FSAP Protects against Histone-Mediated Increase in Endothelial Permeability In Vitro

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Combined prompt gamma activation and neutron diffraction analyses of historic metal objects and limestone samples

Two non-destructive neutron techniques have been used for the analysis of archaeological objects, among them English monumental brass plates, Dutch tin-lead spoons, a Roman leaded bronze fibula and several limestone samples. Prompt Gamma Activation Analysis (PGAA) is a non-destructive method for determination of the major and trace element compositions of various archaeological materials. Time-Of-Flight Neutron Diffraction (TOF-ND), on the other hand, is a non-invasive diagnostic tool for obtaining structural information from ceramic and metal objects. The element information (PGAA) holds the key information for addressing questions of provenance and authentication, whereas the structure information (TOF-ND) addresses questions of ancient materials and making techniques. Here we present data from those two complementary neutron methods, applied to different types of materials and artefacts, in order to highlight commonalities and differences

Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke:an individual patient data meta-analysis of randomised controlled trials

SummaryBackgroundMany international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke.MethodsWe obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome “dead or dependent” in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta-analysis.FindingsPatients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0·63 (95% CI 0·59–0·67) and for haemorrhagic events was 0·60 (0·55–0·64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events.InterpretationThere was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised.FundingMRC

Health‑related quality of life after deep vein thrombosis

Background: Health-related quality of life (HRQoL) is known to be impaired in patients who develop post-thrombotic syndrome (PTS) following deep vein thrombosis (DVT). However, there is limited knowledge of the long-term HRQoL after DVT compared to controls without DVT. The objectives of this study were to evaluate long-term HRQoL following DVT and to compare that with age and sex matched control group and to population norms as well as to investigate possible predictors for reduced HRQoL. Methods: HRQoL was evaluated in 254 patients with confirmed DVT using the generic EQ-5D and the diseases specific VEINES-QOL/Sym questionnaire, whereas PTS was assessed by the Villalta scale. Patients were asked to give the EQ-5D questionnaire to two friends of same age- (±5 years) and sex (buddy controls). Results: Patients scored significantly lower on all dimensions of EQ-5D compared to controls. EQ-5D index value was lower in patients compared with buddy controls; mean 0.79 (SD 0.17; IQR 0.72–1.00) versus 0.9 (SD 0.12; IQR 0.80–1.00), p < 0.001. EQ-5D index value was also significantly lower than age- and sex-adjusted population norms (p 30/m2) were significantly associated with impaired HRQoL assessed by EQ-5D index value (odds ratio [OR] 11.0: 95 % confidence interval [CI] 4.6–29.7; and 2.3: 95 % CI 1.1–4.8, respectively) and VEINES-QOL (OR 28.2: 95 % CI 10.6–75.0; and OR 4.1: 95 % CI 1.7–9.7, respectively). Conclusion: Long-term HRQoL was significantly impaired in DVT patients compared with buddy controls and population norms. PTS and obesity were independently associated with impaired HRQoL

Health-related quality of life after pulmonary embolism: a cross-sectional study

Objectives The psychological effects of acute pulmonary embolism (PE) have scarcely been studied. The aims of this study were to evaluate health-related quality of life (HRQoL) in patients with a history of PE compared with that of the general population and buddy controls, and to explore factors that may predict impaired HRQoL. Design Cross-sectional. Setting Haematology and thrombosis unit in Fredrikstad, Norway. Participants 213 consecutive patients treated for PE were identified from hospital registries. Eligible patients were scheduled for a single study visit, including a functional capacity test (6 min walking test). HRQoL was assessed using the EuroQol 5D dimensions 3-level (EQ-5D-3L) questionnaire, of which the results were compared with Danish population norms and age-matched and sex-matched buddy controls. The buddy controls were recruited by asking every patient to hand over the EQ-5D questionnaire to 2 age-matched and sex-matched friends or relatives. Multivariable regression analyses were used to examine possible determinants of reduced HRQoL. Results Mean age was 61 years (SD 15), 117 (55%) were males, and median time since diagnosis was 3.8 years (range 0.3–9.5). Mean EuroQol visual analogue scale (EQ VAS) was 67 in PE as compared with 81 in the general population (p<0.005) and corresponding EQ-5D index values were 0.80 and 0.86 (p<0.005). Patients reported more problems in all 5 EQ-5D compared with both the buddy controls and the general population, p<0.05. Shorter 6 min walking distance (β=0.09, p<0.005) and patient-reported dyspnoea (β=11.27, p<0.005) were independent predictors of lower EQ VAS scores. Conclusions Our findings show that patients with a history of PE have impaired HRQoL when compared with the general population and buddy controls. Reduced functional capacity and persistent dyspnoea were the main predictors of this impairment

Thromboembolic events after high-intensity training duringcisplatin-based chemotherapy for testicular cancer: Casereports and review of the literature

The randomized “Testicular cancer and Aerobic and Strength Training trial” (TAST‐trial) aimed to evaluate the effect of high‐intensity interval training (HIIT) on cardiorespiratory fitness during cisplatin‐based chemotherapy (CBCT) for testicular cancer (TC). Here, we report on an unexpected high number of thromboembolic (TE) events among patients randomized to the intervention arm, and on a review of the literature on TE events in TC patients undergoing CBCT. Patients aged 18 to 60 years with a diagnosis of metastatic germ cell TC, planned for 3 to 4 CBCT cycles, were randomized to a 9 to 12 weeks exercise intervention, or to a single lifestyle counseling session. The exercise intervention included two weekly HIIT sessions, each with 2 to 4 intervals of 2 to 4 minutes at 85% to 95% of peak heart rate. The study was prematurely discontinued after inclusion of 19 of the planned 94 patients, with nine patients randomized to the intervention arm and 10 to the control arm. Three patients in the intervention arm developed TE complications; two with pulmonary embolism and one with myocardial infarction. All three patients had clinical stage IIA TC. No TE complications were observed among patients in the control arm. Our observations indicate that high‐intensity aerobic training during CBCT might increase the risk of TE events in TC patients, leading to premature closure of the TAST‐trial

SARS-CoV-2 vaccines are not associated with hypercoagulability in apparently healthy people

Background: SARS-CoV-2 adenoviral vector DNA vaccines have been linked to the rare but serious thrombotic postvaccine complication vaccine-induced immune thrombotic thrombocytopenia. This has raised concerns regarding the possibility of increased thrombotic risk after any SARS-CoV-2 vaccines. Objectives: To investigate whether SARS-CoV-2 vaccines cause coagulation activation leading to a hypercoagulable state. Methods: This observational study included 567 health care personnel; 521 were recruited after the first dose of adenoviral vector ChAdOx1-S (Vaxzevria, AstraZeneca) vaccine and 46 were recruited prospectively before vaccination with a messenger RNA (mRNA) vaccine, either Spikevax (Moderna, n = 38) or Comirnaty (Pfizer-BioNTech, n = 8). In the mRNA group, samples were acquired before and 1 to 2 weeks after vaccination. In addition to the prevaccination samples, 56 unvaccinated blood donors were recruited as controls (total n = 102). Thrombin generation, D-dimer levels, and free tissue factor pathway inhibitor (TFPI) levels were analyzed. Results: No participant experienced thrombosis, vaccine-induced immune thrombotic thrombocytopenia, or thrombocytopenia (platelet count 9 /L) 1 week to 1 month postvaccination. There was no increase in thrombin generation, D-dimer level, or TFPI level in the ChAdOx1-S vaccine group compared with controls or after the mRNA vaccines compared with baseline values. Eleven of 513 (2.1%) participants vaccinated with ChAdOx1-S had anti-PF4/polyanion antibodies without a concomitant increase in thrombin generation. Conclusion: In this study, SARS-CoV-2 vaccines were not associated with thrombosis, thrombocytopenia, increased thrombin generation, D-dimer levels, or TFPI levels compared with baseline or unvaccinated controls. These findings argue against the subclinical activation of coagulation post-COVID-19 vaccination

Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia:Recent Progress on the Mechanisms and Interventional Strategies

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.</p

Protein C Mutation (A267T) Results in ER Retention and Unfolded Protein Response Activation

BACKGROUND: Protein C (PC) deficiency is associated with a high risk of venous thrombosis. Recently, we identified the PC-A267T mutation in a patient with PC deficiency and revealed by in vitro studies decreased intracellular and secreted levels of the mutant. The aim of the present study was to characterize the underlying mechanism(s). METHODOLOGY/PRINCIPAL FINDINGS: CHO-K1 cells stably expressing the wild-type (PC-wt) or the PC mutant were generated. In order to examine whether the PC mutant was subjected to increased intracellular degradation, the cells were treated with several inhibitors of various degradation pathways and pulse-chase experiments were performed. Protein-chaperone complexes were analyzed by treating the cells with a cross-linker followed by Western blotting (WB). Expression levels of the immunoglobulin-binding protein (BiP) and the phosphorylated eukaryotic initiation factor 2α (P-eIF2α), both common ER stress markers, were determined by WB to examine if the mutation induced ER stress and unfolded protein response (UPR) activation. We found no major differences in the intracellular degradation between the PC variants. The PC mutant was retained in the endoplasmic reticulum (ER) and had increased association with the Grp-94 and calreticulin chaperones. Retention of the PC-A267T in ER resulted in UPR activation demonstrated by increased expression levels of the ER stress markers BiP and P-eIF2α and caused also increased apoptotic activity in CHO-K1 cells as evidenced by elevated levels of DNA fragmentation. CONCLUSIONS/SIGNIFICANCE: The reduced intracellular level and impaired secretion of the PC mutant were due to retention in ER. In contrast to other PC mutations, retention of the PC-A267T in ER resulted in minor increased proteasomal degradation, rather it induced ER stress, UPR activation and apoptosis