Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke

Abstract Introduction: Although pathogenesis of small vessel disease is poorly understood, increasing evidence suggests that endothelial dysfunction may have a relevant role in development and progression of small vessel disease. In this crosssectional study, we investigated the associations between imaging signs of small vessel disease and blood biomarkers of endothelial dysfunction at two different time points in a population of ischaemic stroke patients. Patients and methods: In stroke patients treated with intravenous thrombolysis, we analysed blood levels of von Willebrand factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and vascular endothelial growth factor. Three reviewers independently assessed small vessel disease features using computed tomography. At baseline and 90 days after the index stroke, we tested the associations between single and combined small vessel disease features and levels of blood biomarkers using linear regression analysis adjusting for age, sex, hypertension, diabetes, smoke. Results: A total of 263 patients were available for the analysis. Mean age (SD) was 69 (13) years, 154 (59%) patients were male.We did not find any relation between small vessel disease and endothelial dysfunction at baseline. At 90 days, leukoaraiosis was independently associated with intercellular adhesionmolecule-1 (b¼0.21; p¼0.016) and vascular cell adhesionmolecule- 1 (b¼0.22; p¼0.009), and lacunes were associated with vascular endothelial growth factor levels (b¼0.21; p¼0.009) whereas global small vessel disease burden was associated with vascular endothelial growth factor (b¼0.26; p¼0.006). Discussion: Leukoaraiosis and lacunes were associated with endothelial dysfunction, which could play a key role in pathogenesis of small vessel disease

The Life Span Determinant p66Shc Localizes to Mitochondria Where It Associates with Mitochondrial Heat Shock Protein 70 and Regulates Trans-membrane Potential

P66Shc regulates life span in mammals and is a critical component of the apoptotic response to oxidative stress. It functions as a downstream target of the tumor suppressor p53 and is indispensable for the ability of oxidative stress-activated p53 to induce apoptosis. The molecular mechanisms underlying the apoptogenic effect of p66Shc are unknown. Here we report the following three findings. (i) The apoptosome can be properly activated in vitro in the absence of p66Shc only if purified cytochrome c is supplied. (ii) Cytochrome c release after oxidative signals is impaired in the absence of p66Shc. (iii) p66Shc induces the collapse of the mitochondrial trans-membrane potential after oxidative stress. Furthermore, we showed that a fraction of cytosolic p66Shc localizes within mitochondria where it forms a complex with mitochondrial Hsp70. Treatment of cells with ultraviolet radiation induced the dissociation of this complex and the release of monomeric p66Shc. We propose that p66Shc regulates the mitochondrial pathway of apoptosis by inducing mitochondrial damage after dissociation from an inhibitory protein complex. Genetic and biochemical evidence suggests that mitochondria regulate life span through their effects on the energetic metabolism (mitochondrial theory of aging). Our data suggest that mitochondrial regulation of apoptosis might also contribute to life span determination

Unbalanced metalloproteinase-9 and tissue inhibitors of metalloproteinases ratios predict hemorrhagic transformation of lesion in ischemic stroke patients treated with thrombolysis: Results from the MAGIC study

Background Experimentally, metalloproteinases (MMPs) play a detrimental role related to severity of ischemic brain lesions. Both MMPs activity and function in tissues reflect the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We aimed to evaluate the role of MMPs/TIMPs balance in the setting of rtPA treated stroke patients Methods Blood was taken before and 24-hours after rtPA from 327 patients (mean age 68 years, median NIHSS 11) with acute ischemic stroke. Delta median values of each MMP/TIMP ratio [(post rtPA MMP/TIMP-baseline MMP/TIMP)/(baseline MMP/TIMP)] were analyzed related to symptomatic intracranial hemorrhage (sICH) according to NINDS criteria, relevant hemorrhagic transformation (HT) defined as hemorrhagic infarction type 2 or any parenchimal hemorrhage, stroke subtypes (according to Oxfordshire Community Stroke Project) and 3-month death. The net effect of each MMP/TIMP ratio was estimated by a logistic regression model including major clinical determinants of outcomes Results Adjusting for major clinical determinants, only increase in MMP9/TIMP1 and MMP9/TIMP2 ratios remained significantly associated with sICH (odds ratio [95% confidence interval], 1.67 [1.17 – 2.38], p = 0.005; 1.74 [1.21 – 2.49], p=0.003 respectively). Only relative increase in MMP9/TIMP1 ratio proved significantly associated with relevant HT (odds ratio [95% confidence interval], 1.74 [1.17 – 2.57], p=0.006) with a trend towards significance for MMP9/TIMP2 ratio (p=0.007).Discussion Our data add substantial clinical evidence about the role of MMPs/TIMPs balance in rtPA treated stroke patients. These results may serve to generate hypotheses on MMPs inhibitors to be administered together with rtPA in order to counteract its deleterious effect

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile

Sex-related differences in risk factors, type of treatment received and outcomes in patients with atrial fibrillation and acute stroke: Results from the RAF-study (Early Recurrence and Cerebral Bleeding in Patients with Acute Ischemic Stroke and Atrial Fibrillation)

Introduction: Atrial fibrillation is an independent risk factor of thromboembolism. Women with atrial fibrillation are at a higher overall risk for stroke compared to men with atrial fibrillation. The aim of this study was to evaluate for sex differences in patients with acute stroke and atrial fibrillation, regarding risk factors, treatments received and outcomes. Methods Data were analyzed from the “Recurrence and Cerebral Bleeding in Patients with Acute Ischemic Stroke and Atrial Fibrillation” (RAF-study), a prospective, multicenter, international study including only patients with acute stroke and atrial fibrillation. Patients were followed up for 90 days. Disability was measured by the modified Rankin Scale (0–2 favorable outcome, 3–6 unfavorable outcome). Results: Of the 1029 patients enrolled, 561 were women (54.5%) (p < 0.001) and younger (p < 0.001) compared to men. In patients with known atrial fibrillation, women were less likely to receive oral anticoagulants before index stroke (p = 0.026) and were less likely to receive anticoagulants after stroke (71.3% versus 78.4%, p = 0.01). There was no observed sex difference regarding the time of starting anticoagulant therapy between the two groups (6.4 ± 11.7 days for men versus 6.5 ± 12.4 days for women, p = 0.902). Men presented with more severe strokes at onset (mean NIHSS 9.2 ± 6.9 versus 8.1 ± 7.5, p < 0.001). Within 90 days, 46 (8.2%) recurrent ischemic events (stroke/TIA/systemic embolism) and 19 (3.4%) symptomatic cerebral bleedings were found in women compared to 30 (6.4%) and 18 (3.8%) in men (p = 0.28 and p = 0.74). At 90 days, 57.7% of women were disabled or deceased, compared to 41.1% of the men (p < 0.001). Multivariate analysis did not confirm this significance. Conclusions: Women with atrial fibrillation were less likely to receive oral anticoagulants prior to and after stroke compared to men with atrial fibrillation, and when stroke occurred, regardless of the fact that in our study women were younger and with less severe stroke, outcomes did not differ between the sexes

Prediction of early recurrent thromboembolic event and major bleeding in patients with acute stroke and atrial fibrillation by a risk stratification schema: the ALESSA score study

Background and Purposes—This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation. Methods—The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00–1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08–2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (≤1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P=0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30–1.00). We assigned to age ≥80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632–0.763; P=0.0001) for ischemic outcome events and 0.585 (0.493–0.678; P=0.10) for major bleedings. Results—The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529–0.763; P=0.009) for ischemic outcome events and 0.407 (0.275–0.540; P=0.14) for hemorrhagic outcome events. Conclusions—In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings

Bollettino Sismico Italiano: Analisys of Early Aftershocks of the 2016 MW 6.0 Amatrice, MW 5.9 Visso and MW 6.5 Norcia earthquakes in Central Italy

The Amatrice-Visso-Norcia seismic sequence is the most important of the last 30 years in Italy. The seismic sequence started on 24 August, 2016 and still is ongoing in central Apennines. At the end of February 2017 more than 57,000 events were located, 80,000 events up to the end of September 2017 (Fig. 1). The mainshocks of the sequence occurred on 24 August 2016 (Mw 6.0 and Mw 5.4), 26 October 2016 (Mw 5.4 and Mw 5.9), 30 October 2016 (Mw 6.5), 18 January 2017 (four earthquakes Mw≥ 5.0). In this seismic sequence, all the waveforms recorded by temporary stations deployed by the SISMIKO emergency group (stations T12**; Moretti et al., 2016) where available in real- time at the surveillance room of INGV. Because of the high level of seismicity and the dense seismic network installed in the region, more than 150 events per day were located at the end of February 2017; still 60 events per day were located up to the end of August 2017.The Amatrice-Visso-Norcia is the most important seismic sequence since 2015, the time when the analysis procedures of the BSI group (Bollettino Sismico Italiano) were revised (Nardi et al., 2015). BSI is now available every four months on the web: bulletins contain revised earthquakes (location and magnitude) with ML≥ 1.5, quasi-real time revision of ML≥ 3.5 earthquakes and phase arrivals from waveforms recorded on seismic stations available from the European Integrated Data Archive (EIDA), (Mazza et al., 2012). These last procedures allow the integration of signals from temporary seismic stations (Moretti et al., 2014) installed by the emergency group SISMIKO (Moretti and Sismiko working group, 2016), even when they are not in real time transmission, if they are rapidly archived in EIDA, together with real time signals from the seismic stations of the permanent INGV network. The analysis strategy of the BSI group for the Amatrice -Visso - Norcia seismic sequence (AVN.s.s in the following) was to select the earthquakes located in the box with min/max latitude: 42.2/43.2 - and min/max longitude: 12.4/14.1 to prepare a special volume of BSI on the seismic sequence.PublishedTrieste, Italy1SR. TERREMOTI - Servizi e ricerca per la Societ

Rapporto Sulle Attività Svolte Dal Gruppo Bollettino Sismico Italiano A Seguito Della Sequenza Sismica Del Centro Italia 2016-2017 Nel Periodo Tra Il 23-9-2016 Ed Il 16-01-2017

La sequenza sismica del centro Italia, successivamente al terremoto di Amatrice di fine agosto, è stata caratterizzata da altri forti terremoti alla fine del mese di ottobre 2016. Il 26 ottobre due eventi di Mw 5.4 e 5.9 hanno interessato l’area posta al confine Marche-Umbria tra i Comuni di Castelsantangelo sul Nera (MC), Norcia (PG) e Arquata del Tronto (AP). La mattina del 30 ottobre un terremoto di Mw 6.5 con epicentro non lontano da Norcia ha interessato l’intera area già profondamente colpita dalla sequenza; questo è stato il più forte terremoto registrato negli ultimi 30 in Italia. A 5 mesi dall’inizio dell’emergenza sismica, il Bollettino Sismico Italiano ha portato a termine la revisione di tutti gli eventi con ML≥ 3.5: parte di questi (insieme alla revisione delle ore che hanno seguito il primo mainshock) sono stati oggetto del primo report (3 ottobre 2016) e del lavoro Marchetti et al. (2016), un’altra parte degli eventi “forti” è stata pubblicata il 17 novembre in ISIDe e nella pagina CNT.ingv.it (insieme anche alla revisione delle prime ore del 30 ottobre, fino alle 7:30 UTC) con relativo comunicato fatto dal funzionario INGV. I restanti eventi già rivisti dagli analisti del BSI sono elencati in questo report e saranno pubbicati a fine gennaio. Gli eventi rivisti integrano all’interno del BSI tutte le stazioni i cui dati sono archiviati nello European Integrated Data Archive, cioè oltre alle stazioni delle varie reti permanenti che costituiscono la Rete Sismica Nazionale Italiana vengono integrate le stazioni delle reti permanenti presenti nelle Marche e le stazioni temporanee installate dal gruppo di emergenza SISMIKO, le cui registrazioni vengono archiviate in EIDA, in tempi brevi, insieme alle stazioni trasmesse in real-time. Durante la sequenza molti degli analisti del BSI sono stati impegnati a coprire la turnazione prevista per lo svolgimento del servizio di sorveglianza nella sala sismica dell’Istituto Nazionale di Geofisica e Vulcanologia (INGV) di Roma e in DICOMAC; questa esigenza non ha consentito di procedere rapidamente nella revisione dell’intera sequenza ma grazie al supporto di personale INGV generalmente non impiegato nel BSI si sta organizzando la revisione della stessa che sarà realizzata nel corso del 2017. A partire dal 23 settembre 2016 (facendo quindi riferimento all’ultimo report del BSI) fini al 16 gennaio 2017 sono stati analizzati e ricontrollati 221 eventi in generale di magnitudo ML≥ 3.5 (con qualche eccezione...INGV DPCPublished1SR. TERREMOTI - Servizi e ricerca per la Societ

Rapporto Sulle Attività Svolte Dal Gruppo Bollettino Sismico Italiano A Seguito Della Sequenza Sismica Del Centro Italia 20162017 Relativo Agli Eventi Nel Periodo Tra Il 17/01/2017 E Il 26/02/2017

La sequenza sismica del centro Italia ha avuto una importante ripresa il 18 gennaio 2017 quando quattro eventi di Mw≥5.0 hanno interessato l’area posta al confine tra Lazio e Abruzzo vicino ai Comuni di Barete, Capitignano e Montereale (AQ). A 8 mesi dall’inizio dell’emergenza sismica, il Bollettino Sismico Italiano ha portato a termine la revisione di tutti gli eventi con ML≥ 3.5: parte di questi (insieme alla revisione delle ore che hanno seguito il primo mainshock) sono stati oggetto del primo report (3 ottobre 2016) e del lavoro Marchetti et al. (2016), un’altra parte degli eventi “forti” già rivisti dagli analisti del BSI sono stati oggetto del report del 31 gennaio. Gli eventi rivisti ad oggi integrano all’interno del BSI tutte le stazioni i cui dati sono archiviati nello European Integrated Data Archive (EIDA), cioè oltre alle stazioni delle varie reti permanenti che costituiscono la Rete Sismica Nazionale Italiana vengono integrate le stazioni delle reti permanenti presenti nelle Marche e le stazioni temporanee installate dal gruppo di emergenza SISMIKO, le cui registrazioni vengono archiviate in EIDA, in tempi brevi, insieme alle stazioni trasmesse in real-time. A partire dal 31 gennaio 2017 (facendo quindi riferimento all’ultimo report del BSI) sono stati revisionati tutti gli eventi forti avvenuti dal 17 gennaio al 26 febbraio 2017; sono stati analizzati e rilocalizzati 37 eventi in generale di magnitudo ML≥ 3.5. Inoltre, sono state modificate alcune delle procedure che selezionano la magnitudo mostrata nella lista dei terremoti pubblicata nel sito web del CNT (cnt.rm.ingv.it) e utilizzata nei conteggi relativi alle diverse classi di magnitudo nelle relazioni di sequenza che vengono inviate giornalmente. Questa revisione, che fa si che la magnitudo mostrata sia sempre quella rivista dal BSI, comporta una lieve variazione nel numero di eventi attribuiti alle diverse classi.INGV- DPCPublished1SR. TERREMOTI - Servizi e ricerca per la Societ