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)

Astrocyte adaptation in Alzheimer's disease:a focus on astrocytic P2X₇R

Astrocytes are key homeostatic and defensive cells of the central nervous system (CNS). They undertake numerous functions during development and in adulthood to support and protect the brain through finely regulated communication with other cellular elements of the nervous tissue. In Alzheimer's disease (AD), astrocytes undergo heterogeneous morphological, molecular and functional alterations represented by reactive remodelling, asthenia and loss of function. Reactive astrocytes closely associate with amyloid β (Aβ) plaques and neurofibrillary tangles in advanced AD. The specific contribution of astrocytes to AD could potentially evolve along the disease process and includes alterations in their signalling, interactions with pathological protein aggregates, metabolic and synaptic impairments. In this review, we focus on the purinergic receptor, P2X7R, and discuss the evidence that P2X7R activation contributes to altered astrocyte functions in AD. Expression of P2X7R is increased in AD brain relative to non-demented controls, and animal studies have shown that P2X7R antagonism improves cognitive and synaptic impairments in models of amyloidosis and tauopathy. While P2X7R activation can induce inflammatory signalling pathways, particularly in microglia, we focus here specifically on the contributions of astrocytic P2X7R to synaptic changes and protein aggregate clearance in AD, highlighting cell-specific roles of this purinoceptor activation that could be targeted to slow disease progression.</p

Reactive astrocytes secrete the chaperone HSPB1 to mediate neuroprotection

Molecular chaperones are protective in neurodegenerative diseases by preventing protein misfolding and aggregation, such as extracellular amyloid plaques and intracellular tau neurofibrillary tangles in Alzheimer's disease (AD). In addition, AD is characterized by an increase in astrocyte reactivity. The chaperone HSPB1 has been proposed as a marker for reactive astrocytes; however, its astrocytic functions in neurodegeneration remain to be elucidated. Here, we identify that HSPB1 is secreted from astrocytes to exert non-cell-autonomous protective functions. We show that in human AD brain, HSPB1 levels increase in astrocytes that cluster around amyloid plaques, as well as in the adjacent extracellular space. Moreover, in conditions that mimic an inflammatory reactive response, astrocytes increase HSPB1 secretion. Concomitantly, astrocytes and neurons can uptake astrocyte-secreted HSPB1, which is accompanied by an attenuation of the inflammatory response in reactive astrocytes and reduced pathological tau inclusions. Our findings highlight a protective mechanism in disease conditions that encompasses the secretion of a chaperone typically regarded as intracellular.</p

LHCb

The LHCb detector is designed to study CP violation and other rare phenomena in decays of hadrons with heavy flavours, in particular $\rm B_s$ mesons. Interest in CP violation comes not only from elementary particle physics but also from cosmology, in order to explain the dominance of matter over antimatter observed in our universe, which could be regarded as the largest CP violation effect ever seen. The LHCb experiment will improve significantly results from earlier experiments both quantitatively and qualitatively, by exploiting the large number of different kinds of b hadrons produced at LHC. This is done by constructing a detector which has \begin{enumerate} \item Good trigger efficiencies for b-hadron final states with only hadrons, as well as those containing leptons. \item Capability of identifying kaons and pions in a momentum range of $\sim 1$ to above 100 GeV/$c$. \item Excellent decay time and mass resolution. \end{enumerate} The LHCb spectrometer shown in the figure consists of the following detector components: \begin{itemize} \item Beam Pipe\\ A 1.8 m-long section of the beam pipe around the interaction point has a large diameter of approximately 120 cm. This accommodates the vertex detector system with its retraction mechanics, and has a thin forward window made of aluminium over the full detector acceptance. This part is followed by two conical sections; the first is 1.5 m long with 25 mrad opening angle, and the second is 16 m long with 10 mrad opening angle. The entire first and most of the second section are made of beryllium in order to reduce the production of the secondary particles. \item Magnet\\ A dipole magnet with the normal conductive Al coil provides a high field integral of 4 Tm. The polarity of the field can be changed to reduce systematic errors in the CP-violation measurements that could result from a left-right asymmetry of the detector. \item Vertex Locator\\ A total of 21 stations made from two layers of silicon detector are used as a vertex detector system (VELO). Additional two stations with only one Si layer are dedicated to the detecting bunch crossings with more than one pp interaction as a part of Level-0 trigger. The closest distance between the active silicon area and the beam is 8 mm. The silicon detectors are placed in Roman pots with 300 $\mu$m thick aluminium windows, which act as a shield against RF pickup from the circulating beam bunches. In order to avoid collapse of the windows, a secondary vacuum is maintained inside the Roman pots. During the injection and acceleration, the Roman pot system will be moved away from the beam to avoid interference with the machine operation and accidental irradiation of the detectors. \item Tracking\\ The LHCb tracking system consists of four stations; one upstream of the magnet (TT) and three just behind the magnet (T1 to T3). No tracking device is positioned in the magnet and most of the tracks are reconstructed by combining the VELO and tracking system. The first station is made of silicon detectors. The stations behind the magnet are split into Inner Tracker (IT) and Outer Tracker (OT) systems due to the high particle density close to the beam pipe. The IT system is made of Si, and drift chambers based on straw technology are used for the OT system. \item Ring Imaging Cherenkov Detectors\\ The RICH system of the LHCb detector consists of two detectors with three different radiators in order to cover the required momentum range, 1-100 GeV/$c$ . The first detector uses aerogel and $\rm C_4 F_ {10}$ gas as radiators. The second detector, used for high momentum particles, is placed after the magnet and has $\rm C F_4$ gas as radiator. The Cherenkov light is detected with planes of Hybrid Photon Detectors (HPD's) placed outside the spectrometer acceptance. \item Calorimeters\\ The calorimeter system consists of a preshower detector followed by electromagnetic and hadronic calorimeters. It also serves as the initial part of the muon filter system. The cells of the Preshower detector are made up from 12 mm-thick lead plates sandwiched by square scintillators, 15 mm thick. For the electromagnetic part a Shashlik calorimeter is used since only modest energy resolution is required. The hadron calorimeter is based on a scintillating tile design similar to that developed for the ATLAS experiment. \item Muon System\\ The Muon system consists of tracking stations and absorber layers. The first tracking station is in front of the calorimeter system, which acts as the first absorber. Behind the calorimeter system, there are four tracking stations with Fe absorber walls in between. An additional Fe absorber is placed after the last tracking station against the muon background from the accelerator tunnel. Multi Wire Proportional Chambers are used everywhere except in the region close to the beam pipe of the first station where Triple-GEM chambers are used. \item Trigger\\ The LHCb trigger has two decision levels. Using custom made electronics, the first decision is made based on high transverse momentum hadrons or electrons found in the calorimeter system, or muons found in the muon system, at the bunch crossing rate of 40 MHz. All data from the detector are then read out at a rate of 1 MHz and sent to a CPU farm for further event reduction. For this purpose, all the detector information is available. With a rate of 2 kHz, events which include calibration data are stored for offline analysis. \end{itemize} Due to the large production cross section for b-$\rm \overline{ b}$ pairs (500~$\rm \mu b$) and efficient trigger, the LHCb experiment requires only a much lower luminosity ($2 \times 10^{32}$~$\rm cm^{-2} s^{-1}$) than the nominal LHC luminosity ($10^{34}$~$\rm cm^{-2}s^{-1}$) for its physics programme. The experiment therefore can reach its full physics potential from the beginning of LHC operation. The luminosity at the LHCb interaction point can be locally tuned so that the experiment is able to continue its physics programme when the machine reaches the nominal operating condition. \end{document

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine