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^)

Is the Latarjet procedure risky? Analysis of complications and learning curve.

Purpose The purpose of this study was to analyse the learning curve and complication rate of the open Latarjet procedure. Methods The first 68 Latarjet procedures performed by a single surgeon for chronic anterior shoulder instability were reviewed retrospectively. The standard open surgical technique was followed faithfully during each procedure. Post-operative complications were taken from patient medical records. Post-operative evaluation consisted of clinical and radiological assessments. Results The rate of early (<3 months) clinical complications was 7.4 % (5.9 % haematoma, 1.5 % neurological deficit), and the delayed complication rate was 7.3 %. Early complication rate, duration of surgery (mean 65 min; 35–135) and hospital stay (mean 3 days; 1–4) were significantly reduced as experience increased (respectively; P = 0.03, ρ = − 0.3; P = 0.009, ρ = − 0.3; P < 0.0001, ρ = − 0.6). On the radiographs, the bone block was healed and in perfect position in 87 % of cases, with no effect of surgical experience (P = 0.3, ρ = 0.1). The rate of complications on radiographs was 17 %: 11 % partial lysis, 2 % complete lysis and 4 % non-union. No recurrence of instability was found after an average follow-up of 21 months

Louis Bachelier On the centenary of Théorie de la Spéculation

International audienceWritten on the occasion of the centenary of Louis Bachelier's 1900 PhD thesis “Théorie de la spéculation”, this paper puts Bachelier into a historical perspective. It explains his role as a pioneer in both mathematical finance and probability theory, and it also gives a careful account of Bachelier's difficult personal and scientific career. This includes a discussion of Poincaré's report on the PhD thesis (the report itself with an English translation is reproduced in the appendix), and an explanation for the controversy between Bachelier's work and Paul L´evy's reports on it. The paper also contains a curriculum vitae and a list of the publications of Bachelier is made available

Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection.

International audienceHuman immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques (MAC) lead to chronic inflammation and AIDS. Natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM), are protected against SIV-induced chronic inflammation and AIDS. Here, we report that AGM plasmacytoid dendritic cells (pDC) express extremely low levels of CD4, unlike MAC and human pDC. Despite this, AGM pDC efficiently sensed SIVagm, but not heterologous HIV/SIV isolates, indicating a virus-host adaptation. Moreover, both AGM and SM pDC were found to be, in contrast to MAC pDC, predominantly negative for CCR5. Despite such limited CD4 and CCR5 expression, lymphoid tissue pDC were infected to a degree similar to that seen with CD4(+) T cells in both MAC and AGM. Altogether, our finding of efficient pDC infection by SIV in vivo identifies pDC as a potential viral reservoir in lymphoid tissues. We discovered low expression of CD4 on AGM pDC, which did not preclude efficient sensing of host-adapted viruses. Therefore, pDC infection and efficient sensing are not prerequisites for chronic inflammation. The high level of pDC infection by SIVagm suggests that if CCR5 paucity on immune cells is important for nonpathogenesis of natural hosts, it is possibly not due to its role as a coreceptor. The ability of certain key immune cell subsets to resist infection might contribute to the asymptomatic nature of simian immunodeficiency virus (SIV) infection in its natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM). This relative resistance to infection has been correlated with reduced expression of CD4 and/or CCR5. We show that plasmacytoid dendritic cells (pDC) of natural hosts display reduced CD4 and/or CCR5 expression, unlike macaque pDC. Surprisingly, this did not protect AGM pDC, as infection levels were similar to those found in MAC pDC. Furthermore, we show that AGM pDC did not consistently produce type I interferon (IFN-I) upon heterologous SIVmac/HIV type 1 (HIV-1) encounter, while they sensed autologous SIVagm isolates. Pseudotyping SIVmac/HIV-1 overcame this deficiency, suggesting that reduced uptake of heterologous viral strains underlays this lack of sensing. The distinct IFN-I responses depending on host species and HIV/SIV isolates reveal the host/virus species specificity of pDC sensing

Detailed investigations of proximal tubular function in Imerslund-Grasbeck syndrome

BACKGROUND: Imerslund-Gräsbeck Syndrome (IGS) is a rare genetic disorder characterised by juvenile megaloblastic anaemia. IGS is caused by mutations in either of the genes encoding the intestinal intrinsic factor-vitamin B(12) receptor complex, cubam. The cubam receptor proteins cubilin and amnionless are both expressed in the small intestine as well as the proximal tubules of the kidney and exhibit an interdependent relationship for post-translational processing and trafficking. In the proximal tubules cubilin is involved in the reabsorption of several filtered plasma proteins including vitamin carriers and lipoproteins. Consistent with this, low-molecular-weight proteinuria has been observed in most patients with IGS. The aim of this study was to characterise novel disease-causing mutations and correlate novel and previously reported mutations with the presence of low-molecular-weight proteinuria. METHODS: Genetic screening was performed by direct sequencing of the CUBN and AMN genes and novel identified mutations were characterised by in silico and/or in vitro investigations. Urinary protein excretion was analysed by immunoblotting and high-resolution gel electrophoresis of collected urines from patients and healthy controls to determine renal phenotype. RESULTS: Genetic characterisation of nine IGS patients identified two novel AMN frameshift mutations alongside a frequently reported AMN splice site mutation and two CUBN missense mutations; one novel and one previously reported in Finnish patients. The novel AMN mutations were predicted to result in functionally null AMN alleles with no cell-surface expression of cubilin. Also, the novel CUBN missense mutation was predicted to affect structural integrity of the IF-B(12) binding site of cubilin and hereby most likely cubilin cell-surface expression. Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin D-binding protein, and albumin. This was, however, only observed in patients where plasma membrane expression of cubilin was predicted to be perturbed. CONCLUSIONS: In the present study, mutational characterisation of nine IGS patients coupled with analyses of urinary protein excretion provide additional evidence for a correlation between mutation type and presence of the characteristic low-molecular-weight proteinuria

Delay in Diagnosis of Influenza Virus in an Elderly Hospitalized Patient: a Fatal Outcome

Influenza is a well established cause of seasonal hospitalizations and deaths among older persons. However, influenza is frequently underdiagnosed by physicians, because its clinical presentations are often complex, particularly in elderly patients. We report the case of a 78-year-old woman admitted to the emergency department in January 2008 with fever, vomiting, and a history of asthenia and falls in the preceding three days. Diagnosis of influenza at admission was missed. Influenza was diagnosed by direct fluorescent antibody in a sputum specimen four days later, but the evolution was rapidly unfavorable with fatal respiratory distress syndrome. This case illustrates that, during the influenza season, influenza should be suspected in elderly patients admitted to hospital even if they do not present with classical symptoms. Immunofluorescence testing on sputum specimens can provide a rapid diagnosis and merits further evaluation

Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. Our aim was to assess whether RIPostC is protective following cerebral hypoxia-ischemia in a piglet model of neonatal encephalopathy (NE) using magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry. After hypoxia-ischemia (HI), 16 Large White female newborn piglets were randomized to: (i) no intervention (n = 8); (ii) RIPostC - with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI (n = 8). RIPostC reduced the hypoxic-ischemic-induced increase in white matter proton MRS lactate/N acetyl aspartate (p = 0.005) and increased whole brain phosphorus-31 MRS ATP (p = 0.039) over the 48 h after HI. Cell death was reduced with RIPostC in the periventricular white matter (p = 0.03), internal capsule (p = 0.002) and corpus callosum (p = 0.021); there was reduced microglial activation in corpus callosum (p = 0.001) and more surviving oligodendrocytes in corpus callosum (p = 0.029) and periventricular white matter (p = 0.001). Changes in gene expression were detected in the white matter at 48 h, including KATP channel and endothelin A receptor. Immediate RIPostC is a potentially safe and promising brain protective therapy for babies with NE with protection in white but not grey matter

Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey

Purpose: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. Methods: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. Results: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. Conclusions: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia

Liver and brain differential expression of one-carbon metabolism genes during ontogenesis

One-carbon metabolism (1C metabolism) is of paramount importance for cell metabolism and mammalian development. It is involved in the synthesis or modification of a wide variety of compounds such as proteins, lipids, purines, nucleic acids and neurotransmitters. We describe here the evolution of expression of genes related to 1C metabolism during liver and brain ontogeny in mouse. The level of expression of 30 genes involved in 1C metabolism was quantified by RT-qPCR in liver and brain tissues of OF1 mice at E9, E11, E13, E15, E17, P0, P3, P5, P10, P15 developmental stages and in adults. In the liver, hierarchical clustering of the gene expression patterns revealed five distinct clades of genes with a first bifurcating hierarchy distinguishing two main developmental stages before and after E15. In the brain most of the 1C metabolism genes are expressed but at a lower levels. The gene expression of enzymes involved in 1C metabolism show dramatic changes during development that are tissue specific. mRNA expression patterns of all major genes involved in 1C metabolism in liver and brain provide clues about the methylation demand and methylation pathways during embryonic development

Square cells in gravitational and capillary thermoconvection

The onset of square convective cells in fluid layers heated from below is investigated. Amplitude equations an deduced from the Boussinesq equations and a standard stability analysis is performed. Square cells are shown to be preferred when the instability is mainly capillarity driven. The influence of the Prandtl and Blot numbers are examined. At small Pr, the Plot number has not very much influence and squares are always observed for thin enough layers. in large Prandtl number fluids, Pi must be larger than the limiting value 0.28 for squares to be stable