaryocytic genes in an erythropoietin-dependent manner. Interestingly, enhanced expression of Spi-1 and Fli-1 genes already was detected in the Ter 119 positive cell population of transgenic mice spleen in vivo. However, like normal Ter 119 erythroid cells, these Ter 119 positive cells from transgenic mice still expressed high levels of beta-globin and very low or undetectable glycoprotein IIb and platelet factor 4 megakaryocytic transcripts. Taken together, these data indicate that the unexpected expression of megakaryocytic genes is a specific property of immortalized cells that cannot be explained only by enhanced expression of Spi-1 and/or Fli-1 genes.

French policy for managing the post-accident phase of a nuclear accident.

In 2005, at the request of the French Government, the Nuclear Safety Authority (ASN) established a Steering Committee for the Management of the Post-Accident Phase of a Nuclear Accident or a Radiological Emergency, with the objective of establishing a policy framework. Under the supervision of ASN, this Committee, involving several tens of experts from different backgrounds (e.g. relevant ministerial offices, expert agencies, local information commissions around nuclear installations, non-governmental organisations, elected officials, licensees, and international experts), developed a number of recommendations over a 7-year period. First published in November 2012, these recommendations cover the immediate post-emergency situation, and the transition and longer-term periods of the post-accident phase in the case of medium-scale nuclear accidents causing short-term radioactive release (less than 24 h) that might occur at French nuclear facilities. They also apply to actions to be undertaken in the event of accidents during the transportation of radioactive materials. These recommendations are an important first step in preparation for the management of a post-accident situation in France in the case of a nuclear accident.

Bilateral brain dysfunction during motor activation in type II schizophrenia measured by EEG mapping.

In this final electroencephalographic (EEG) mapping study of our series on motor dysfunction in neuroleptic-treated schizophrenic patients, we studied 10 right-handed patients with marked negative symptomatology [type II; raw score on the SANS (Munich version) 31.4 +/- 5.1]. Simple and multisensorimotor tasks involving both the dominant and nondominant hand were used for cortical activation. All tasks were referred to resting states obtained after specially designed relaxation procedures. In contrast to predominantly type I patients (SANS-MV score 12.3 +/- 4.9) of our previous EEG mapping studies, we found for resting states minor evidence (only) of increased power values in the frequency bands delta and theta. Furthermore, in contrast to signs of "left hemisphere dysfunction" and possible "compensatory right hemisphere overactivation" during motor tasks, which we discussed previously for our type I patients, we found for the type II schizophrenics a bilateral brain dysfunction. This consisted of "nonreactivity" in all frequency bands except alpha, in which, on the contrary, a "hyperreactivity" seemed to be present. In combination with evidence of bilateral hemispheric dysfunction in type II patients reported by other authors using EEG, evoked potentials, regional cerebral blood flow (rCBF) and magnetic resonance imaging (MRI) methods, this suggests that marked bilateral brain dysfunction may be correlated in schizophrenia with a clinical syndrome corresponding rather to the "negative pole" of the positive-negative dimension. In contrast, "left hemisphere dysfunction" and "signs of compensatory overactivation" seem to be linked more to a "positive" symptomatology. Finally, discrepancies of our EEG mapping and rCBF findings during motor activity suggest, speculatively, "uncoupling" between electrical and circulatory parameters in schizophrenia involving both hemispheres in type II, and predominantly the left hemisphere in type I, patients.