Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.Published versionThe authors thank the UK MS Society for financial support (grant number: C008-16.1). DRO was funded by an MRC Clinician Scientist Award (MR/N008219/1). P.M.M. acknowledges generous support from Edmond J Safra Foundation and Lily Safra, the NIHR Senior Investigator programme and the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. P.M.M. and D.R.O. thank the Imperial College Healthcare Trust-NIHR Biomedical Research Centre for infrastructure support and the Medical Research Council for support of TSPO studies (MR/N016343/1). E.A. was supported by the ALS Stichting (grant “The Dutch ALS Tissue Bank”). P.M. and B.B.T. are funded by the Swiss National Science Foundation (projects 320030_184713 and 310030_212322, respectively). S.T. was supported by an “Early Postdoc.Mobility” scholarship (P2GEP3_191446) from the Swiss National Science Foundation, a “Clinical Medicine Plus” scholarship from the Prof Dr. Max Cloëtta Foundation (Zurich, Switzerland), from the Jean et Madeleine Vachoux Foundation (Geneva, Switzerland) and from the University Hospitals of Geneva. This work was funded by NIH grants U01AG061356 (De Jager/Bennett), RF1AG057473 (De Jager/Bennett), and U01AG046152 (De Jager/Bennett) as part of the AMP-AD consortium, as well as NIH grants R01AG066831 (Menon) and U01AG072572 (De Jager/St George-Hyslop)

New insights on the mechanisms of disease course variability in ALS from mutant SOD1 mouse models

Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous disease in terms of progression rate and survival. This is probably one of the reasons for the failure of many clinical trials and the lack of effective therapies. Similar variability is also seen in SOD1G93A mouse models based on their genetic background. For example, when the SOD1G93A transgene is expressed in C57BL6 background the phenotype is mild with slower disease progression than in the 129Sv mice expressing the same amount of transgene but showing faster progression and shorter lifespan. This review summarizes and discusses data obtained from the analysis of these two mouse models under different aspects such as the motor phenotype, neuropathological alterations in the central nervous system (CNS) and peripheral nervous system (PNS) and the motor neuron autonomous and non-cell autonomous mechanisms with the aim of finding elements to explain the different rates of disease progression. We also discuss the identification of promising prognostic biomarkers by comparative analysis of the two ALS mouse models. This analysis might possibly suggest new strategies for effective therapeutic intervention in ALS to slow significantly or even block the course of the disease

Serum levels of soluble CD30 improve International Prognostic Score in predicting the outcome of advanced Hodgkin's lymphoma

The International Prognostic Score (IPS) and circulating levels of the soluble form of CD30 molecule (sCD30) have both been associated with poor outcome in patients with advanced Hodgkin's lymphoma (HL). The aim of this study was to assess the prognostic power of the combined evaluation of sCD30 and IPS in these patients

A bedform phase diagram for dense granular currents

Pyroclastic density currents (PDCs) are a life-threatening volcanic hazard. Our understanding and hazard assessments of these flows rely on interpretations of their deposits. The occurrence of stratified layers, cross-stratification, and bedforms in these deposits has been assumed as indicative of dilute, turbulent, supercritical flows causing traction-dominated deposition. Here we show, through analogue experiments, that a variety of bedforms can be produced by denser, aerated, granular currents, including backset bedforms that are formed in waning flows by an upstream-propagating granular bore. We are able to, for the first time, define phase fields for the formation of bedforms in PDC deposits. We examine how our findings impact the understanding of bedform features in outcrop, using the example of the Pozzolane Rosse ignimbrite of the Colli Albani volcano, Italy, and thus highlight that interpretations of the formative mechanisms of these features observed in the field must be reconsidered

Very rapid cooling of the energetic pyroclastic density currents associated with the 5 November 2010 Merapi eruption (Indonesia)

International audienceUnderstanding the thermal behavior of pyroclastic density currents (PDCs) is crucial for forecasting impact scenarios for exposed populations as it affects their lethality and destructiveness. Here we report the emplacement temperatures of PDC deposits produced during the paroxysmal explosive eruption of Merapi (Central Java) on 5 November 2010 based on the reflectance of entombed charcoal fragments. This event was anomalously explosive for Merapi, and destroyed the summit dome that had been rapidly growing, with partial collapses and associated PDCs, since October 26. Results show mean reflectance values mainly between 0.17 and 0.41. These new data provide a minimum temperature of the flow of 240-320 °C, consistent with previous estimations determined from independent field, engineering, and medical observations published in the literature for this eruption. A few charcoal fragments recorded higher values, suggestive of temperatures up to 450 °C, and we suggest that this is due to the thermal disequilibrium of the deposits, with larger block-size clasts being much hotter than the surrounding ash matrix. Charring temperatures show no major differences between proximal and distal PDC deposits and are significantly lower than those that may be associated with a fast growing dome dominated by dense and vitric non-vesicular rocks. We therefore infer that the decrease in temperature from that at fragmentation (>900 °C) occurred in the very initial part of the current, <2 km from source. We discuss possible processes that allow the very fast cooling of these energetic PDCs, as well as the conservative thermal behavior shown during the depositional phase, across the entire depositional area

Resting VO2, maximal VO2 and metabolic equivalents in free-living healthy elderly women.

BACKGROUND &#38; AIMS: Maximal VO2 (VO2max) and metabolic equivalents (METs) decline with aging due to body composition and cardiovascular modifications. However, a detailed evaluation of these variables for this population has not been done. The aim of this study was to evaluate VO2max and METs in healthy elderly women, and to establish whether the calculated resting VO2 (3.5 ml/min/kg) underestimates the true METs. METHODS: 81 females over 65 years old attending a twice-weekly mild fitness program were studied. Body composition was measured by DEXA. VO2max and resting VO2 (VO(2rest-meas)) were measured by indirect calorimetry. METs were measured (METs-meas) using the VO2max/VO(2rest-meas) ratio, and calculated (METs-cal) from the ratio between measured VO2max and calculated resting VO2 (3.5 ml/min/kg of body weight). RESULTS: The VO(2rest-meas) and VO2max measured by indirect calorimetry were 2.9+/-0.4 ml/min/kg and 17.5+/-2.8 ml/min/kg, respectively. The METs-meas were higher than the METs-cal (6.1+/-1.2 vs 5.0+/-0.8; p<0.001). The 25th-75th percentile range of measured METs was 5.2-6.8. CONCLUSIONS: Our study confirmed that, in elderly women, METs values ranging between 5 and 7 are compatible with an acceptable physical activity. The estimated resting VO2 (3.5 ml/min/kg) does not appear to be applicable to elderly women, because it underestimates the real METs in this population