Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation.

A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA, mainly due to post-transcriptional mechanisms that account for over 40% of the age-regulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly/disassembly and are enriched in protein aggregates in old brains. Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo. Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is a major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Papadiamantis’ Athenian short stories: social representation and characterization

As a contribution to the re-evaluation of Papadiamantis’ literary oeuvre this thesis sets out to explore the social dimension of his work by focusing on his Athenian short stories. This literary corpus, a significant part of the literature describing the urban environment in the last decade of the nineteenth and the first decade of the twentieth century, offers an insight into Papadiamantis’ views on the social reality of the Greek capital and society at large. The first chapter outlines the socio-historical parameters that contributed to the increasing presence of Athens in Greek prose fiction of that period and explores the ways different urban narratives sought to record the changing physiognomy of the capital. The second and third chapters focus on the texts and provide a close reading of the Athenian stories. In particular, the second chapter concentrates on the social context and brings to the fore the complex range of social ills that the author wishes to stigmatize either explicitly or implicitly. The third chapter centres on the characters in the Athenian short stories and demonstrates how the urban social context moulds the individual’s character and victimizes the most vulnerable social members. The critical representation of the capital in the Athenian short stories points to Papadiamantis’ scepticism about the emerging norms of modern existence and reveals a socially conscious author

Θρομβοφιλία στην κύηση

H φυσιολογική κύηση χαρακτηρίζεται από μεταβολές που αφορούν σχεδόν κάθε όργανο, ώστε να καταφέρει ο οργανισμός της γυναίκας να προσαρμοστεί στις απαιτήσεις της εμβρυοπλακουντιακής κυκλοφορίας και της ομαλής ανάπτυξης του εμβρύου. Aποτελεί κατάσταση υπερπηκτικότητας καθώς χαρακτηρίζεται από αύξηση των παραγόντων πήξης, μείωση των φυσικών ανασταλτών καθώς και αναστολή ενεργοποίησης της ινωδόλυσης. Φαίνεται ότι οι αιμοστατικές αυτές μεταβολές της κύησης συνεισφέρουν στην φυσιολογική ανάπτυξη και λειτουργικότητα του πλακούντα και επομένως στην φυσιολογική ανάπτυξη του εμβρύου. Η υπερπηκτικότητα, όμως, αυξάνει τον κίνδυνο για θρόμβωση κατά 4-5 φορές κατά την κύηση και ακόμη περισσότερο κατά την λοχεία. Η φλεβική θρομβοεμβολή, που περιλαμβάνει την εν τω βάθει φλεβική θρόμβωση και την πνευμονική εμβολή, ευθύνεται για το 3% όλων των θανάτων γυναικών κατά την εγκυμοσύνη και την λοχεία, παγκοσμίως. Επιπλέον, η υπερπηκτικότητα της κύησης έχει συνδεθεί με δυσμενείς εκβάσεις όπως: αυτόματη αποβολή, ενδομήτριο θάνατο, προεκλαμψία, αποκόλληση πλακούντα και καθυστέρηση ενδομήτριας ανάπτυξης. Ο κίνδυνος είναι ιδιαίτερα αυξημένος σε σύγχρονη παρουσία θρομβοφιλίας και ιστορικό θρομβοεμβολικής νόσου. Ο όρος θρομβοφιλία προσδιορίζει συγκεκριμένες διαταραχές στον μηχανισμό της αιμόστασης που προδιαθέτουν σε θρόμβωση. Η θρομβοφιλία αποτελεί ένα πολύπλοκο, πολυγονιδιακό σύνδρομο, στο οποίο κληρονομικοί, επίκτητοι και φυσιολογικοί (ηλικία, κύηση) παράγοντες αυξημένου κινδύνου, αλληλεπιδρούν, διαδραματίζοντας σημαντικό ρόλο, σε μια θεωρία πολυπαραγοντικού μηχανισμού (multi-hit theory). Πολλαπλές μελέτες έχουν διενεργηθεί για να διερευνήσουν την συσχέτιση μεταξύ των διαφόρων παραγόντων κληρονομικής και επίκτητης θρομβοφιλίας με δυσμενείς εκβάσεις και επιπλοκές της κύησης. Σκοπός της παρούσας εργασίας είναι να περιγράψει την σχέση μεταξύ θρομβοφιλίας και φυσιολογικής υπερπηκτικότητας της κύησης με τις επιπλοκές αυτής, μέσω ανασκόπησης της υπάρχουσας βιβλιογραφίας.Normal pregnancy is characterized by profound maternal physiological changes relating to almost every organ, and are essential for optimal fetal growth and development. These maternal adaptive changes in pregancy include a shift in the balance between hemostatic and fibrinolytic mechanisms, towards a prothrombotic state. Hypercoagulability in pregnancy is characterized by an increase in procoagulation factors, a decrease in anticoagulant proteins and inhibition of fibrinolysis activation. It seems that these hemostatic contribute to the normal growth and function of the placenta and the fetal development. Hypercoagulability, however, increases the risk of thrombosis by 4-5 times during pregnancy and even more after the labor, during the puerperium. Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is responsible for 3% of all deaths of women during pregnancy and labor worldwide. In addition, hypercoagulability has been linked to adverse outcomes such as spontaneous abortion, fetal loss, placental abruption and intrauterine growth retardation. The risk becomes even higher in the presence of thrombophilia and previous history of VTE. The term thrombophilia includes specific disorders in which hereditary, acquired and situational (e.g. age, pregnancy etc.) risk factors interact, are interacting and resulting in various thrombotic events. Several studies have aimed to investigate the interactions between the various hereditary and acquired hypercoagulability syndromes and the adverse outcomes and complications of pregnancy. The aim of the current thesis is to describe the relation between thrombophilia, the normal hypercoagulability of pregnancy and the outcome of pregnancy by extensively reviewing the relevant studies in the literature

Redox regulation of proteasome function

Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) were initially regarded mainly as metabolic by-products with damaging properties. Over the last decade, our understanding of their role in metabolism was drastically changed and they were recognized as essential mediators in cellular signaling cascades, as well as modulators of biochemical pathways. Proteostasis is highly affected by the various levels of intracellular and extracellular free radicals with either mild or severe outcomes. As part of the proteostatic network, the proteasome system is equally affected by redox alterations. This short review summarizes the effects of oxidative stress on proteasome status while it also recapitulates conditions and processes where redox alterations signal changes to proteasome expression, assembly and function

Protein ingestion preserves proteasome activity during intense aseptic inflammation and facilitates skeletal muscle recovery in humans

The ubiquitin–proteasome system (UPS) is the main cellular proteolytic system responsible for the degradation of normal and abnormal (e.g. oxidised) proteins. Under catabolic conditions characterised by chronic inflammation, the UPS is activated resulting in proteolysis, muscle wasting and impaired muscle function. Milk proteins provide sulphur-containing amino acid and have been proposed to affect muscle inflammation. However, the response of the UPS to aseptic inflammation and protein supplementation is largely unknown. The aim of this study was to investigate how milk protein supplementation affects UPS activity and skeletal muscle function under conditions of aseptic injury induced by intense, eccentric exercise. In a double-blind, cross-over, repeated measures design, eleven men received either placebo (PLA) or milk protein concentrate (PRO, 4×20 g on exercise day and 20 g/d for the following 8 days), following an acute bout of eccentric exercise (twenty sets of fifteen eccentric contractions at 30°/s) on an isokinetic dynamometer. In each trial, muscle biopsies were obtained from the vastus lateralis muscle at baseline, as well as at 2 and 8 d post exercise, whereas blood samples were collected before exercise and at 6 h, 1 d, 2 d and 8 d post exercise. Muscle strength and soreness were assessed before exercise, 6 h post exercise and then daily for 8 consecutive days. PRO preserved chymotrypsin-like activity and attenuated the decrease of strength, facilitating its recovery. PRO also prevented the increase of NF-κB phosphorylation and HSP70 expression throughout recovery. We conclude that milk PRO supplementation following exercise-induced muscle trauma preserves proteasome activity and attenuates strength decline during the pro-inflammatory phase

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